## 5 Therapeutic Implications of WA in AD
### Role of WA and Its Derivatives
#### 5.1.3 WA Inhibits AChE and BuChE Activities  
The first unsuccessful research that investigated cholinesterase inhibition laid the groundwork for other treatments that were developed based on cholinesterase inhibition [154]. The current treatment of AD comprises drugs such as AChE inhibitors and N-methyl-D-aspartate receptor antagonists [155]. It is important to note that AChE inhibitors only temporarily relieve some of the disease's cognitive symptoms and do not stop the patient's cognitive loss. According to a literature assessment, the efficacy of conventional medications is statistically substantial, but clinical relevance is restricted to disease slowing rather than reversal [156]. In addition, adverse effects such as disorientation, falls, dizziness, and fatigue may occur with these medications and should be used only as recommended [156]. The limited clinical effectiveness of existing AChE inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists has sparked a search for therapeutic approaches that target the causes of neurodegeneration that are closer to the source.  
Within this context, WA exhibited beneficial properties for the prevention of AD. WA has an important role in AD by reversing the reduction in cholinergic markers such as choline acetyltransferase (ChAT) and acetylcholine [28; 150; 151]. In an in vitro assay, the AChE and BuChE enzyme activity was blocked by WA [21]. Based on sub-acute toxicity findings, _Withania sommifera_ extract (containing 4.5% of WA) up to a dose of 2000 mg/kg/day did not cause adverse effects when administered orally [157]. These actions of WA could illustrate the well-known cognition enhancement effects due to preferential activity on cholinergic neurotransmission to the brain areas like the basal and cortical forebrain, which is involved in cognitive function [153; 122]. It is, however, unknown how this effect occurs, although it may be related to the way cholinergic neurotransmission is controlled. The neurotransmitter systems in the brain were monitored after the administration of an extract containing WA. Findings demonstrated that the extract increases cholinesterase activity in the globus pallidus and lateral septum parts of the brain and enhances muscarinic M1 receptor binding in cortical regions. Additionally, WA increased the level of ACh, the amount of choline acetyltransferase (ChAT), and other cholinergic indicators such as choline acetyltransferase (ChAT) in rats [158]. The preferred influence on cholinergic neurotransmission in the cortical and basal forebrain, brain regions that are important in cognitive function, may be able to explain the reported cognition-enhancing benefits of WA. Another advantage of WA is that it has neither effect on GABAA, NMDA, or glutamate receptor subtypes, nor does it interact with benzodiazepine receptors [159]. WA might have future value in the treatment of AD, but additional research is needed to confirm this assumption [98; 158; 159].  
On the other hand, the neuroprotective potential of WA (50 mg/kg b.w.) revealed a recurrence of homo vanmillic acid (HVA) and dopamine (DA) in striatum and substantia nigra. Reduction of these catecholamines results in motor deficits. The neuroprotective potential of WA is also indicated by the elevated level of DA and HVA in the treatment of AD [21]. Within this context, a powerful neurotoxicant, bbotenic acid, has been used to study the effect of brain lesions. When it is injected into the brains of rats, mice, or monkeys, it results in reflective destruction of the basal cholinergic neurons of the forebrain. Recent studies showed that WA and sitoindsides significantly reverse ibotenic acid-induced cognitive impairment in an AD model [15; 17; 28; 152; 160; 161].