# Traditional Chinese Medicine for Senile Dementia

Authors: Zhihong Lin; Jie Gu; Jin Xiu; Tingyan Mi; Jie Dong; Jyoti Kumar Tiwari
Journal: Evidence-Based Complementary and Alternative Medicine
 (2012)

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## Abstract

Traditional Chinese Medicine (TCM) has a 3000 years' history of human use. A literature survey addressing traditional evidence from human studies was done, with key result that top 10 TCM herb ingredients includingPoria cocos, Radix polygalae, Radix glycyrrhizae, Radix angelica sinensis, and Radix rehmanniae were prioritized for highest potential benefit to dementia intervention, related to the highest frequency of use in 236 formulae collected from 29 ancient Pharmacopoeias, ancient formula books, or historical archives on ancient renowned TCM doctors, over the past 10 centuries.
Based on the history of use, there was strong clinical support that Radix polygalae is memory improving. Pharmacological investigation also indicated that all the five ingredients mentioned above can elicit memory-improving effects in vivo and in vitro via multiple mechanisms of action, covering estrogen-like, cholinergic, antioxidant, anti-inflammatory, antiapoptotic, neurogenetic, and anti-Aβ activities. Furthermore, 11 active principles were identified, including sinapic acid, tenuifolin, isoliquiritigenin, liquiritigenin, glabridin, ferulic acid, Z-ligustilide, N-methyl-beta-carboline-3-carboxamide, coniferyl ferulate and 11-angeloylsenkyunolide F, and catalpol. It can be concluded that TCM has a potential for complementary and alternative role in treating senile dementia. The scientific evidence is being continuously mined to back up the traditional medical wisdom.


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## Body

## 1. Introduction

Cognitive impairment or dementia in elderly is associated with many disorders [1]. Alzheimer’s disease (AD) is the principal type of dementia and represents about 70% of the dementia patients.The pathologic hallmarks of AD are senile plaques, neurofibrillary tangles, dystrophic neurites, and neuronal loss. The development of AD may be due to the improper biochemical processing of amyloid precursor protein (APP) leading to subsequent accumulation ofβ-amyloid (Aβ). The amyloid and tangle cascade hypothesis is the dominant explanation for the pathogenesis of AD [2]. Other relevant factors, including cholinergic dysfunction [3], neuroinflammation [4, 5], oxidative stress [6], and disturbance of neuronal plasticity [7], age-related loss of sex hormones [8, 9], are important and contribute to the understanding of AD pathology.The 2nd most common form of dementia is vascular dementia (VD) or multi-infarct dementia, which accounts for about 15% of dementia cases [10, 11]. VD may follow after a succession of acute cerebrovascular events or, less commonly, a single major stroke. The compromised cerebrovascular circulation causes ischemia that leads to damage of the brain structure, for example, formation of white matter lesions or silent brain infarctions. VD is often related to the loss of fine motor control besides memory impairment.Currently, there is no effective treatment for AD, although many treatment strategies exist [12]. Clinically, cholinesterase inhibitors (ChEIs) and N-methyl-D-aspartate (NMDA) receptor antagonists are first-line pharmacotherapy for mild-to-moderate AD, with high nonresponse rate 50–75% [13].Lots of folk plants in traditional medicine are being used in age-related brain disorders for improvement of memory and cognitive function [14–16]. In China, a number of herb ingredients known from Traditional Chinese Medicine (TCM) have a long history of use for mental health. In this study, we exploited the empirically driven TCM lore and surveyed scientific data to back up the cognitive benefits, claimed by TCM.


## 2. Ancient Records on TCM for Cognitive Decline

The term “senile dementia” refers to a clinical syndrome seen in the elderly characterized by impairment of memory and cognition. So in a search of the ancient literature of TCM, the etiology, pathogenesis, and treatment for “dementia or amnesia” have been used for the survey in detail.


### 2.1. Etiology and Pathogenesis

#### 2.1.1. Deficiency of Energy

Deficiency of energy is similar to “Qi” deficiency in TCM. According TCM lore Qi is the essential substance that makes up the body and maintains various physiological activities, similar to flow of energy in the body. The energy is mainly from the kidney, heart, and spleen, especially from the kidney.  In TCM, the energy from the kidney is called kidney essence which can produce marrow including cerebral marrow, spinal cord, and bone marrow. The cerebral marrow can nourish the brain and maintain the physiological functions of the brain. If the kidney essence is insufficient, the production of cerebral marrow will be reduced, leading to various symptoms, such as headache, dizziness, amnesia, and retard response [17].


#### 2.1.2. Blood Stasis

Normally the blood is pumped by the heart to flow in the vessels. If blood circulation is stagnated or slowed down by certain factors such as cold, emotional disorder, aging, consumptive disease, and overstrain, it will result in retention of blood flow in the vessels or organs, a pathological condition named blood stasis. The cognitive function will decline, due to long-term global hypo-perfusion in cerebral blood flow or acute focal stroke in memory-related cerebral parenchyma [17].


#### 2.1.3. Toxin

As the function of internal organs in the elderly decline, the balance between host defense and external toxins in the body is disrupted. Pathological or physiological products occur and form toxin including waste of “water” and “endogenous fire”, which result from the poor digestion, accumulates into phlegm and retention of fluid, and caused by mental disorder, attack from pathological factors, and imbalance within the body, respectively. If such toxins can not be eliminated quickly the blood circulation and mental acuity will be affected, eventually contributing to the onset of dementia.


### 2.2. Therapy of TCM

TCM has a long history for preventing and treating cognitive decline. Although AD is a modern disease entity and has no direct analogue in the ancient Chinese medicine literature, disorders of memory and cognitive deficit are referred to throughout the classical literature. For example, inSheng Nong Ben Cao Jing (Han dynasty, 1-2 century), the earliest pharmacopeia existing on materia medica in China, some TCM ingredients such as Yuan Zhi (Thinleaf milkwort), Ren Shen (Ginseng), Huang Lian (Golden thread), and Long Yan (Longan) were recorded to ameliorate the decline of people’s memory.In this study, 27 ancient TCM books were selected, which could be divided into 3 types, namely, Pharmacopoeias, formulae monographs and renowned TCM doctor’s case studies.A database was established to determine the frequency of herbs in these documents. Totally 236 formulae for improving cognitive function were identified among 27 books mentioned above (Table1); 139 herbs were gathered from those 236 formulae and 10 TCM herbs were prioritized due to the highest frequency over 50 times (Table 2).Table 1
TCM formulae selected from ancient Chinese documents.
ClassificationBook nameDynastyFormulae amountPharmacopoeiaSheng Ji Zhong LuSong (10–13 century)45Tai Ping Hui Min He Ji Ju FangSong (10–13 century)2Tai Ping Sheng Hui FangSong (10–13 century)2Pu Ji FangMing (14–17 century)2Yi Fang Lei JuMing (14–17 century)2Yi Zong Jin JianQing (17–19 century)9Formulae monographsZhou Hou FangJin (3-4 century)1Qian Jin Yao FangTang (7–10 century)3Ren Zhai Zhi Zhi Fang LunSong (10–13 century)3Fu Ren Da Quan Liang FangSong (10–13 century)1Shi Zhai Bai Yi Xuan FangSong (10–13 century)5Shi Yi De Jiu FangYuan (13-14 century)4Qi Xiao Liang FangMing (14–17 century)29Gu Jin Yi JianMing (14–17 century)1She Sheng Zhong Miao FangMing (14–17 century)1Zheng Zhi Bao JianQing (17–19 century)1Ji Yan Liang FangQing (17–19 century)4Medical editionYan Yonghe’s medical editionSong (10–13 century)13Chen Wuze’s medical editionSong (10–13 century)9Dan Xi Xin FaYuan (13-14 century)4Shou Shi Bao YuanMing (14–17 century)21Jing Yue Quan ShuMing (14–17 century)21Zheng Ti Lei YaoMing (14–17 century)2Lei Zheng Zhi ChaiQing (17–19 century)16Bian Zheng LuQing (17–19 century)16Zha Bing Yuan Liu Xi ZhuQing (17–19 century)2Yi Xue Zhong Zhong Can Xi LuModern (20 century)7Sum236Table 2
Top 10 memory-improving TCM herbs.
Chi nameEnglish nameLatin namePartPlantFrequencyFu LingPoriaPoria cocosSclerotiumPoria cocos(Schw.) Wolf182Ren ShenGinsengRadix et rhizoma ginsengRoot, stemPanax ginseng C. A. Mey.169Yuan ZhiThinleaf milkwortRadix polygalaeRootPolygala tenuifoliawilld. Polygala sibiricaL.139Gan CaoLicoriceRadix et rhizoma glycyrrhizaeRoot, stemGlycyrrhiza inflata Bat.  Glycyrrhiza uralensisFisch. Glycyrrhiza grabra L.100Dang GuiChinese AngelicaRadix Angelica sinensisRootAngelica sinensis (Oliv.) Diels84Shi Chang PuGrassleaf sweelflag rhizomeRhizoma acori tatarinowiiStemAcorus tatarinowiiSchott.80Suan Zao RenSpina date seedSemen ziziphi spinosaeSeedZiziphus jujuba Mill.var.spinosa.(Bunge) Hu ex H.F. Chou79Shu Di HuangPrepared rehmannia rootRadix rehmanniaeRootRehmannia glutinosa Libosch.62Mai DongDwarf lilyturf tuberRadix ophiopogonisRootOphiopogon japonicus(L.f.) Ker-Gawl.62Sheng JiangFresh gingerRhizoma zingiberisStemZingiber officinale Rosc.53(Note: data are cited from Pharmacopoeia of PR China 2005).According to specification documented in Chinese Pharmacopeia [18], (i) Poria cocos is a diuretic with capacity to invigorate spleen function and calm the mind. Clinically, it is applicable for memory decline due to spleen deficiency and phlegm blockage; (ii) Radix polygalaeis able to anchor the mind and eliminate the phlegm, and indicated in forgetfulness and insomnia; (iii) Radix glycyrrhizae is a qi tonic to invigorate the stomach and spleen, resolve phlegm, and clear away heat and toxin; (iv) Radix Angelica sinensis, as a vital blood tonic and antithrombotic agent, is especially used to treat stroke and poststroke vascular dementia induced by blood stasis; (v) Radix rehmanniae is another tonic used to reinforce kidney essence and marrow. Because of functionality to invigorate the energy, activate blood circulation, or eliminate the toxin, these herbs can be prescribed along or combined to exhibit a good therapeutic effect for senile dementia, for example,  Zhi Ling Tang [19].


## 2.1. Etiology and Pathogenesis

### 2.1.1. Deficiency of Energy

Deficiency of energy is similar to “Qi” deficiency in TCM. According TCM lore Qi is the essential substance that makes up the body and maintains various physiological activities, similar to flow of energy in the body. The energy is mainly from the kidney, heart, and spleen, especially from the kidney.  In TCM, the energy from the kidney is called kidney essence which can produce marrow including cerebral marrow, spinal cord, and bone marrow. The cerebral marrow can nourish the brain and maintain the physiological functions of the brain. If the kidney essence is insufficient, the production of cerebral marrow will be reduced, leading to various symptoms, such as headache, dizziness, amnesia, and retard response [17].


### 2.1.2. Blood Stasis

Normally the blood is pumped by the heart to flow in the vessels. If blood circulation is stagnated or slowed down by certain factors such as cold, emotional disorder, aging, consumptive disease, and overstrain, it will result in retention of blood flow in the vessels or organs, a pathological condition named blood stasis. The cognitive function will decline, due to long-term global hypo-perfusion in cerebral blood flow or acute focal stroke in memory-related cerebral parenchyma [17].


### 2.1.3. Toxin

As the function of internal organs in the elderly decline, the balance between host defense and external toxins in the body is disrupted. Pathological or physiological products occur and form toxin including waste of “water” and “endogenous fire”, which result from the poor digestion, accumulates into phlegm and retention of fluid, and caused by mental disorder, attack from pathological factors, and imbalance within the body, respectively. If such toxins can not be eliminated quickly the blood circulation and mental acuity will be affected, eventually contributing to the onset of dementia.


## 2.1.1. Deficiency of Energy

Deficiency of energy is similar to “Qi” deficiency in TCM. According TCM lore Qi is the essential substance that makes up the body and maintains various physiological activities, similar to flow of energy in the body. The energy is mainly from the kidney, heart, and spleen, especially from the kidney.  In TCM, the energy from the kidney is called kidney essence which can produce marrow including cerebral marrow, spinal cord, and bone marrow. The cerebral marrow can nourish the brain and maintain the physiological functions of the brain. If the kidney essence is insufficient, the production of cerebral marrow will be reduced, leading to various symptoms, such as headache, dizziness, amnesia, and retard response [17].


## 2.1.2. Blood Stasis

Normally the blood is pumped by the heart to flow in the vessels. If blood circulation is stagnated or slowed down by certain factors such as cold, emotional disorder, aging, consumptive disease, and overstrain, it will result in retention of blood flow in the vessels or organs, a pathological condition named blood stasis. The cognitive function will decline, due to long-term global hypo-perfusion in cerebral blood flow or acute focal stroke in memory-related cerebral parenchyma [17].


## 2.1.3. Toxin

As the function of internal organs in the elderly decline, the balance between host defense and external toxins in the body is disrupted. Pathological or physiological products occur and form toxin including waste of “water” and “endogenous fire”, which result from the poor digestion, accumulates into phlegm and retention of fluid, and caused by mental disorder, attack from pathological factors, and imbalance within the body, respectively. If such toxins can not be eliminated quickly the blood circulation and mental acuity will be affected, eventually contributing to the onset of dementia.


## 2.2. Therapy of TCM

TCM has a long history for preventing and treating cognitive decline. Although AD is a modern disease entity and has no direct analogue in the ancient Chinese medicine literature, disorders of memory and cognitive deficit are referred to throughout the classical literature. For example, inSheng Nong Ben Cao Jing (Han dynasty, 1-2 century), the earliest pharmacopeia existing on materia medica in China, some TCM ingredients such as Yuan Zhi (Thinleaf milkwort), Ren Shen (Ginseng), Huang Lian (Golden thread), and Long Yan (Longan) were recorded to ameliorate the decline of people’s memory.In this study, 27 ancient TCM books were selected, which could be divided into 3 types, namely, Pharmacopoeias, formulae monographs and renowned TCM doctor’s case studies.A database was established to determine the frequency of herbs in these documents. Totally 236 formulae for improving cognitive function were identified among 27 books mentioned above (Table1); 139 herbs were gathered from those 236 formulae and 10 TCM herbs were prioritized due to the highest frequency over 50 times (Table 2).Table 1
TCM formulae selected from ancient Chinese documents.
ClassificationBook nameDynastyFormulae amountPharmacopoeiaSheng Ji Zhong LuSong (10–13 century)45Tai Ping Hui Min He Ji Ju FangSong (10–13 century)2Tai Ping Sheng Hui FangSong (10–13 century)2Pu Ji FangMing (14–17 century)2Yi Fang Lei JuMing (14–17 century)2Yi Zong Jin JianQing (17–19 century)9Formulae monographsZhou Hou FangJin (3-4 century)1Qian Jin Yao FangTang (7–10 century)3Ren Zhai Zhi Zhi Fang LunSong (10–13 century)3Fu Ren Da Quan Liang FangSong (10–13 century)1Shi Zhai Bai Yi Xuan FangSong (10–13 century)5Shi Yi De Jiu FangYuan (13-14 century)4Qi Xiao Liang FangMing (14–17 century)29Gu Jin Yi JianMing (14–17 century)1She Sheng Zhong Miao FangMing (14–17 century)1Zheng Zhi Bao JianQing (17–19 century)1Ji Yan Liang FangQing (17–19 century)4Medical editionYan Yonghe’s medical editionSong (10–13 century)13Chen Wuze’s medical editionSong (10–13 century)9Dan Xi Xin FaYuan (13-14 century)4Shou Shi Bao YuanMing (14–17 century)21Jing Yue Quan ShuMing (14–17 century)21Zheng Ti Lei YaoMing (14–17 century)2Lei Zheng Zhi ChaiQing (17–19 century)16Bian Zheng LuQing (17–19 century)16Zha Bing Yuan Liu Xi ZhuQing (17–19 century)2Yi Xue Zhong Zhong Can Xi LuModern (20 century)7Sum236Table 2
Top 10 memory-improving TCM herbs.
Chi nameEnglish nameLatin namePartPlantFrequencyFu LingPoriaPoria cocosSclerotiumPoria cocos(Schw.) Wolf182Ren ShenGinsengRadix et rhizoma ginsengRoot, stemPanax ginseng C. A. Mey.169Yuan ZhiThinleaf milkwortRadix polygalaeRootPolygala tenuifoliawilld. Polygala sibiricaL.139Gan CaoLicoriceRadix et rhizoma glycyrrhizaeRoot, stemGlycyrrhiza inflata Bat.  Glycyrrhiza uralensisFisch. Glycyrrhiza grabra L.100Dang GuiChinese AngelicaRadix Angelica sinensisRootAngelica sinensis (Oliv.) Diels84Shi Chang PuGrassleaf sweelflag rhizomeRhizoma acori tatarinowiiStemAcorus tatarinowiiSchott.80Suan Zao RenSpina date seedSemen ziziphi spinosaeSeedZiziphus jujuba Mill.var.spinosa.(Bunge) Hu ex H.F. Chou79Shu Di HuangPrepared rehmannia rootRadix rehmanniaeRootRehmannia glutinosa Libosch.62Mai DongDwarf lilyturf tuberRadix ophiopogonisRootOphiopogon japonicus(L.f.) Ker-Gawl.62Sheng JiangFresh gingerRhizoma zingiberisStemZingiber officinale Rosc.53(Note: data are cited from Pharmacopoeia of PR China 2005).According to specification documented in Chinese Pharmacopeia [18], (i) Poria cocos is a diuretic with capacity to invigorate spleen function and calm the mind. Clinically, it is applicable for memory decline due to spleen deficiency and phlegm blockage; (ii) Radix polygalaeis able to anchor the mind and eliminate the phlegm, and indicated in forgetfulness and insomnia; (iii) Radix glycyrrhizae is a qi tonic to invigorate the stomach and spleen, resolve phlegm, and clear away heat and toxin; (iv) Radix Angelica sinensis, as a vital blood tonic and antithrombotic agent, is especially used to treat stroke and poststroke vascular dementia induced by blood stasis; (v) Radix rehmanniae is another tonic used to reinforce kidney essence and marrow. Because of functionality to invigorate the energy, activate blood circulation, or eliminate the toxin, these herbs can be prescribed along or combined to exhibit a good therapeutic effect for senile dementia, for example,  Zhi Ling Tang [19].


## 3. Evidence-Based Efficacy of TCM Herbs on Cognitive Decline

### 3.1. Poria cocos

Poria cocos (Chinese name: Fu Ling) is the dried sclerotium of the fungus, Poria cocos (Schw.) Wolf (Fam. Polyporaceae).


#### 3.1.1. Functionality/Efficacy

There is suggestive evidence thatP. cocos is memory improving regardless of absence of available clinical reports. Pharmacological research exhibited that the water extract of P. cocos enhanced hippocampal long-term potentiation (LTP) and improved scopolamine-induced spatial memory impairment in rats ([20, 21], Table 3).Table 3
Memory-improving and neuro-protective effects ofPoria cocos.
TestTest materials/doseTest modelEndpoints/biomarkersEffectsReferenceIn vivoExtracts  20–100 mg/kgScopolamine-treated ratsEight-arm radial mazeImprove spatial memory[20]Extracts 250–500 mg/kgInnate ratsElectro-physiology Spike amplitudeEnhance hippocampal  LTP[21]Methanol  extracts 200 mg/mLEllman ChEChE activityInhibit ChE by 27.8%[22]Aqueous extracts 0.2 mg/mLInnate ICR miceAChE activityInhibit AChE by 13.9%[23]In vitroAqueous extracts 31–250μg/mLBrain neurons–neonatal ratsCytosolic [Ca2+] iRegulate bi-directly [Ca2+] i[24]Long-term potentiation (LTP); choline esterase (ChE);acetylcholinesterase (AChE).


#### 3.1.2. Mechanism of Action

Its cognitive action has been ascribed to slight cholinesterase (ChE) or acetylcholinesterase (AChE) inhibition and bidirectional regulation on cytosolic free calcium ([22–24], Table 3).


#### 3.1.3. Active Principles

The responsible actives for the cognitive benefits are unclear for the time being.  Triterpene acids and polysaccharides are principal constituents ofP. cocos, responsible for diverse bioactivities, including antitumor, anti-inflammatory, nematicidal, antioxidant, antirejection, antiemetic effects, as inhibitors against DNA topoisomerases, phospholipase A2. Besides, lecithin and choline present in the fungus are beneficially nutritional substance [25–29].


### 3.2. Radix polygalae

Radix polygalaeis the root Polygala tenuifoliaWilld. or P. sibirica L. (Fam. Polygalaceae), used as a cardiotonic and cerebrotonic, sedative and tranquilliser, and for amnesia, neuritis, and insomnia [30, 31].


#### 3.2.1. Functionality/Efficacy

There is strong support that thinleaf milkwort root is memory improving. BT-11, the extract of dried root ofRadix polygalae, was developed in Korea as a functional diet with cognitive enhancing activity.  Elderly with subjective memory impairment and mild cognitive impairment ascend with oral BT-11 at 300 mg/d for 4–8 weeks. Except for mild dyspepsia, no adverse events were reported [32, 33].


#### 3.2.2. Mechanism of Action

A number of investigations also sustained thatRadix polygalaeextracts functioned to promote neuronal proliferation and neurite outgrowth in normal brain and improve memory impaired by scopolamine, stress, nucleus basalis magnocellularis-lesioning operation via a variety of molecular pathways, including increasing glucose utilization and inhibiting AChE activity.  Besides nootropic effects, Radix polygalaeextracts protected neurons against insults induced by NMDA, glutamate, and Aβ ([34–39], Table 4(a)).  In addition, anti-inflammatory activity probably contributed to the cognitive and neuroprotective efficacy, as Radix polygalaeextracts inhibited interleukin-1 (IL-1)-mediated tumour necrosis factor (TNF)-α secretion, and ethanol-induced IL-1 secretion by astrocytes [40, 41].Table 4(a)
Memory-improving and neuro-protective effects ofRadix polygalae
TestTest materials/doseTest modelEndpoint/biomarkersEffectsMechanismsReferenceClinicExtracts 300 mg/d, 4 wHealthy Korean elderly with subjective memory impairment and mild cognitive impairmentdouble-blind, placebo-controlled, randomized, parallel studyKorean version of California verbal learning testSelf-ordered pointing testImprove verbal memory No adverse events, except  mild dyspepsiaN.A.[32, 33]In vivoExtracts i.p., 2 mg/kgInnate ratsNestin/BrdU Tuj1/BrdUImprove memory Promote neuro-genesisPromote proliferation Promote neurite  outgrowth[34]ExtractsStress-treated ratsGlucose utilization Cell adhesion moleculeImprove memoryIncrease glucose  utilization Increase total NCAM[35]Extracts 2 g/kg, 1–3 wNBM-lesioning ratsNeurological test  Step-through testImprove memoryN.A.[36]Extracts i.p., 10 mg/kgScopolamine-treated ratsPassive avoidance test water maze test AChEImprove memoryInhibit AChE[36]In vitroExtracts 0.5–5μg/mLRat primary neurons exposed to Glutamate or AβCell viabilityProtect neuronsN.A.[37]Extracts 0.05–5μg/mLRat cerebellar granule neurons exposed to NMDAGlutamate release    (Ca2+)i/ROSProtect neuronsN.A.[38]Extracts  0.1–100μg/mLRat cortical neurons exposed to Aβ 25–35Axonal length Neuro-filament-H/MAP-2Cell viabilityActivate axonal extension Protect neuronsN.A.[39]Acetylcholinesterase (AChE); bromodeoxyuridine (BrdU); microtubule-associated protein-2 (MAP-2); nucleus basalis magnocellularis (NBM); neural cell adhesion molecule (NCAM); N-methyl-D-aspartic acid (NMDA); reactive oxygen species (ROS);β amyloid (Aβ); not available (N.A.); intraperitoneally (ip.).(b)
Memory-improving and neuro-protective effects of active components fromRadix polygalae
TestTest materials/doseTest modelEndpoints/biomarkersEffectsMechanismsReferenceIn vivoSinapic acid 10–100 mg/kgScopolamine-treated ratsRadial maze testImprove  memoryN.A.[42, 43]Sinapic acid 3–100 mg/kg, 1 hScopolamine-treat mice  Basal forebrain lesioning miceStep-through test Ach/ChATImprove  memoryN.A.[49]Tenuifolin 20–80 mg/kg, 15 dAged mice  Dysmnesia miceStep-down test  Y maze trial AChE,NE,DA,5-HTImprove  memoryIncrease NE and DA Inhibit AChE[45]Tenuigenin 18.5–74 mg/kgAβ 1-40-treated rats  ibotenic acid-treated ratsStep-through test  AchE, ChATImprove  memoryCholinergic[46]Acylated  oligosaccharides1–10 mg/kgScopolamine-treated ratsStep-through testImprove  memoryCholinergic[44]In vitroTenuigenin 1–4μg/mLAPP-transfected  SH-SY5Y cellsFluorescence resonance energy transferInhibit Aβ  secretionInhibit BACE1[47]Onjisaponin 10μMSerum deficiency or glutamate-treated PC12 cellsCell survivalProtect PC 12  cellsN.A.[48]Acetylcholine (Ach); acetylcholinesterase (AChE);choline acetyltransferase (ChAT); 5-hydroxytryptamine (5-HT); dopamine (DA); norepinephrine (NE); beta-site APP cleaving enzyme (BACE);  amyloid precursor protein (APP); β amyloid (Aβ); not available (N.A.).


#### 3.2.3. Active Principles

Phytochemically,Radix polygalaemainly contains a variety of active constituents, including saponins, xanthones, and acylated oligiosaccharides [42–44].Saponins, especially tenuifolin isolated from tenuigenin might reinforce cognitive performance in aged and dysmnesia mice, via elevating levels of dopamine (DA) and norepinephrine (NE), and inhibiting AChE activity (Figure1). Meanwhile, onjisaponin indicated cytoprotective activity in PC12 cells, exposed to serum deficiency or glutamate. In addition, tenuigenin facilitated memory in rats, damaged by Aβ 1–40 or ibotenic acid, via enhancing cholinergic function, or inhibiting Aβ secretion ([45–48], Table 4(b)).Chemical structures of sinapic acid and tenuifolin.
(a)(b)Few phytochemical principles have been isolated and identified as CNS active components. Besides tenuifolin, sinapic acid [49], a common moiety of tenuifoliside B and 3, 6′-disinapoylsucrose, reversed memory deficit induced by scopolamine and basal forebrain lesion (Table 4(b), Figure 1).


### 3.3. Radix et Rhizoma Glycyrrhizae

Radix et rhizoma glycyrrhizaeis the dried root and rhizome, generally derived from a different plant species, with similar properties, including Glycyrrhiza uralensis Fisch., G. inflataBat., or G. glabra L. (Fam. Leguminosae).


#### 3.3.1. Functionality/Efficacy

The extracts ofRadix glycyrrhizaereversed the cognitive deficits induced by diazepam, scopolamine, and beta-amyloid peptide 25–35 in mice at doses of 75, 150, and 300 mg/kg per oral, or diet containing either 0.5 or 1% extract, through anti-AChE and antioxidant activities. In addition, roasted licorice extracts elicited neuroprotection against brain damage after transient forebrain ischemia in Mongolian gerbils, behind which antioxidant activity was also implicated, for example, maintaining superoxide dismutase (SOD)1 level in hippocampal CA1 pyramidal cells ([50–54], Table 5).Table 5
Memory-improving and neuro-protective effects ofRadix et rhizoma glycyrrhizae.
TestTest materials /doseTest modelEndpoint/biomarkersEffectsMechanismsReferenceIn vivoExtracts 75–300 mg/kg, 7d diet 0.5 or 1%,  6wDiazepam treated miceElevated plus-maze testImprove memoryCholinergic[50]Scopolamine treated micepassive avoidance test[51]Aβ 25–35 treated micepassive avoidance testMorris water-maze test TBARS/Catalase/AChEImprove memoryQuench oxidative stress Inhibit AChE[52]Aqueous extracts  150 mg/kg, 7d n-hexane extracts 5 mg/kg, 3dInnate miceAChEInhibit AChEN.A.[53]Methanol extract  50–100 mg/kg, 21dIR treated Mongolian gerbilsCu, Zn-SOD1CA1 pyramidal cellsProtect neuronsRestore Cu, Zn-SOD1[54]Liquiritigenin  2.3–21 mg/kg, 7dAβ (25–35)-treated ratsMorris water maze testReference memory taskProbe taskTwo-way shuttle avoidance taskMAP, Nissle, Notch-2[55]In vivoIsoliquiritigenin 5–20 mg/kg, 7dMCAO-treated ratsMDASOD,GSH-Px, CatalaseNa+-K+-ATPase, ATPEnergy charge, total adenine nucleotidesProtect brainPromote energy metabolismInhibit oxidative stress[56]Glabridin  1–4 mg/kg, 3dInnate MiceChEImprove memoryInhibit ChE[57]Glabridin 5–25 mg/kgIR-treated rats Staurosporine-treated neuronsMDA, GSH and SODBax, caspase-3,bcl-2Protect neuronsInhibit apoptosisInhibit oxidative stress[58]Acetylcholinesterase (AChE); cholinesterase (ChE); thiobarbituric acid-reactive substances (TBARS); superoxide dismutase (SOD); malondialdehyde (MDA); glutathione (GSH); microtubule-associated protein (MAP) 2; middle cerebral artery occlusion (MCAO);β amyloid (Aβ); Ischemia-reperfusion (IR); not available (N.A.).


#### 3.3.2. Mechanism of Action and Active Principles

Radix glycyrrhizaecontains glycyrrhizin, glycyrrhizic acid, glabridin and derivatives, glabrol, glabrene, 17β-hydroxysteroid dehydrogenase, glucoliquiritin apioside, prenyllicoflavone A, shinflavone, shinpterocarpin, 1-methoxyphaseollin, salicylic acid, and derivatives, as well as other saponins, flavonoid glycosides, and flavonoids.Isoliquiritigenin, liquiritigenin, and glabridin have been identified from theRadix glycyrrhizae to be possible bioactive compounds ([55–58], Table 5, Figure 2). (1)
Isoliquiritigenin also has the protective potential against transient middle cerebral artery occlusion-induced focal cerebral ischemia in rats, at the doses of 5, 10, and 20 mg/kg. Its protection may be attributed to amelioration of cerebral energy metabolism and antioxidant property.(2)
Liquiritigenin, a plant-derived highly selective estrogen receptorβ agonist has been identified to alleviate the cognitive recession in the elders.(3)
Glabridin appears to be an active isoflavone as it improved learning and memory in mice at 1, 2, and 4 mg/kg, through targeting at ChE. Glabridin had a protective effect on cerebral ischemia injury, and neuron insult induced by staurosporine at 5, 25 mg/kg (i.p). Its underlying mechanism is probably linked to antioxidant and antiapoptotic activity.(4)
Glabrene also could be beneficial to memory due to estrogen-like activities, like isoliquiritigenin, liquiritigenin, and glabridin [59–61].Chemical structures of isoliquiritigenin, liquiritigenin, and glabridin.
(a)(b)(c)


### 3.4. Radix Angelica sinensis

Radix Angelica sinensis (Chinese: Danggui, Dong quai, Donggui; Korean Danggwi), is the dried root of Angelica sinensis (Oliv.) Diels (Umbelliferae).


#### 3.4.1. Functionality/Efficacy

Behaviour test displayed thatRadix Angelica sinensis extracts ameliorated scopolamine and cycloheximide, but not p-chloroamphetamine-induced amnesia at 1 g/kg bw. In addition in vitro study showed that Radix Angelica sinensis extracts prevented the neurotoxicity induced by Aβin Neuro 2A cells, at the doses ranging 25–200 μg/mL, through antioxidant pathway ([62, 63], Table 6(a)).  Furthermore, estrogenic activity of Angelica sinensis will probably help alleviate peri- or postmenopausal symptoms including cognitive decline in women [64, 65].Table 6(a)
Memory-improving and neuro-protective effects ofRadix Angelica sinensis
TestTest materials/doseTest modelEndpoint/biomarkersEffectsMechanismsReferenceIn vivoExtracts  1 g/kgscopolamine-treated rats cycloheximide-treated ratsStep-through testImprove memoryN.A.[62]In vitroExtracts  25–200μg/mlAβ-treated Neuro 2A cellsMTT assay/ΔΨm   ROS/LPO/GSHProtect neuronsQuench oxidative stress[63]3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT); Lipid peroxidation (LPO); mitochondrial transmembrane potential (ΔΨm); β amyloid (Aβ); glutathione (GSH); not available (N.A.).(b)
Memory-improving and neuro-protective effects of active components fromRadix Angelica sinensis
TestTest materials/doseTest modelEndpoint/biomarkersEffectsMechanismsReferenceIn vivoFerulic acid  s.c., 5 mg/kg/d, 6 ddl-buthionine-(S,R)-Sulfoximine treated  miceObject recognition test Oxidative carbonyl proteinImprove memoryElevate carbonyl protein[66]Ferulic acid 28 dTrimethyltin-treated miceY-maze testPassive avoidance testChATImprove memoryActivate ChAT[67]Ferulic acid i.p., 20–80 mg/kg, 3 dGlutamate-treated miceBehavioral test  histopathology [(3)H]-labeled glutamate bcl-2/caspase-3Protect brainNMDA receptor antagonist[68]Ferulic acid 0.006%, 4 wAβ1-42-treated miceStep-through test  Y-maze test  Water maze test GFAP/IL-1βImprove memoryProtect brainSuppress  astrocytes immunoreactivities[69]Ferulic acid 50–100 mg/kgScopolamine-treated rats Cycloheximide-treated ratsStep-through testImprove memoryCholinergic  Enhance CBF[70]Z-ligustilide 10–40 mg/kg,  4 wCCAO-treated ratsMorris water maze Neurons/astrocytes count  MDA/SOD/ChAT/AChEImprove memoryInhibit oxidative stress   Cholinergic[71]Z-ligustilide 20–80 mg/kgMCAO-treated ratsTTC staining Brain swelling Behavioural scoreProtect brainN.A.[72]Z-ligustilide 5–20 mg/kgIR-treated ICR miceTTC staining MDA/GSH-Px/SOD  Bcl-2/Bax/caspase-3Protect brainInhibit oxidative stress  Inhibit apoptosis[73]Choline acetyltransferase (ChAT); cerebral blood flow (CBF); glial fibrillary acidic protein (GFAP); interleukin-1 (IL-1); glutathione peroxidase (GSH-PX);2,3,5-triphenyltetrazolium chloride (TTC); subcutaneously (s.c.); ischemia-reperfusion (IR); superoxide dismutase (SOD); malondialdehyde (MDA); acetylcholinesterase (AChE); common carotid arteries occlusion (CCAO); middle cerebral artery occlusion (MCAO); β amyloid (Aβ); N-methyl-D-aspartate (NMDA); not available (N.A.).


#### 3.4.2. Mechanism of Action and Active Principles

(1)
Ferulic acid has been identified to be an active principle because it may reverse memory deficits induced by a variety of toxins, including dl-buthionine-(S,R)-sulfoximine,  trimethyltin, glutamate, Aβ1-42, scopolamine, and cycloheximide.  Multiple mechanisms are probably implicated into its cognitive benefits, including inhibition on oxidative stress, activation of ChAT or enhance the cholinergic activities, competitive N-methyl-D-aspartate (NMDA) receptor antagonism, suppression on immunoreactivities of the astrocyte, and facilitation of cerebral blood flow ([66–70], Table 6(b), Figure 3).(2)
Z-ligustilide has been identified to be another active component from volatile ofRadix Angelica sinensis. It may protect brain and cognition especially against focal and global ischemia induced by permanent common carotid arteries occlusion (CCAO) and transient middle cerebral artery occlusion(MCAO) [71–73], (Table 6(b), Figure 3).(3)
Additionally, N-methyl-beta-carboline-3-carboxamide, Coniferyl ferulate, and 11-angeloylsenkyunolide F were identified to be anti-AD components probably by inhibiting Aβ1-40 induced toxicity and AChE activity ([62, 74], Figure 3).Chemical structures of ferulic acid, Z-ligustilide, N-methyl-beta-carboline-3-carboxamide, coniferyl ferulate, and 11-angeloylsenkyunolide F.
(a)(b)(c)(d)(e)


### 3.5. Radix rehmanniae

Radix rehmanniae is the roots of Rehmannia glutinosaLibosch., family Scrophulariaceae.


#### 3.5.1. Functionality/Efficacy

There have been growing evidences thatRadix rehmanniaeextract possesses significant neuroprotective activity ([75, 76], Table 7).Table 7
Memory-improving and neuro-protective effects ofRadix rehmanniae.
TestTest materials/doseTest modelEndpoint/biomarkersEffectsMechanismsReferenceIn vivoExtracts 4.5–9.0 g/kgMSG-treated ratsMorris maze test Step-down test c-fos, NGF  expressionImprove  memoryMotivate  hippocampal c-fos /NGF expression[75]Extracts 4.5–9.0 g/kgMSG-treated ratsMorris maze test Step-down test NMDA-R1,  GABA-R  Glutamine,  GABA levelsImprove   memoryMotivate  hippocampal  NMDA-R1/GABA-R  expression adjust  Glutamine/GABA levels[77]In vitroExtracts 0.1–1.0 mg/mL, 1–3 dC6 glioblastoma cellsGDNF gene  expressionStimulate GDNF expressionUp-regulate  cPKC/ERK1/2  pathways[76]In vivoCatalpol i.p., 10 mg/kg, 10 dLPS-treated miceMMPNF-κBImprove memoryInhibit inflammationInhibit NF-κB activation protect  mitochondrial  function[78]Catalpol 2.5–10 mg/kg, 2 wD-galactose-treated micePassive avoidance  test LDH, GSH-ST,  GS, CKImprove memoryInhibit oxidative  stress  Maintain energy  metabolism[79–81]Catalpol  i.p., 1–10 mg/kgIR-treated  GerbilsBcl-2, Bax, NOProtect CA1 neuronsImprove memoryInhibit apoptosis Inhibit oxidative  stress[82–84]Catalpol i.p., 5 mg/kg, 10 dAged ratsGAP-43/synaptophysin   PKC, BDNFProtect neuroplasticityUp-regulate PKC  and BDNF (hippocampus)[85]In vitroCatalpol 0.5 mM, 1 hMPTP-treated  neuronsCells Viability,  MAO-B, ROS,  MCI, MMP, MPTProtect neuronsProtect  mitochondriaMaintain MAO-B  activity[86]Catalpol 0.5 mM, 30 minAβ1-42-treated  Cortical  neurons-gliaCells Viability TNF-α, iNOS,  NO, ROSProtect neuronsInhibit  inflammation[87]Catalpol 0.25–5 mg/mlPrimary rat cortical  neuronsCells Viability NF-200 antigenEnhance axonal growthNo impact on survivalN.A.[88]Catalpol 0.1–100μg/mlOGD-treated  PC12 cellsBcl-2, caspase-3/MMP  SOD, GSH-PxInhibit apoptosisRetain Bcl-2 and  MMP suppress caspase-3  activation  maintain SOD and  GSH-Px[89]Catalpol 0.1–1.0 mMH2O2-treated   PC12 cellsBcl-2 cytochrome c  caspaseProtect neuronsInhibit apoptosisPrevent  cytochrome c  release Inactivate caspase   cascade[90]Catalpol 0.05–0.5 mMH2O2-treated  astrocytesCells Viability ROSInhibit oxidative stressmaintain glutathione  Scavenge ROS[91]Catalpol 0.3–275.9μM, 24 hOGD-treated mice  astrocytesCell  survival/MMP ROS, NO, iNOS, MDASOD, GSH-Px, GSHProtect  astrocytesInhibit oxidative  stress[92]Nerve growth factor (NGF);oxygen-glucose deprivation (OGD); lactate dehydrogenase (LDH); glutathione S-transferase (GSH-ST); glutamine synthetase (GS); creatine kinase (CK); mitochondrial complex I (MCI);  mitochondrial membrain potential (MMP); mitochondrial permeability transition (MPT); brain-derived neurotrophic factor (BDNF);  γ-amiobutyic acid (GABA); lactate dehydrogenase (LDH); nitric oxide (NO); inducible nitric oxide synthase (iNOS);  nuclear factor-kappa B (NF-κB); protein kinase C (PKC); 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); monosodium glutamate (MSG); lipopolysaccharide (LPS); ischemia-reperfusion (IR); monoamine oxidase (MAO);  tumour necrosis factor (TNF)-α; reactive oxygen species (ROS); superoxide dismutase (SOD); malondialdehyde (MDA); glutathione (GSH); glutathione peroxidase (GSH-Px); glial cell-derived neurotrophic factor (GDNF).


#### 3.5.2. Mechanism of Action

Radix rehmanniae extract improved learning and memory in rats with Monosodium-glutamate-(MSG-) injured thalamic arcuate nucleus at 4.5, and 9.0 g/kg, through adjusting glutamates and γ-amiobutyic acid (GABA) levels, as well as increasing the expression of hippocampal c-fos, nerve growth factor(NGF), NMDA receptor 1, and GABA receptor. Moreover, Rehmannia extract stimulated glial cell-derived neurotrophic factor (GDNF) gene expression in C6 glioblastoma cells, through upregulating cPKC and ERK 1/2 pathways ([76, 77], Table 7).


#### 3.5.3. Active Components

Catalpol, an iridoid glycoside, was isolated from the freshRadix rehmanniae. It exists broadly in many plants all over the world and has many biological functions such as anti-inflammation, promoting of sex hormones production, protection of liver damage, and reduction of elevated blood sugar.Recently, catalpol has been identified as a vital active with robust cognitive potential (Figure4). Behaviour studies exhibited that catalpol reversed brain damage and memory deficits in mice induced by lipopolysaccharide (LPS) and D-galactose and in gerbils by cerebral ischemia. The nootropic and neuroprotective efficacy of catalpol probably resulted from a variety of underlying molecular mechanisms (Table 7). (i)
Antioxidant activity: catalpol promoted endogenous antioxidant enzyme activities,  superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and antioxidant glutathione (GSH), cut down malondialdehyde (MDA) and reactive oxygen species (ROS) generation in PC12 cells and astrocytes primary cultures, exposed to oxygen and glucose deprivation  or H2O2, and in senescent mice induced by D-galactose [79–81, 86, 89, 91, 92].(ii)
Anti-inflammatory activity: catalpol significantly reduced the release of ROS, TNF-α, nitric oxide (NO) and inducible nitric oxide synthase (iNOS) expression after Aβ (1–42)-induced microglial activation in primary cortical neuron-glia cultures, and LPS-induced nuclear factor-kappa B (NF-κB) activation in mice [78, 87].(iii)
Neurogenetic activity: catalpol can enhance axonal growth of cortical neurons culturedin vitro from 24 h newly born rat, at 1–5 mg/mL and ameliorate age-related presynaptic proteins decline (synaptophysin and GAP-43), and neuroplasticity loss in the hippocampus of the aged rats, by upregulating protein kinase C (PKC) and brain-derived neurotrophic factor (BDNF) [85, 88].(iv)
Antiapoptotic activity: catalpol not only suppressed the downregulation of Bcl-2, upregulation of Bax, and the release of mitochondrial cytochrome c to cytosol, but also attenuated caspase-3 activation, poly-ADP-ribose polymerase (PARP) cleavage, and eventually protected against H2O2-induced apoptosis in PC12 cells and in the ischemic dorsal hippocampus of gerbils subject to CCAO [82–84, 90].(v)
In addition, the function to stimulate the production of adrenal cortical hormones, which increases the production of sex hormones, is likely implicated into the cognitive benefit of catalpol in menopausal women [92].Figure 4
Chemical structure of catalpol.


## 3.1. Poria cocos

Poria cocos (Chinese name: Fu Ling) is the dried sclerotium of the fungus, Poria cocos (Schw.) Wolf (Fam. Polyporaceae).


### 3.1.1. Functionality/Efficacy

There is suggestive evidence thatP. cocos is memory improving regardless of absence of available clinical reports. Pharmacological research exhibited that the water extract of P. cocos enhanced hippocampal long-term potentiation (LTP) and improved scopolamine-induced spatial memory impairment in rats ([20, 21], Table 3).Table 3
Memory-improving and neuro-protective effects ofPoria cocos.
TestTest materials/doseTest modelEndpoints/biomarkersEffectsReferenceIn vivoExtracts  20–100 mg/kgScopolamine-treated ratsEight-arm radial mazeImprove spatial memory[20]Extracts 250–500 mg/kgInnate ratsElectro-physiology Spike amplitudeEnhance hippocampal  LTP[21]Methanol  extracts 200 mg/mLEllman ChEChE activityInhibit ChE by 27.8%[22]Aqueous extracts 0.2 mg/mLInnate ICR miceAChE activityInhibit AChE by 13.9%[23]In vitroAqueous extracts 31–250μg/mLBrain neurons–neonatal ratsCytosolic [Ca2+] iRegulate bi-directly [Ca2+] i[24]Long-term potentiation (LTP); choline esterase (ChE);acetylcholinesterase (AChE).


### 3.1.2. Mechanism of Action

Its cognitive action has been ascribed to slight cholinesterase (ChE) or acetylcholinesterase (AChE) inhibition and bidirectional regulation on cytosolic free calcium ([22–24], Table 3).


### 3.1.3. Active Principles

The responsible actives for the cognitive benefits are unclear for the time being.  Triterpene acids and polysaccharides are principal constituents ofP. cocos, responsible for diverse bioactivities, including antitumor, anti-inflammatory, nematicidal, antioxidant, antirejection, antiemetic effects, as inhibitors against DNA topoisomerases, phospholipase A2. Besides, lecithin and choline present in the fungus are beneficially nutritional substance [25–29].


## 3.1.1. Functionality/Efficacy

There is suggestive evidence thatP. cocos is memory improving regardless of absence of available clinical reports. Pharmacological research exhibited that the water extract of P. cocos enhanced hippocampal long-term potentiation (LTP) and improved scopolamine-induced spatial memory impairment in rats ([20, 21], Table 3).Table 3
Memory-improving and neuro-protective effects ofPoria cocos.
TestTest materials/doseTest modelEndpoints/biomarkersEffectsReferenceIn vivoExtracts  20–100 mg/kgScopolamine-treated ratsEight-arm radial mazeImprove spatial memory[20]Extracts 250–500 mg/kgInnate ratsElectro-physiology Spike amplitudeEnhance hippocampal  LTP[21]Methanol  extracts 200 mg/mLEllman ChEChE activityInhibit ChE by 27.8%[22]Aqueous extracts 0.2 mg/mLInnate ICR miceAChE activityInhibit AChE by 13.9%[23]In vitroAqueous extracts 31–250μg/mLBrain neurons–neonatal ratsCytosolic [Ca2+] iRegulate bi-directly [Ca2+] i[24]Long-term potentiation (LTP); choline esterase (ChE);acetylcholinesterase (AChE).


## 3.1.2. Mechanism of Action

Its cognitive action has been ascribed to slight cholinesterase (ChE) or acetylcholinesterase (AChE) inhibition and bidirectional regulation on cytosolic free calcium ([22–24], Table 3).


## 3.1.3. Active Principles

The responsible actives for the cognitive benefits are unclear for the time being.  Triterpene acids and polysaccharides are principal constituents ofP. cocos, responsible for diverse bioactivities, including antitumor, anti-inflammatory, nematicidal, antioxidant, antirejection, antiemetic effects, as inhibitors against DNA topoisomerases, phospholipase A2. Besides, lecithin and choline present in the fungus are beneficially nutritional substance [25–29].


## 3.2. Radix polygalae

Radix polygalaeis the root Polygala tenuifoliaWilld. or P. sibirica L. (Fam. Polygalaceae), used as a cardiotonic and cerebrotonic, sedative and tranquilliser, and for amnesia, neuritis, and insomnia [30, 31].


### 3.2.1. Functionality/Efficacy

There is strong support that thinleaf milkwort root is memory improving. BT-11, the extract of dried root ofRadix polygalae, was developed in Korea as a functional diet with cognitive enhancing activity.  Elderly with subjective memory impairment and mild cognitive impairment ascend with oral BT-11 at 300 mg/d for 4–8 weeks. Except for mild dyspepsia, no adverse events were reported [32, 33].


### 3.2.2. Mechanism of Action

A number of investigations also sustained thatRadix polygalaeextracts functioned to promote neuronal proliferation and neurite outgrowth in normal brain and improve memory impaired by scopolamine, stress, nucleus basalis magnocellularis-lesioning operation via a variety of molecular pathways, including increasing glucose utilization and inhibiting AChE activity.  Besides nootropic effects, Radix polygalaeextracts protected neurons against insults induced by NMDA, glutamate, and Aβ ([34–39], Table 4(a)).  In addition, anti-inflammatory activity probably contributed to the cognitive and neuroprotective efficacy, as Radix polygalaeextracts inhibited interleukin-1 (IL-1)-mediated tumour necrosis factor (TNF)-α secretion, and ethanol-induced IL-1 secretion by astrocytes [40, 41].Table 4(a)
Memory-improving and neuro-protective effects ofRadix polygalae
TestTest materials/doseTest modelEndpoint/biomarkersEffectsMechanismsReferenceClinicExtracts 300 mg/d, 4 wHealthy Korean elderly with subjective memory impairment and mild cognitive impairmentdouble-blind, placebo-controlled, randomized, parallel studyKorean version of California verbal learning testSelf-ordered pointing testImprove verbal memory No adverse events, except  mild dyspepsiaN.A.[32, 33]In vivoExtracts i.p., 2 mg/kgInnate ratsNestin/BrdU Tuj1/BrdUImprove memory Promote neuro-genesisPromote proliferation Promote neurite  outgrowth[34]ExtractsStress-treated ratsGlucose utilization Cell adhesion moleculeImprove memoryIncrease glucose  utilization Increase total NCAM[35]Extracts 2 g/kg, 1–3 wNBM-lesioning ratsNeurological test  Step-through testImprove memoryN.A.[36]Extracts i.p., 10 mg/kgScopolamine-treated ratsPassive avoidance test water maze test AChEImprove memoryInhibit AChE[36]In vitroExtracts 0.5–5μg/mLRat primary neurons exposed to Glutamate or AβCell viabilityProtect neuronsN.A.[37]Extracts 0.05–5μg/mLRat cerebellar granule neurons exposed to NMDAGlutamate release    (Ca2+)i/ROSProtect neuronsN.A.[38]Extracts  0.1–100μg/mLRat cortical neurons exposed to Aβ 25–35Axonal length Neuro-filament-H/MAP-2Cell viabilityActivate axonal extension Protect neuronsN.A.[39]Acetylcholinesterase (AChE); bromodeoxyuridine (BrdU); microtubule-associated protein-2 (MAP-2); nucleus basalis magnocellularis (NBM); neural cell adhesion molecule (NCAM); N-methyl-D-aspartic acid (NMDA); reactive oxygen species (ROS);β amyloid (Aβ); not available (N.A.); intraperitoneally (ip.).(b)
Memory-improving and neuro-protective effects of active components fromRadix polygalae
TestTest materials/doseTest modelEndpoints/biomarkersEffectsMechanismsReferenceIn vivoSinapic acid 10–100 mg/kgScopolamine-treated ratsRadial maze testImprove  memoryN.A.[42, 43]Sinapic acid 3–100 mg/kg, 1 hScopolamine-treat mice  Basal forebrain lesioning miceStep-through test Ach/ChATImprove  memoryN.A.[49]Tenuifolin 20–80 mg/kg, 15 dAged mice  Dysmnesia miceStep-down test  Y maze trial AChE,NE,DA,5-HTImprove  memoryIncrease NE and DA Inhibit AChE[45]Tenuigenin 18.5–74 mg/kgAβ 1-40-treated rats  ibotenic acid-treated ratsStep-through test  AchE, ChATImprove  memoryCholinergic[46]Acylated  oligosaccharides1–10 mg/kgScopolamine-treated ratsStep-through testImprove  memoryCholinergic[44]In vitroTenuigenin 1–4μg/mLAPP-transfected  SH-SY5Y cellsFluorescence resonance energy transferInhibit Aβ  secretionInhibit BACE1[47]Onjisaponin 10μMSerum deficiency or glutamate-treated PC12 cellsCell survivalProtect PC 12  cellsN.A.[48]Acetylcholine (Ach); acetylcholinesterase (AChE);choline acetyltransferase (ChAT); 5-hydroxytryptamine (5-HT); dopamine (DA); norepinephrine (NE); beta-site APP cleaving enzyme (BACE);  amyloid precursor protein (APP); β amyloid (Aβ); not available (N.A.).


### 3.2.3. Active Principles

Phytochemically,Radix polygalaemainly contains a variety of active constituents, including saponins, xanthones, and acylated oligiosaccharides [42–44].Saponins, especially tenuifolin isolated from tenuigenin might reinforce cognitive performance in aged and dysmnesia mice, via elevating levels of dopamine (DA) and norepinephrine (NE), and inhibiting AChE activity (Figure1). Meanwhile, onjisaponin indicated cytoprotective activity in PC12 cells, exposed to serum deficiency or glutamate. In addition, tenuigenin facilitated memory in rats, damaged by Aβ 1–40 or ibotenic acid, via enhancing cholinergic function, or inhibiting Aβ secretion ([45–48], Table 4(b)).Chemical structures of sinapic acid and tenuifolin.
(a)(b)Few phytochemical principles have been isolated and identified as CNS active components. Besides tenuifolin, sinapic acid [49], a common moiety of tenuifoliside B and 3, 6′-disinapoylsucrose, reversed memory deficit induced by scopolamine and basal forebrain lesion (Table 4(b), Figure 1).


## 3.2.1. Functionality/Efficacy

There is strong support that thinleaf milkwort root is memory improving. BT-11, the extract of dried root ofRadix polygalae, was developed in Korea as a functional diet with cognitive enhancing activity.  Elderly with subjective memory impairment and mild cognitive impairment ascend with oral BT-11 at 300 mg/d for 4–8 weeks. Except for mild dyspepsia, no adverse events were reported [32, 33].


## 3.2.2. Mechanism of Action

A number of investigations also sustained thatRadix polygalaeextracts functioned to promote neuronal proliferation and neurite outgrowth in normal brain and improve memory impaired by scopolamine, stress, nucleus basalis magnocellularis-lesioning operation via a variety of molecular pathways, including increasing glucose utilization and inhibiting AChE activity.  Besides nootropic effects, Radix polygalaeextracts protected neurons against insults induced by NMDA, glutamate, and Aβ ([34–39], Table 4(a)).  In addition, anti-inflammatory activity probably contributed to the cognitive and neuroprotective efficacy, as Radix polygalaeextracts inhibited interleukin-1 (IL-1)-mediated tumour necrosis factor (TNF)-α secretion, and ethanol-induced IL-1 secretion by astrocytes [40, 41].Table 4(a)
Memory-improving and neuro-protective effects ofRadix polygalae
TestTest materials/doseTest modelEndpoint/biomarkersEffectsMechanismsReferenceClinicExtracts 300 mg/d, 4 wHealthy Korean elderly with subjective memory impairment and mild cognitive impairmentdouble-blind, placebo-controlled, randomized, parallel studyKorean version of California verbal learning testSelf-ordered pointing testImprove verbal memory No adverse events, except  mild dyspepsiaN.A.[32, 33]In vivoExtracts i.p., 2 mg/kgInnate ratsNestin/BrdU Tuj1/BrdUImprove memory Promote neuro-genesisPromote proliferation Promote neurite  outgrowth[34]ExtractsStress-treated ratsGlucose utilization Cell adhesion moleculeImprove memoryIncrease glucose  utilization Increase total NCAM[35]Extracts 2 g/kg, 1–3 wNBM-lesioning ratsNeurological test  Step-through testImprove memoryN.A.[36]Extracts i.p., 10 mg/kgScopolamine-treated ratsPassive avoidance test water maze test AChEImprove memoryInhibit AChE[36]In vitroExtracts 0.5–5μg/mLRat primary neurons exposed to Glutamate or AβCell viabilityProtect neuronsN.A.[37]Extracts 0.05–5μg/mLRat cerebellar granule neurons exposed to NMDAGlutamate release    (Ca2+)i/ROSProtect neuronsN.A.[38]Extracts  0.1–100μg/mLRat cortical neurons exposed to Aβ 25–35Axonal length Neuro-filament-H/MAP-2Cell viabilityActivate axonal extension Protect neuronsN.A.[39]Acetylcholinesterase (AChE); bromodeoxyuridine (BrdU); microtubule-associated protein-2 (MAP-2); nucleus basalis magnocellularis (NBM); neural cell adhesion molecule (NCAM); N-methyl-D-aspartic acid (NMDA); reactive oxygen species (ROS);β amyloid (Aβ); not available (N.A.); intraperitoneally (ip.).(b)
Memory-improving and neuro-protective effects of active components fromRadix polygalae
TestTest materials/doseTest modelEndpoints/biomarkersEffectsMechanismsReferenceIn vivoSinapic acid 10–100 mg/kgScopolamine-treated ratsRadial maze testImprove  memoryN.A.[42, 43]Sinapic acid 3–100 mg/kg, 1 hScopolamine-treat mice  Basal forebrain lesioning miceStep-through test Ach/ChATImprove  memoryN.A.[49]Tenuifolin 20–80 mg/kg, 15 dAged mice  Dysmnesia miceStep-down test  Y maze trial AChE,NE,DA,5-HTImprove  memoryIncrease NE and DA Inhibit AChE[45]Tenuigenin 18.5–74 mg/kgAβ 1-40-treated rats  ibotenic acid-treated ratsStep-through test  AchE, ChATImprove  memoryCholinergic[46]Acylated  oligosaccharides1–10 mg/kgScopolamine-treated ratsStep-through testImprove  memoryCholinergic[44]In vitroTenuigenin 1–4μg/mLAPP-transfected  SH-SY5Y cellsFluorescence resonance energy transferInhibit Aβ  secretionInhibit BACE1[47]Onjisaponin 10μMSerum deficiency or glutamate-treated PC12 cellsCell survivalProtect PC 12  cellsN.A.[48]Acetylcholine (Ach); acetylcholinesterase (AChE);choline acetyltransferase (ChAT); 5-hydroxytryptamine (5-HT); dopamine (DA); norepinephrine (NE); beta-site APP cleaving enzyme (BACE);  amyloid precursor protein (APP); β amyloid (Aβ); not available (N.A.).


## 3.2.3. Active Principles

Phytochemically,Radix polygalaemainly contains a variety of active constituents, including saponins, xanthones, and acylated oligiosaccharides [42–44].Saponins, especially tenuifolin isolated from tenuigenin might reinforce cognitive performance in aged and dysmnesia mice, via elevating levels of dopamine (DA) and norepinephrine (NE), and inhibiting AChE activity (Figure1). Meanwhile, onjisaponin indicated cytoprotective activity in PC12 cells, exposed to serum deficiency or glutamate. In addition, tenuigenin facilitated memory in rats, damaged by Aβ 1–40 or ibotenic acid, via enhancing cholinergic function, or inhibiting Aβ secretion ([45–48], Table 4(b)).Chemical structures of sinapic acid and tenuifolin.
(a)(b)Few phytochemical principles have been isolated and identified as CNS active components. Besides tenuifolin, sinapic acid [49], a common moiety of tenuifoliside B and 3, 6′-disinapoylsucrose, reversed memory deficit induced by scopolamine and basal forebrain lesion (Table 4(b), Figure 1).


## 3.3. Radix et Rhizoma Glycyrrhizae

Radix et rhizoma glycyrrhizaeis the dried root and rhizome, generally derived from a different plant species, with similar properties, including Glycyrrhiza uralensis Fisch., G. inflataBat., or G. glabra L. (Fam. Leguminosae).


### 3.3.1. Functionality/Efficacy

The extracts ofRadix glycyrrhizaereversed the cognitive deficits induced by diazepam, scopolamine, and beta-amyloid peptide 25–35 in mice at doses of 75, 150, and 300 mg/kg per oral, or diet containing either 0.5 or 1% extract, through anti-AChE and antioxidant activities. In addition, roasted licorice extracts elicited neuroprotection against brain damage after transient forebrain ischemia in Mongolian gerbils, behind which antioxidant activity was also implicated, for example, maintaining superoxide dismutase (SOD)1 level in hippocampal CA1 pyramidal cells ([50–54], Table 5).Table 5
Memory-improving and neuro-protective effects ofRadix et rhizoma glycyrrhizae.
TestTest materials /doseTest modelEndpoint/biomarkersEffectsMechanismsReferenceIn vivoExtracts 75–300 mg/kg, 7d diet 0.5 or 1%,  6wDiazepam treated miceElevated plus-maze testImprove memoryCholinergic[50]Scopolamine treated micepassive avoidance test[51]Aβ 25–35 treated micepassive avoidance testMorris water-maze test TBARS/Catalase/AChEImprove memoryQuench oxidative stress Inhibit AChE[52]Aqueous extracts  150 mg/kg, 7d n-hexane extracts 5 mg/kg, 3dInnate miceAChEInhibit AChEN.A.[53]Methanol extract  50–100 mg/kg, 21dIR treated Mongolian gerbilsCu, Zn-SOD1CA1 pyramidal cellsProtect neuronsRestore Cu, Zn-SOD1[54]Liquiritigenin  2.3–21 mg/kg, 7dAβ (25–35)-treated ratsMorris water maze testReference memory taskProbe taskTwo-way shuttle avoidance taskMAP, Nissle, Notch-2[55]In vivoIsoliquiritigenin 5–20 mg/kg, 7dMCAO-treated ratsMDASOD,GSH-Px, CatalaseNa+-K+-ATPase, ATPEnergy charge, total adenine nucleotidesProtect brainPromote energy metabolismInhibit oxidative stress[56]Glabridin  1–4 mg/kg, 3dInnate MiceChEImprove memoryInhibit ChE[57]Glabridin 5–25 mg/kgIR-treated rats Staurosporine-treated neuronsMDA, GSH and SODBax, caspase-3,bcl-2Protect neuronsInhibit apoptosisInhibit oxidative stress[58]Acetylcholinesterase (AChE); cholinesterase (ChE); thiobarbituric acid-reactive substances (TBARS); superoxide dismutase (SOD); malondialdehyde (MDA); glutathione (GSH); microtubule-associated protein (MAP) 2; middle cerebral artery occlusion (MCAO);β amyloid (Aβ); Ischemia-reperfusion (IR); not available (N.A.).


### 3.3.2. Mechanism of Action and Active Principles

Radix glycyrrhizaecontains glycyrrhizin, glycyrrhizic acid, glabridin and derivatives, glabrol, glabrene, 17β-hydroxysteroid dehydrogenase, glucoliquiritin apioside, prenyllicoflavone A, shinflavone, shinpterocarpin, 1-methoxyphaseollin, salicylic acid, and derivatives, as well as other saponins, flavonoid glycosides, and flavonoids.Isoliquiritigenin, liquiritigenin, and glabridin have been identified from theRadix glycyrrhizae to be possible bioactive compounds ([55–58], Table 5, Figure 2). (1)
Isoliquiritigenin also has the protective potential against transient middle cerebral artery occlusion-induced focal cerebral ischemia in rats, at the doses of 5, 10, and 20 mg/kg. Its protection may be attributed to amelioration of cerebral energy metabolism and antioxidant property.(2)
Liquiritigenin, a plant-derived highly selective estrogen receptorβ agonist has been identified to alleviate the cognitive recession in the elders.(3)
Glabridin appears to be an active isoflavone as it improved learning and memory in mice at 1, 2, and 4 mg/kg, through targeting at ChE. Glabridin had a protective effect on cerebral ischemia injury, and neuron insult induced by staurosporine at 5, 25 mg/kg (i.p). Its underlying mechanism is probably linked to antioxidant and antiapoptotic activity.(4)
Glabrene also could be beneficial to memory due to estrogen-like activities, like isoliquiritigenin, liquiritigenin, and glabridin [59–61].Chemical structures of isoliquiritigenin, liquiritigenin, and glabridin.
(a)(b)(c)


## 3.3.1. Functionality/Efficacy

The extracts ofRadix glycyrrhizaereversed the cognitive deficits induced by diazepam, scopolamine, and beta-amyloid peptide 25–35 in mice at doses of 75, 150, and 300 mg/kg per oral, or diet containing either 0.5 or 1% extract, through anti-AChE and antioxidant activities. In addition, roasted licorice extracts elicited neuroprotection against brain damage after transient forebrain ischemia in Mongolian gerbils, behind which antioxidant activity was also implicated, for example, maintaining superoxide dismutase (SOD)1 level in hippocampal CA1 pyramidal cells ([50–54], Table 5).Table 5
Memory-improving and neuro-protective effects ofRadix et rhizoma glycyrrhizae.
TestTest materials /doseTest modelEndpoint/biomarkersEffectsMechanismsReferenceIn vivoExtracts 75–300 mg/kg, 7d diet 0.5 or 1%,  6wDiazepam treated miceElevated plus-maze testImprove memoryCholinergic[50]Scopolamine treated micepassive avoidance test[51]Aβ 25–35 treated micepassive avoidance testMorris water-maze test TBARS/Catalase/AChEImprove memoryQuench oxidative stress Inhibit AChE[52]Aqueous extracts  150 mg/kg, 7d n-hexane extracts 5 mg/kg, 3dInnate miceAChEInhibit AChEN.A.[53]Methanol extract  50–100 mg/kg, 21dIR treated Mongolian gerbilsCu, Zn-SOD1CA1 pyramidal cellsProtect neuronsRestore Cu, Zn-SOD1[54]Liquiritigenin  2.3–21 mg/kg, 7dAβ (25–35)-treated ratsMorris water maze testReference memory taskProbe taskTwo-way shuttle avoidance taskMAP, Nissle, Notch-2[55]In vivoIsoliquiritigenin 5–20 mg/kg, 7dMCAO-treated ratsMDASOD,GSH-Px, CatalaseNa+-K+-ATPase, ATPEnergy charge, total adenine nucleotidesProtect brainPromote energy metabolismInhibit oxidative stress[56]Glabridin  1–4 mg/kg, 3dInnate MiceChEImprove memoryInhibit ChE[57]Glabridin 5–25 mg/kgIR-treated rats Staurosporine-treated neuronsMDA, GSH and SODBax, caspase-3,bcl-2Protect neuronsInhibit apoptosisInhibit oxidative stress[58]Acetylcholinesterase (AChE); cholinesterase (ChE); thiobarbituric acid-reactive substances (TBARS); superoxide dismutase (SOD); malondialdehyde (MDA); glutathione (GSH); microtubule-associated protein (MAP) 2; middle cerebral artery occlusion (MCAO);β amyloid (Aβ); Ischemia-reperfusion (IR); not available (N.A.).


## 3.3.2. Mechanism of Action and Active Principles

Radix glycyrrhizaecontains glycyrrhizin, glycyrrhizic acid, glabridin and derivatives, glabrol, glabrene, 17β-hydroxysteroid dehydrogenase, glucoliquiritin apioside, prenyllicoflavone A, shinflavone, shinpterocarpin, 1-methoxyphaseollin, salicylic acid, and derivatives, as well as other saponins, flavonoid glycosides, and flavonoids.Isoliquiritigenin, liquiritigenin, and glabridin have been identified from theRadix glycyrrhizae to be possible bioactive compounds ([55–58], Table 5, Figure 2). (1)
Isoliquiritigenin also has the protective potential against transient middle cerebral artery occlusion-induced focal cerebral ischemia in rats, at the doses of 5, 10, and 20 mg/kg. Its protection may be attributed to amelioration of cerebral energy metabolism and antioxidant property.(2)
Liquiritigenin, a plant-derived highly selective estrogen receptorβ agonist has been identified to alleviate the cognitive recession in the elders.(3)
Glabridin appears to be an active isoflavone as it improved learning and memory in mice at 1, 2, and 4 mg/kg, through targeting at ChE. Glabridin had a protective effect on cerebral ischemia injury, and neuron insult induced by staurosporine at 5, 25 mg/kg (i.p). Its underlying mechanism is probably linked to antioxidant and antiapoptotic activity.(4)
Glabrene also could be beneficial to memory due to estrogen-like activities, like isoliquiritigenin, liquiritigenin, and glabridin [59–61].Chemical structures of isoliquiritigenin, liquiritigenin, and glabridin.
(a)(b)(c)


## 3.4. Radix Angelica sinensis

Radix Angelica sinensis (Chinese: Danggui, Dong quai, Donggui; Korean Danggwi), is the dried root of Angelica sinensis (Oliv.) Diels (Umbelliferae).


### 3.4.1. Functionality/Efficacy

Behaviour test displayed thatRadix Angelica sinensis extracts ameliorated scopolamine and cycloheximide, but not p-chloroamphetamine-induced amnesia at 1 g/kg bw. In addition in vitro study showed that Radix Angelica sinensis extracts prevented the neurotoxicity induced by Aβin Neuro 2A cells, at the doses ranging 25–200 μg/mL, through antioxidant pathway ([62, 63], Table 6(a)).  Furthermore, estrogenic activity of Angelica sinensis will probably help alleviate peri- or postmenopausal symptoms including cognitive decline in women [64, 65].Table 6(a)
Memory-improving and neuro-protective effects ofRadix Angelica sinensis
TestTest materials/doseTest modelEndpoint/biomarkersEffectsMechanismsReferenceIn vivoExtracts  1 g/kgscopolamine-treated rats cycloheximide-treated ratsStep-through testImprove memoryN.A.[62]In vitroExtracts  25–200μg/mlAβ-treated Neuro 2A cellsMTT assay/ΔΨm   ROS/LPO/GSHProtect neuronsQuench oxidative stress[63]3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT); Lipid peroxidation (LPO); mitochondrial transmembrane potential (ΔΨm); β amyloid (Aβ); glutathione (GSH); not available (N.A.).(b)
Memory-improving and neuro-protective effects of active components fromRadix Angelica sinensis
TestTest materials/doseTest modelEndpoint/biomarkersEffectsMechanismsReferenceIn vivoFerulic acid  s.c., 5 mg/kg/d, 6 ddl-buthionine-(S,R)-Sulfoximine treated  miceObject recognition test Oxidative carbonyl proteinImprove memoryElevate carbonyl protein[66]Ferulic acid 28 dTrimethyltin-treated miceY-maze testPassive avoidance testChATImprove memoryActivate ChAT[67]Ferulic acid i.p., 20–80 mg/kg, 3 dGlutamate-treated miceBehavioral test  histopathology [(3)H]-labeled glutamate bcl-2/caspase-3Protect brainNMDA receptor antagonist[68]Ferulic acid 0.006%, 4 wAβ1-42-treated miceStep-through test  Y-maze test  Water maze test GFAP/IL-1βImprove memoryProtect brainSuppress  astrocytes immunoreactivities[69]Ferulic acid 50–100 mg/kgScopolamine-treated rats Cycloheximide-treated ratsStep-through testImprove memoryCholinergic  Enhance CBF[70]Z-ligustilide 10–40 mg/kg,  4 wCCAO-treated ratsMorris water maze Neurons/astrocytes count  MDA/SOD/ChAT/AChEImprove memoryInhibit oxidative stress   Cholinergic[71]Z-ligustilide 20–80 mg/kgMCAO-treated ratsTTC staining Brain swelling Behavioural scoreProtect brainN.A.[72]Z-ligustilide 5–20 mg/kgIR-treated ICR miceTTC staining MDA/GSH-Px/SOD  Bcl-2/Bax/caspase-3Protect brainInhibit oxidative stress  Inhibit apoptosis[73]Choline acetyltransferase (ChAT); cerebral blood flow (CBF); glial fibrillary acidic protein (GFAP); interleukin-1 (IL-1); glutathione peroxidase (GSH-PX);2,3,5-triphenyltetrazolium chloride (TTC); subcutaneously (s.c.); ischemia-reperfusion (IR); superoxide dismutase (SOD); malondialdehyde (MDA); acetylcholinesterase (AChE); common carotid arteries occlusion (CCAO); middle cerebral artery occlusion (MCAO); β amyloid (Aβ); N-methyl-D-aspartate (NMDA); not available (N.A.).


### 3.4.2. Mechanism of Action and Active Principles

(1)
Ferulic acid has been identified to be an active principle because it may reverse memory deficits induced by a variety of toxins, including dl-buthionine-(S,R)-sulfoximine,  trimethyltin, glutamate, Aβ1-42, scopolamine, and cycloheximide.  Multiple mechanisms are probably implicated into its cognitive benefits, including inhibition on oxidative stress, activation of ChAT or enhance the cholinergic activities, competitive N-methyl-D-aspartate (NMDA) receptor antagonism, suppression on immunoreactivities of the astrocyte, and facilitation of cerebral blood flow ([66–70], Table 6(b), Figure 3).(2)
Z-ligustilide has been identified to be another active component from volatile ofRadix Angelica sinensis. It may protect brain and cognition especially against focal and global ischemia induced by permanent common carotid arteries occlusion (CCAO) and transient middle cerebral artery occlusion(MCAO) [71–73], (Table 6(b), Figure 3).(3)
Additionally, N-methyl-beta-carboline-3-carboxamide, Coniferyl ferulate, and 11-angeloylsenkyunolide F were identified to be anti-AD components probably by inhibiting Aβ1-40 induced toxicity and AChE activity ([62, 74], Figure 3).Chemical structures of ferulic acid, Z-ligustilide, N-methyl-beta-carboline-3-carboxamide, coniferyl ferulate, and 11-angeloylsenkyunolide F.
(a)(b)(c)(d)(e)


## 3.4.1. Functionality/Efficacy

Behaviour test displayed thatRadix Angelica sinensis extracts ameliorated scopolamine and cycloheximide, but not p-chloroamphetamine-induced amnesia at 1 g/kg bw. In addition in vitro study showed that Radix Angelica sinensis extracts prevented the neurotoxicity induced by Aβin Neuro 2A cells, at the doses ranging 25–200 μg/mL, through antioxidant pathway ([62, 63], Table 6(a)).  Furthermore, estrogenic activity of Angelica sinensis will probably help alleviate peri- or postmenopausal symptoms including cognitive decline in women [64, 65].Table 6(a)
Memory-improving and neuro-protective effects ofRadix Angelica sinensis
TestTest materials/doseTest modelEndpoint/biomarkersEffectsMechanismsReferenceIn vivoExtracts  1 g/kgscopolamine-treated rats cycloheximide-treated ratsStep-through testImprove memoryN.A.[62]In vitroExtracts  25–200μg/mlAβ-treated Neuro 2A cellsMTT assay/ΔΨm   ROS/LPO/GSHProtect neuronsQuench oxidative stress[63]3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT); Lipid peroxidation (LPO); mitochondrial transmembrane potential (ΔΨm); β amyloid (Aβ); glutathione (GSH); not available (N.A.).(b)
Memory-improving and neuro-protective effects of active components fromRadix Angelica sinensis
TestTest materials/doseTest modelEndpoint/biomarkersEffectsMechanismsReferenceIn vivoFerulic acid  s.c., 5 mg/kg/d, 6 ddl-buthionine-(S,R)-Sulfoximine treated  miceObject recognition test Oxidative carbonyl proteinImprove memoryElevate carbonyl protein[66]Ferulic acid 28 dTrimethyltin-treated miceY-maze testPassive avoidance testChATImprove memoryActivate ChAT[67]Ferulic acid i.p., 20–80 mg/kg, 3 dGlutamate-treated miceBehavioral test  histopathology [(3)H]-labeled glutamate bcl-2/caspase-3Protect brainNMDA receptor antagonist[68]Ferulic acid 0.006%, 4 wAβ1-42-treated miceStep-through test  Y-maze test  Water maze test GFAP/IL-1βImprove memoryProtect brainSuppress  astrocytes immunoreactivities[69]Ferulic acid 50–100 mg/kgScopolamine-treated rats Cycloheximide-treated ratsStep-through testImprove memoryCholinergic  Enhance CBF[70]Z-ligustilide 10–40 mg/kg,  4 wCCAO-treated ratsMorris water maze Neurons/astrocytes count  MDA/SOD/ChAT/AChEImprove memoryInhibit oxidative stress   Cholinergic[71]Z-ligustilide 20–80 mg/kgMCAO-treated ratsTTC staining Brain swelling Behavioural scoreProtect brainN.A.[72]Z-ligustilide 5–20 mg/kgIR-treated ICR miceTTC staining MDA/GSH-Px/SOD  Bcl-2/Bax/caspase-3Protect brainInhibit oxidative stress  Inhibit apoptosis[73]Choline acetyltransferase (ChAT); cerebral blood flow (CBF); glial fibrillary acidic protein (GFAP); interleukin-1 (IL-1); glutathione peroxidase (GSH-PX);2,3,5-triphenyltetrazolium chloride (TTC); subcutaneously (s.c.); ischemia-reperfusion (IR); superoxide dismutase (SOD); malondialdehyde (MDA); acetylcholinesterase (AChE); common carotid arteries occlusion (CCAO); middle cerebral artery occlusion (MCAO); β amyloid (Aβ); N-methyl-D-aspartate (NMDA); not available (N.A.).


## 3.4.2. Mechanism of Action and Active Principles

(1)
Ferulic acid has been identified to be an active principle because it may reverse memory deficits induced by a variety of toxins, including dl-buthionine-(S,R)-sulfoximine,  trimethyltin, glutamate, Aβ1-42, scopolamine, and cycloheximide.  Multiple mechanisms are probably implicated into its cognitive benefits, including inhibition on oxidative stress, activation of ChAT or enhance the cholinergic activities, competitive N-methyl-D-aspartate (NMDA) receptor antagonism, suppression on immunoreactivities of the astrocyte, and facilitation of cerebral blood flow ([66–70], Table 6(b), Figure 3).(2)
Z-ligustilide has been identified to be another active component from volatile ofRadix Angelica sinensis. It may protect brain and cognition especially against focal and global ischemia induced by permanent common carotid arteries occlusion (CCAO) and transient middle cerebral artery occlusion(MCAO) [71–73], (Table 6(b), Figure 3).(3)
Additionally, N-methyl-beta-carboline-3-carboxamide, Coniferyl ferulate, and 11-angeloylsenkyunolide F were identified to be anti-AD components probably by inhibiting Aβ1-40 induced toxicity and AChE activity ([62, 74], Figure 3).Chemical structures of ferulic acid, Z-ligustilide, N-methyl-beta-carboline-3-carboxamide, coniferyl ferulate, and 11-angeloylsenkyunolide F.
(a)(b)(c)(d)(e)


## 3.5. Radix rehmanniae

Radix rehmanniae is the roots of Rehmannia glutinosaLibosch., family Scrophulariaceae.


### 3.5.1. Functionality/Efficacy

There have been growing evidences thatRadix rehmanniaeextract possesses significant neuroprotective activity ([75, 76], Table 7).Table 7
Memory-improving and neuro-protective effects ofRadix rehmanniae.
TestTest materials/doseTest modelEndpoint/biomarkersEffectsMechanismsReferenceIn vivoExtracts 4.5–9.0 g/kgMSG-treated ratsMorris maze test Step-down test c-fos, NGF  expressionImprove  memoryMotivate  hippocampal c-fos /NGF expression[75]Extracts 4.5–9.0 g/kgMSG-treated ratsMorris maze test Step-down test NMDA-R1,  GABA-R  Glutamine,  GABA levelsImprove   memoryMotivate  hippocampal  NMDA-R1/GABA-R  expression adjust  Glutamine/GABA levels[77]In vitroExtracts 0.1–1.0 mg/mL, 1–3 dC6 glioblastoma cellsGDNF gene  expressionStimulate GDNF expressionUp-regulate  cPKC/ERK1/2  pathways[76]In vivoCatalpol i.p., 10 mg/kg, 10 dLPS-treated miceMMPNF-κBImprove memoryInhibit inflammationInhibit NF-κB activation protect  mitochondrial  function[78]Catalpol 2.5–10 mg/kg, 2 wD-galactose-treated micePassive avoidance  test LDH, GSH-ST,  GS, CKImprove memoryInhibit oxidative  stress  Maintain energy  metabolism[79–81]Catalpol  i.p., 1–10 mg/kgIR-treated  GerbilsBcl-2, Bax, NOProtect CA1 neuronsImprove memoryInhibit apoptosis Inhibit oxidative  stress[82–84]Catalpol i.p., 5 mg/kg, 10 dAged ratsGAP-43/synaptophysin   PKC, BDNFProtect neuroplasticityUp-regulate PKC  and BDNF (hippocampus)[85]In vitroCatalpol 0.5 mM, 1 hMPTP-treated  neuronsCells Viability,  MAO-B, ROS,  MCI, MMP, MPTProtect neuronsProtect  mitochondriaMaintain MAO-B  activity[86]Catalpol 0.5 mM, 30 minAβ1-42-treated  Cortical  neurons-gliaCells Viability TNF-α, iNOS,  NO, ROSProtect neuronsInhibit  inflammation[87]Catalpol 0.25–5 mg/mlPrimary rat cortical  neuronsCells Viability NF-200 antigenEnhance axonal growthNo impact on survivalN.A.[88]Catalpol 0.1–100μg/mlOGD-treated  PC12 cellsBcl-2, caspase-3/MMP  SOD, GSH-PxInhibit apoptosisRetain Bcl-2 and  MMP suppress caspase-3  activation  maintain SOD and  GSH-Px[89]Catalpol 0.1–1.0 mMH2O2-treated   PC12 cellsBcl-2 cytochrome c  caspaseProtect neuronsInhibit apoptosisPrevent  cytochrome c  release Inactivate caspase   cascade[90]Catalpol 0.05–0.5 mMH2O2-treated  astrocytesCells Viability ROSInhibit oxidative stressmaintain glutathione  Scavenge ROS[91]Catalpol 0.3–275.9μM, 24 hOGD-treated mice  astrocytesCell  survival/MMP ROS, NO, iNOS, MDASOD, GSH-Px, GSHProtect  astrocytesInhibit oxidative  stress[92]Nerve growth factor (NGF);oxygen-glucose deprivation (OGD); lactate dehydrogenase (LDH); glutathione S-transferase (GSH-ST); glutamine synthetase (GS); creatine kinase (CK); mitochondrial complex I (MCI);  mitochondrial membrain potential (MMP); mitochondrial permeability transition (MPT); brain-derived neurotrophic factor (BDNF);  γ-amiobutyic acid (GABA); lactate dehydrogenase (LDH); nitric oxide (NO); inducible nitric oxide synthase (iNOS);  nuclear factor-kappa B (NF-κB); protein kinase C (PKC); 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); monosodium glutamate (MSG); lipopolysaccharide (LPS); ischemia-reperfusion (IR); monoamine oxidase (MAO);  tumour necrosis factor (TNF)-α; reactive oxygen species (ROS); superoxide dismutase (SOD); malondialdehyde (MDA); glutathione (GSH); glutathione peroxidase (GSH-Px); glial cell-derived neurotrophic factor (GDNF).


### 3.5.2. Mechanism of Action

Radix rehmanniae extract improved learning and memory in rats with Monosodium-glutamate-(MSG-) injured thalamic arcuate nucleus at 4.5, and 9.0 g/kg, through adjusting glutamates and γ-amiobutyic acid (GABA) levels, as well as increasing the expression of hippocampal c-fos, nerve growth factor(NGF), NMDA receptor 1, and GABA receptor. Moreover, Rehmannia extract stimulated glial cell-derived neurotrophic factor (GDNF) gene expression in C6 glioblastoma cells, through upregulating cPKC and ERK 1/2 pathways ([76, 77], Table 7).


### 3.5.3. Active Components

Catalpol, an iridoid glycoside, was isolated from the freshRadix rehmanniae. It exists broadly in many plants all over the world and has many biological functions such as anti-inflammation, promoting of sex hormones production, protection of liver damage, and reduction of elevated blood sugar.Recently, catalpol has been identified as a vital active with robust cognitive potential (Figure4). Behaviour studies exhibited that catalpol reversed brain damage and memory deficits in mice induced by lipopolysaccharide (LPS) and D-galactose and in gerbils by cerebral ischemia. The nootropic and neuroprotective efficacy of catalpol probably resulted from a variety of underlying molecular mechanisms (Table 7). (i)
Antioxidant activity: catalpol promoted endogenous antioxidant enzyme activities,  superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and antioxidant glutathione (GSH), cut down malondialdehyde (MDA) and reactive oxygen species (ROS) generation in PC12 cells and astrocytes primary cultures, exposed to oxygen and glucose deprivation  or H2O2, and in senescent mice induced by D-galactose [79–81, 86, 89, 91, 92].(ii)
Anti-inflammatory activity: catalpol significantly reduced the release of ROS, TNF-α, nitric oxide (NO) and inducible nitric oxide synthase (iNOS) expression after Aβ (1–42)-induced microglial activation in primary cortical neuron-glia cultures, and LPS-induced nuclear factor-kappa B (NF-κB) activation in mice [78, 87].(iii)
Neurogenetic activity: catalpol can enhance axonal growth of cortical neurons culturedin vitro from 24 h newly born rat, at 1–5 mg/mL and ameliorate age-related presynaptic proteins decline (synaptophysin and GAP-43), and neuroplasticity loss in the hippocampus of the aged rats, by upregulating protein kinase C (PKC) and brain-derived neurotrophic factor (BDNF) [85, 88].(iv)
Antiapoptotic activity: catalpol not only suppressed the downregulation of Bcl-2, upregulation of Bax, and the release of mitochondrial cytochrome c to cytosol, but also attenuated caspase-3 activation, poly-ADP-ribose polymerase (PARP) cleavage, and eventually protected against H2O2-induced apoptosis in PC12 cells and in the ischemic dorsal hippocampus of gerbils subject to CCAO [82–84, 90].(v)
In addition, the function to stimulate the production of adrenal cortical hormones, which increases the production of sex hormones, is likely implicated into the cognitive benefit of catalpol in menopausal women [92].Figure 4
Chemical structure of catalpol.


## 3.5.1. Functionality/Efficacy

There have been growing evidences thatRadix rehmanniaeextract possesses significant neuroprotective activity ([75, 76], Table 7).Table 7
Memory-improving and neuro-protective effects ofRadix rehmanniae.
TestTest materials/doseTest modelEndpoint/biomarkersEffectsMechanismsReferenceIn vivoExtracts 4.5–9.0 g/kgMSG-treated ratsMorris maze test Step-down test c-fos, NGF  expressionImprove  memoryMotivate  hippocampal c-fos /NGF expression[75]Extracts 4.5–9.0 g/kgMSG-treated ratsMorris maze test Step-down test NMDA-R1,  GABA-R  Glutamine,  GABA levelsImprove   memoryMotivate  hippocampal  NMDA-R1/GABA-R  expression adjust  Glutamine/GABA levels[77]In vitroExtracts 0.1–1.0 mg/mL, 1–3 dC6 glioblastoma cellsGDNF gene  expressionStimulate GDNF expressionUp-regulate  cPKC/ERK1/2  pathways[76]In vivoCatalpol i.p., 10 mg/kg, 10 dLPS-treated miceMMPNF-κBImprove memoryInhibit inflammationInhibit NF-κB activation protect  mitochondrial  function[78]Catalpol 2.5–10 mg/kg, 2 wD-galactose-treated micePassive avoidance  test LDH, GSH-ST,  GS, CKImprove memoryInhibit oxidative  stress  Maintain energy  metabolism[79–81]Catalpol  i.p., 1–10 mg/kgIR-treated  GerbilsBcl-2, Bax, NOProtect CA1 neuronsImprove memoryInhibit apoptosis Inhibit oxidative  stress[82–84]Catalpol i.p., 5 mg/kg, 10 dAged ratsGAP-43/synaptophysin   PKC, BDNFProtect neuroplasticityUp-regulate PKC  and BDNF (hippocampus)[85]In vitroCatalpol 0.5 mM, 1 hMPTP-treated  neuronsCells Viability,  MAO-B, ROS,  MCI, MMP, MPTProtect neuronsProtect  mitochondriaMaintain MAO-B  activity[86]Catalpol 0.5 mM, 30 minAβ1-42-treated  Cortical  neurons-gliaCells Viability TNF-α, iNOS,  NO, ROSProtect neuronsInhibit  inflammation[87]Catalpol 0.25–5 mg/mlPrimary rat cortical  neuronsCells Viability NF-200 antigenEnhance axonal growthNo impact on survivalN.A.[88]Catalpol 0.1–100μg/mlOGD-treated  PC12 cellsBcl-2, caspase-3/MMP  SOD, GSH-PxInhibit apoptosisRetain Bcl-2 and  MMP suppress caspase-3  activation  maintain SOD and  GSH-Px[89]Catalpol 0.1–1.0 mMH2O2-treated   PC12 cellsBcl-2 cytochrome c  caspaseProtect neuronsInhibit apoptosisPrevent  cytochrome c  release Inactivate caspase   cascade[90]Catalpol 0.05–0.5 mMH2O2-treated  astrocytesCells Viability ROSInhibit oxidative stressmaintain glutathione  Scavenge ROS[91]Catalpol 0.3–275.9μM, 24 hOGD-treated mice  astrocytesCell  survival/MMP ROS, NO, iNOS, MDASOD, GSH-Px, GSHProtect  astrocytesInhibit oxidative  stress[92]Nerve growth factor (NGF);oxygen-glucose deprivation (OGD); lactate dehydrogenase (LDH); glutathione S-transferase (GSH-ST); glutamine synthetase (GS); creatine kinase (CK); mitochondrial complex I (MCI);  mitochondrial membrain potential (MMP); mitochondrial permeability transition (MPT); brain-derived neurotrophic factor (BDNF);  γ-amiobutyic acid (GABA); lactate dehydrogenase (LDH); nitric oxide (NO); inducible nitric oxide synthase (iNOS);  nuclear factor-kappa B (NF-κB); protein kinase C (PKC); 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); monosodium glutamate (MSG); lipopolysaccharide (LPS); ischemia-reperfusion (IR); monoamine oxidase (MAO);  tumour necrosis factor (TNF)-α; reactive oxygen species (ROS); superoxide dismutase (SOD); malondialdehyde (MDA); glutathione (GSH); glutathione peroxidase (GSH-Px); glial cell-derived neurotrophic factor (GDNF).


## 3.5.2. Mechanism of Action

Radix rehmanniae extract improved learning and memory in rats with Monosodium-glutamate-(MSG-) injured thalamic arcuate nucleus at 4.5, and 9.0 g/kg, through adjusting glutamates and γ-amiobutyic acid (GABA) levels, as well as increasing the expression of hippocampal c-fos, nerve growth factor(NGF), NMDA receptor 1, and GABA receptor. Moreover, Rehmannia extract stimulated glial cell-derived neurotrophic factor (GDNF) gene expression in C6 glioblastoma cells, through upregulating cPKC and ERK 1/2 pathways ([76, 77], Table 7).


## 3.5.3. Active Components

Catalpol, an iridoid glycoside, was isolated from the freshRadix rehmanniae. It exists broadly in many plants all over the world and has many biological functions such as anti-inflammation, promoting of sex hormones production, protection of liver damage, and reduction of elevated blood sugar.Recently, catalpol has been identified as a vital active with robust cognitive potential (Figure4). Behaviour studies exhibited that catalpol reversed brain damage and memory deficits in mice induced by lipopolysaccharide (LPS) and D-galactose and in gerbils by cerebral ischemia. The nootropic and neuroprotective efficacy of catalpol probably resulted from a variety of underlying molecular mechanisms (Table 7). (i)
Antioxidant activity: catalpol promoted endogenous antioxidant enzyme activities,  superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and antioxidant glutathione (GSH), cut down malondialdehyde (MDA) and reactive oxygen species (ROS) generation in PC12 cells and astrocytes primary cultures, exposed to oxygen and glucose deprivation  or H2O2, and in senescent mice induced by D-galactose [79–81, 86, 89, 91, 92].(ii)
Anti-inflammatory activity: catalpol significantly reduced the release of ROS, TNF-α, nitric oxide (NO) and inducible nitric oxide synthase (iNOS) expression after Aβ (1–42)-induced microglial activation in primary cortical neuron-glia cultures, and LPS-induced nuclear factor-kappa B (NF-κB) activation in mice [78, 87].(iii)
Neurogenetic activity: catalpol can enhance axonal growth of cortical neurons culturedin vitro from 24 h newly born rat, at 1–5 mg/mL and ameliorate age-related presynaptic proteins decline (synaptophysin and GAP-43), and neuroplasticity loss in the hippocampus of the aged rats, by upregulating protein kinase C (PKC) and brain-derived neurotrophic factor (BDNF) [85, 88].(iv)
Antiapoptotic activity: catalpol not only suppressed the downregulation of Bcl-2, upregulation of Bax, and the release of mitochondrial cytochrome c to cytosol, but also attenuated caspase-3 activation, poly-ADP-ribose polymerase (PARP) cleavage, and eventually protected against H2O2-induced apoptosis in PC12 cells and in the ischemic dorsal hippocampus of gerbils subject to CCAO [82–84, 90].(v)
In addition, the function to stimulate the production of adrenal cortical hormones, which increases the production of sex hormones, is likely implicated into the cognitive benefit of catalpol in menopausal women [92].Figure 4
Chemical structure of catalpol.


## 4. Discussion and Conclusion

TCM has a long history of human use for mental health. The current literature survey addressing traditional evidence from human studies has been primarily carried out. The top 10 TCM herb ingredients were identified. Poria, thinleaf milkwort, licorice, Chinese Angelica, and Rehmannia were further prioritized to have the highest potential benefit to dementia intervention, due to their highest frequency of use in 236 formulae collected from 29 ancient Pharmacopoeias, ancient formula books, or historical archives on ancient renowned TCM doctors, over the past 10 centuries.In TCM philosophy, AD is assumed to be induced by kidney essence vacuity and toxin (turbid phlegm).  The amnestic mild cognitive impairment in elderly population has been disclosed in a clinical investigation to correlate with kidney essence vacuity and turbid phlegm blocking upper orifices. The whole cognitive function may worsen because of the aggravation of kidney essence vacuity, deficiency of blood andqi, phlegm and heat toxin and may eventually lead to multiple cognitive domains impairment, even dementia [93].Based on the history of use, there is strong clinical support thatRadix polygalaeis memory improving since its efficacy has been demonstrated in elderly with mild cognitive decline [32, 33]. There is suggestive evidence that Poria cocos, Radix glycyrrhizae, Radix Angelica sinensis, or Radix rehmanniaeare memory improving, though modern clinical reports concerning the four herbs are absent yet.Furthermore, pharmacological investigations in 39 animal studies and 18in vitro studies also indicated that the five ingredients can elicit memory-improving effects via multiple mechanisms of action, covering estrogen-like, cholinergic, antioxidant, anti-inflammatory, antiapoptotic, Neurogenetic, and anti-Aβ activities. These mechanisms are in well accordance with modern pharmacotherapy for AD and VD, by prescribing ChEIs, anti-inflammatory mediations, antioxidants, estrogen, neurotrophic factors, and nootropics, depending on difference situations.In the meantime, 11 active molecules have also been identified, including sinapic acid, tenuifolin, isoliquiritigenin, liquiritigenin, glabridin, ferulic acid, Z-ligustilide, N-methyl-beta-carboline-3-carboxamide, coniferyl ferulate and 11-angeloylsenkyunolide F, and catalpol.  Most of them are lipophilic compounds with comparatively low-molecular weight (200 ~ 700) and likely to be absorbed into blood and distributed to brain according to Lipinski rule of 5 [94].  The 11 compounds can serve as active markers for characterisation and standardization of corresponding TCM herbal extracts and pharmacokinetics markers for bioavailability study. In drug discovery, these phyto-chemicals can also be used as candidates to optimize derivatives [95].Taken together, it is concluded that TCM could have a complementary and alternative role in preventing and treating cognitive disorder in the elderly. The scientific evidence is being continuously mined to back up the traditional medical wisdom and product innovation in the healthcare sectors.



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*Source: 692621-2011-07-25.xml*