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Current Neuropharmacology, 2015, 13, 776-785

Eicosanoids Derived From Arachidonic Acid and Their
Prostaglandins and Cyclooxygenase in Psychiatric Disorders

FamilyKunio Yui1,*, George Imataka2, Hiroyuki Nakamura3, Naoki Ohara4 and Yukiko Naito5
1

Research Institute of Pervasive Developmental Disorders, Ashiya University Graduate School of
Education. Rokurokusocho 13-22, Ashiya 659-8511, Hyogo, Japan; 2Department of Pediatrics,
Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Mibu, 321-0293, Tochigi, Japan;
3
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba
University, Chiba 260-8675, Japan; 4School of Pharmacy, Kinjo Gakuin University, Nagoya, 4638521, Japan; 5Department of Genomic Medicine, National Cerebral and Cardiovascular Center.
Osaka 565-8565, JapanK. Yui
Abstract: Arachidonic acid (AA)-derived lipid mediators are called eicosanoids. Eicosanoids haveemerged as key regulators of a wide variety of physiological responses and pathological processes,
and control important cellular processes. AA can be converted into biologically active compounds by metabolism by
cyclooxygenases (COX). Beneficial effect of COX-2 inhibitor celecoxib add-on therapy has been reported in early stageof schizophrenia. Moreover, add-on treatment of celecoxib attenuated refractory depression and bipolar depression.
Further, the COX/prostaglandin E pathway play an important role in synaptic plasticity and may be included inpathophysiology in autism spectrum disorders (ASD). In this regard, plasma transferrin, which is an iron mediator related
to eicosanoid signaling, may be related to social impairment of ASD. COX-2 is typically induced by inflammatory stimuli
in the majority of tissues, and the only isoform responsible for propagating the inflammatory response. Thus, COX-2
inhibitors considered as the best target for Alzheimer’s disease.

Keywords: Alzheimer’s disease, arachidonic acid, autism spectrum disorder, cyclooxygenases-1 inhibitors, cyclooxygenases-2
inhibitors, depression, eicosanoids, schizophrenia.
1. INTRODUCTION
Arachidonic acid (AA) is an abundant polyunsaturated
fatty acid of the membrane phospholipids, where it isstored in the sn-2 position of phosphatidylinositol and/or
phosphatidylcholine [1]. AA-derived eicosanoids belong to acomplex family of lipid signaling mediators that regulate awide variety of physiological responses and pathologicalprocesses [2], and control important cellular processes,
including cell proliferation, apoptosis, metabolism andmigration [3]. Eicosanoids perform numerous regulatory
functions in the brain and throughout the rest of the body, inparticular for the regulation of immune and inflammatory
responses [4]. In addition, eicosanoids play a role in regulating
mainly immunopathological processes of inflammatory responses
and chronic tissue remodeling [5]. Eicosanoid biosynthesis is
usually initiated by the activation of phospholipase A2(PLA2) from membrane phospholipids in mammalian cells[5] (Fig. 1). There are four families of eicosanoids—theprostaglandins (PG), prostacyclins (PGI), the thromboxanes(TX) and the leukotrienes (LT) [3]. The AA is transformedby cyclooxygenase (COX) and lipoxygenase (LO) pathways toprostaglandins, thromboxane and leukotriene [6]. AA-derived*Address correspondence to this author at the Research Institute ofPervasive Developmental Disorders, Ashiya University Graduate School of
Education. Rokurokusocho 13-22, Ashiya 659-8511, Hyogo, Japan;
Tel: +81 78 791 8981; Fax: +81 797 23 1901;
E-mail: yui16@bell.ocn.ne.jp
1570-159X/15 $58.00+.00

eicosanoids from COX and lipoxygenases are important lipid
mediators involved in numerous homeostatic and pathophysiological processes [7], including neurodegenerative andneuropsychiatric conditions [8-10] such as schizophrenia[11], autism spectrum disorders (ASD) [12], refractory major
depression [13] and Alzheimer’s disease (AD) [14, 15].
COX-2 induction and resultant prostaglandin synthesis areoften implicated in neurodegeneration [16]. The brain
is known to be sensitive to oxidative stress and lipid
peroxidation. Lipid peroxidation has been shown tocontribute to pathophysiology of many psychiatric disease
including neurodegenerative disorders [17] and autism
spectrum disorder (ASD) [18, 19]. In this regard, PLA2
activation induced by oxidative stress contributes tocognitive impairment, neuronal dysfunction and disease [20]and neurodegenerative diseases [21].
Among prostaglandins, prostaglandin E (PGE) has closely
related to Wnt signaling, which regulates crucial aspects ofcell fate determination, cell migration, cell polarity, neuralpatterning and organogenesis during embryonic development[22] in prenatal development of the nervous systems [23],and a predictive biomarker in ASD [24]. Moreover,
PLA2 activity may play a crucial role in neurodegeneration
and also be essential in prevention of neuropsychiatricdiseases [25]. Additionally, animal studies reported that
PLA2-related signaling pathway mediated long-term
potentiation induction [26].

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Eicosanoids Derived From Arachidonic Acid and Their Family

Current Neuropharmacology, 2015, Vol. 13, No. 6

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2.2. The Relationship between Phospholipase A2 andSchizophrenia
Neurotransmitter systems of schizophrenia weremodulated by the activation of PLA2 [33]. PLA2 enzyme
activities and in vivo brain membrane breakdown specific toschizophrenia are biological processes mediated by three
PLA2 isomers such as PLA2G6A, PLA2G4A and PLA2G2A[33]. These three PLA2 enzymes lie downstream of activationof neurotransmitter pathways implicated in schizophrenia,
such as dopaminergic, serotoninergic or glutamatergic systems[33].

Fig. (1). Synthesis pathways for eicosanoids from arachidonic acid
(Harizi et al., 2008. [5] ). Arachidonic acid (AA) is released frommembrane phopholipids by phospholipases, especially cytosolic
phospholipase A2 (cPLA2). The AA is transformed by cyclooxygenase(COX) and lipoxygenase (LO) pathways to prostaglandins, thromboxane
and leukotriene. This review addressed the role of COX, andprostaglandins and PGE2.

Eicosanoids families are modulated by neuroglia such as
microglia and astrocyte. Eicosanoids are produced by
microglia [27]. Microglia are a type of glial cell that are theresident macrophages of the brain and spinal cord, and thus
act as the first and main form of have active immune defensein the central nervous system. PGE synthesis may be related
to activation of microglia [28]. Microglia are a major sourceof PGE2 production through the COX-2 pathway [29]. PLA2
enhances PG synthesis via increased availability of AA, thethrough the COX pathway in astrocyte [30]. Astrocytes in
the hypothalamus release PGE2 in response to cell–cellsignaling initiated by neurons and glial cells in human brain[31]. PGD2 mediates microglia/astrocyte interaction [32].
The perspective provided in this review addressed the roleof COX in neuropsychiatric disorders such as schizophrenia,
major depression, ASD and Alzheimer disease.
2. THE ROLE OF AA-DERIVED EICOSANOIDS IN
NRURONAL FUNCTION AND DISEASE
2.1. The Role of Eicosanoids in Neuronal Systems
Downstream targets of the activity of a key set of lipidmodifying enzymes, such as prostaglandin synthase,
constitute a complex lipid signaling network with multiple
nodes of interaction and cross-regulation. Imbalances in thisnetwork contribute to the pathogenesis of human diseases
including psychiatric disorders [3].

A previous study on the efficacy of PLA2 in schizophrenia
revealed that baseline intracellular PLA2 activity wassignificantly increased in 35 young drug-naïve and treatedfirst episode patients as compared to 22 healthy controls.
Baseline intracellular PLA2 activity was also associated withseverity of negative symptoms and lower functioning atbaseline [34]. Furthermore, baseline intracellular PLA2
activity was associated with improvement in negative
symptoms and functioning within the first 12 weeks oftreatment with second-generation antipsychotics [34]. Thus,
intracellular PLA2 activity has been considered as a potential
predictor of treatment response for different antipsychotic
agents [34].
2.3. Efficacy of COX Inhibitors in Psychiatric Disorders
COX is the key enzyme that converts AA to PG play animportant role in the nervous system via production ofdownstream signalling molecules such PGE [12]. COX-2/
PG2 pathway play an important function in synaptic
plasticity and refining of mature neuronal connections [12].
Altered COX-2 levels have been found in psychiatricdisorders [12]. COX inhibitors are known to influence theimmune system in a way that may redirect imbalance of thissystem [35] and might have additive or even synergistic
neuroprotectant effect [28]. Thus, COX inhibitors havetherapeutic potential for schizophrenia [36, 37].
2.3.1. Efficacy of COX-inhibitors in Schizophrenia
Increasing evidence from clinical research studies on
COX-2 inhibitors points to an advantageous effect of add-on
therapy to atypical antipsychotic neuroleptics in schizophrenia,
especially in the early stages of the disease [38] through theireffects in reducing PGE2, type-2 cytokine and kynurenic
acid production and strengthening glutamatergic neurotransmission [39]. In previous clinical study, COX-2 inhibitor
such as celecoxib in addition to amisulpiride, which is atypicalantipsychotic, induced a significantly better outcome in the
25 patients with schizophrenia (mean age ± SD: 26.2 ± 7.7
years) compared to 25 patients (mean age ± SD: 30.9 ± 8.1
years) treated with amisulpride plus placebo [36]. Particularly,
a significantly superior therapeutic effect was observed innegative symptoms in the celecoxib plus amisulpride group[36]. Update, five clinical studies reported efficacy of
COX-2 inhibitor such as celecoxib in schizophrenia. Table 1
summarized these double-blind randomized-placebocontrolled trials. Taking a view of these clinical studies,celecoxib has been reported to be effective add-on treatment
to atypical neuroleptics such as risperidone and amisluiride

778 Current Neuropharmacology, 2015, Vol. 13, No. 6

Table 1.

Yui et al.

Summaries of findings of clinical trial of celecoxib.

Design	  Treatment, Subject Characteristics	
  Duration	
  Efficacy	
  Interlukin	
  References

RCT	
  

celecoxib + risperidone (2-6 mg/day) or
placebo (n=25)
Acute exacerbation	  5 weeks	  PANSS, significant group effect	  Soluble IL-2
no significant
different	  Muller(n=25) et al.,
2004

RCT	
  

celecoxib + risperidone (3.0 mg/day) (n=25) orplacebo (n=25) out patients with chizophrenia	
  8 weeks	  PANSS, no significant group effects	
  

NA	
  

Rapaport etal., 2004RCT	
  celecoxib (400 mg/day+risperidone(2-6 mg/day) (n=25) or placebo (n=25)
Acute exacerbation	  5 weeks	  PANSS, significant effect on cognition	
  

NA	
  

Muller et al.,
2005

RCT	
  

celecoxib (400mg) + risperidone (6 mg)(n=30) or placebo (n=30) Chronic	  8 weeks	  PANSS-positive symptoms and general
psycho-psychopathology, significant effect.	
  

NA	
  

Akhondzadeh
et al., 2007

RCT	
  

celecoxib (400 mg) + amisulporide
amisulporide (200-1000mg or placebo (n=30)
Chronic	
  8 weeks	  PANSS-negative symptoms and general
psycho-psychopathology, significant effect 	
  

NA	
  

Muller et al.,2010

RCT: Randomized Controlled Trial; PANSS: Positive and Negative Syndrome Scale; NA: no available.

for 5-8 weeks in patients with acute exacerbation [40, 41]
or chronic schizophrenia [36, 42] (Table 1). Whereas,
another double-blind placebo-controlled trial did not find
improvement of celecoxib (400 mg/day for 8 weeks) add-on
atypical neuroleptics such as risperidone (3.0 mg/day) orolanzapine (12.6 mg/day) in 18 outpatients with schizophrenia[43]. In this regard, a recent review article commented that
results on efficacy of colecoxib in schizophrenia were very
heterogeneous, ranging from negative to strong positiveeffects [44]. The treatment cohorts did not differ on any
clinical outcome measures. Review of the data of theprevious add-on therapy [36, 40-42] suggests that thepsychopathology ratings for the celecoxib augmentationgroup and placebo group were converging with time.
Celecoxib augmentation might potentiate the speed of
response but not the overall magnitude of response [43].
Future studies are necessary to elucidate the relationshipbetween doses and treatment periods of atypical neuroleptics
and the augmentation effects using a large sample size.
2.3.2. Mechanisms of Action of COX-2 Inhibitors in
Schizophrenia
The main mechanism of action underlying the efficacy of
COX-2 inhibitors in schizophrenia is inhibiting conversion
of AA into active prostanoids such as PGE2, prostatanoids
D2, prostatanoids 12 and others [45]. Increases or
imbalances in cytokines may be related to produce
vulnerability to schizophrenia [46]. Thus, cytokine modulation
may offer the promise of tailored psychopharmacologic
intervention based on individual peripheral and central
neuroimmune biomarker profiles [47] (Table 2). Therapeutic
effects of COX-2 inhibitors may depend on reducing PGE2,
type-2 cytokine and kynurenic acid production andstrengthening
glutamatergic
neurotransmission[39].
Moreovrer, the immunological imbalance in an inflammatory
state combined with increased PLA2 production andincreased COX-2 expression may be involved in themechanisms of action of COX-2 inhibitors [48]. The
immune response in schizophrenia is confounded by factors
partly disease-inherent such as disease duration, chronicity,
prevailing symptoms and response to medical treatment [36].
Whereas, another study reported that celecoxib (400 mg/day)
add-on treatment to risperidone (mean dose, 3.6 mg/day) orolanzapine (mean dose, 15.0 mg/day) for 8 weeks did notalter any of the cytokine parameters such as IL-6 and TNF-α
in 14 patients with schizophrenia compared to 14 normal
healthy controls [49]. The relationship between the long
duration of disease, treatment resistance and higher IL-6
levels may be related to different immune response possibly
linking place in different stages of diseases [36]. In thisregard, the blunted type-1 response, which promotes the cellmediated immune directly against intracellular pathogens, isfound primarily in early stages of schizophrenia. While,in later stages of disease, an autoimmune process might
additionally play a role in immune function [36]. The
findings of the previous many studies shown in Table 2
suggest that schizophrenia is associated with a systemic
imbalance in the plasma or serum levels of pro-inflammatory/
anti-inflammatory prostaglandins in favor of former [50].
2.4. The Efficacy of COX-2 Inhibitors in Major
Depression, Bipolar Depression and Refractory Major
Depression
2.4.1. Summaries of the Efficacy of COX-2 Inhibitors in
Major Depression
There are two review articles on the efficacy of COX-2
inhibitors or non-selective COX inhibitors. Five randomized
controlled trials (four unipolar depression studies and one
bipolar depression study) has reported that the add-on
celecoxib treatment had a statistically significant decrease inmeans of the Hamilton Depression Rating Scale score atweek 4 and week 6. The add-on celecoxib treatment also
showed higher remission rates compared with the placebogroup [51]. Thus, celecoxib can be considered as an effective

Eicosanoids Derived From Arachidonic Acid and Their Family

Table 2.

Current Neuropharmacology, 2015, Vol. 13, No. 6

779

Biomarkers of treatment with COX-2 inhibitors in schizophrenia.
Subjects Characteristics

Results of Biomarkers

Chronic schizophrenia (n = 25)
Healthy normal controls (n = 25)

Plasma levels of IL-2: significantly increased
Plasma levels of IL-6: no significantly
Correlated to SANS and duration of illness

Kim et al.
2000

Paranoid schizophrenia (n = 24)
Healthy normal controls (n = 24)

Serum levels of cytokines (IL-6, IL-8 and IFN-γ): significantly increased
Serum levels of IL-2, IL-4 and IFN-α: no significant changesKamińska
et al., 2001

Schizophrenia (n = 2298)
Healthy controls (n = 1858)
A research of computerized
Literature databases
PubMed and EMBASE

Periopheral levels of IL-IRA, sIL-2R and IL-6: significantly increased
Periopheral levels of IL-2: significantly deceased
Periopheral levels of IFN-γ, IL-4, IL-1RA, IL-2,
soluble IL-2receptor and IL-β: no significant changes

Potvinet al., 2008

Schizophrenia (n = 28)
Colecoxi 400 mg/day vs. olanzapine

No alterations of blood TNF-alpha and IL-2 levels

Breseeet al., 2006

SANS: The Scale for the Assessment of Negative Symptoms. IL-2, IL-6 and IFN-γ are known as cytokines.

add-on treatment for unipolar depressive patients [51].
While, a current review article has reported that the efficacy
of COX-2 and non-selective COX inhibitors on depressive
symptoms appears to be inconsistent [52]. According to thisreview article, 4 of a total of 6 randomized controlled trials
showed a significant effect of COX-2 inhibitors [52]. In
addition, in a total of 5 studies exploring the efficacy of nonselective COX inhibitor, the randomized controlled trials
failed to show a significant result [52]. Among the 3 cohort
studies, one showed a positive result and the other 2 showedno effect [52]. With regard to these inconsistent findings,
significant methodological heterogeneity (i.e. age range, sex,
presence of antidepressant use, method of depression
measure, severity of depressive symptoms, duration andstudy design (randomized controlled trial vs. cohort) has
been suggested. Further high quality research is needed to
explore the effects of COX-2 inhibitors and non-selective
COX inhibitors as monotherapy or add-on treatment tovarious antidepressants [52].
2.4.2. The Efficacy of COX-2 Inhibitors in Refractory
Major Depression
It is well known that number of patients with major
depression do not respond adequately to current antidepressant
pharmacological treatments [53]. Recent studies suggested
that inflammatory processes may contribute to pathophysiological processes, since increased levels of proinflammatory cytokines and PGE2 have been found in a
subset of patients with major depression [53]. In this regard,
add-on treatment with COX-2 inhibitors enhance theefficacy of both reboxetine and fluoxetine in treatmentresistant depression. A previous study examined the acuteeffects of a combined treatment with celecoxib and reboxetineand fluoxetine on noradrenaline, dopamine and 5-HT output
in the medial prefrontal cortex in rats [53]. Acute effects of a
combined treatment with celecoxib significantly potentiatedthe efficacy of reboxetine and fluoxetine on increases incortical noradrenaline and 5-HT output [53]. Thus, theclinical utility of combined treatment with antidepressants inrefractory depression may be evident [53]. A previous study

reported the case of an elderly depressed woman with acutecognitive deficit who was refractory to multiple antidepressantsbut only responsive to celecoxib in acute treatment andsustaining remission for a 5-year treatment course [54].
Depressed patients showed lower production of cytokine
responses, indicating that their immune cells are in arefractory phase, induced by a pre-existing pro-inflammatory
state [55]. Thus, a drug effect could only be shown for
imipramine and celecoxib, which were beneficial in terms of
re-balancing the immune function [55].
While, in another previous clinical study in 1,245
individuals (mean ± SD age, 53 ± 15.3 years old) who
remained depressed despite two or more antidepressanttreatments, treatment outcomes with anti-inflammatory drugs(e.g., cytokines) was associated with a greater likelihood ofdepression classified as treatment resistant depression [56].
This association was apparent in the anti-inflammatory druggroup but not in those using other agents with NSAID-likemechanisms such as COX-2 inhibitors [56]. With regard tono effects of COX-2 inhibitors, the authors suggested thatgeneral medical comorbidity and painful symptoms seems tobe associated with poorer outcomes [56].
2.4.3. The Efficacy of COX -2 Inhibitors in Bipolar
Depression
There are few studies on clinical effects of COX-2
inhibitors in bipolar depression. A previous double-blind
placebo-controlled trial examined efficacy of celecoxib (400
mg/day) for 6 weeks in 28 patient with DSM-IV bipolar
depression 1 and II [57]. In this trial, 28 patients were
included if they were experiencing a major depression or
mixed episode, with a Hamilton score > 18 and if they had
previously been on therapeutic and regular doses of a moodstabilizer or atypical antipsychotic for at least 1 month [57].
The 14 celecoxib treated patients (mean ± SD age, 42.3 ±10.4 years old) showed significant decreased score in the
Hamilton Depression Rating Scale in the first week oftreatment as compared to 14 placebo-controlled patients(mean ± SD age, 41.1 ± 9.5 years old). The two groups did
not differ significantly on depressive or manic symptoms at

780 Current Neuropharmacology, 2015, Vol. 13, No. 6

any later week [57]. These findings suggest that adjunctive
treatment with celecoxib may produce a rapid-onset
antidepressant effect in patients with bipolar depression [57].
A previous systemic review of the literature summarized
the effects of COX-2 inhibitors on bipolar depression basedon articles published from 1950 to April 2008 [58] reported
that celecoxib may offer antidepressant effects because
inflammation is closely linked with behavioral parameterssuch as exercise, sleep, alcohol abuse, and smoking, as wellas with medical comorbidities including coronary arterydisease, obesity and insulin resistance, osteoporosis, and pain[58]. However, methodological limitations precluding definitive
conclusions are heterogeneity in sample composition, cytokine
assessment procedures, and treatment regimens [58].
2.5. Eicosanoids in Alzheimer’s Disease
2.5.1. The Role of COX in Alzheimer’s Disease
AD is a neurodegenerative disorder characterized by aprogressive decline of memory and cognition. The subtlety
and variability of the earliest amnestic symptoms, occurringin the absence of any other clinical signs of brain injury,
suggest that something is discretely, perhaps intermittently,interrupts the function of synapses that help encode new
declarative memories [59]. Although the most common formof dementia, characterized by the excessive accumulation ofamyloid-β peptide leads to neurofibrillary tangles composedof aggregated hyperphosphorylated tau, several epidemiologicaland preclinical studies indicated the pathological role of
COX based on the neuroinflammation theory. In this regard,
elevated levels of several proinflammatory factors including
cytokines and peroxidants in the central nervous system havebeen detected in patients with AD [60]. These proinflammatory
factors act as potent stimuli in brain inflammation throughupregulation of cytosolic PLA2 and COX-2 [60]. Moreover,the mechanisms underlying the intracellular signaling
pathways may be involved in the expression of several
inflammatory proteins induced by proinflammatory factors
in AD [60].
In an early stage of AD pathology, when low-fibrillar
Abeta deposits are present and only very few neurofibrillarytangles are observed in the cortical areas, COX-2 expression
is increased in neurons. COX-1 is primarily expressed in
microglia, and associated with fibrillar Abeta deposits. Thus,
COX-1 and COX-2 are involved in inflammatory andregenerating pathways respectively in AD pathology [61]2.5.2. Efficacy of COX-2 and COX-1 Inhibitors in
Alzheimer’s Disease
Because COX-2 is typically induced by inflammatory
stimuli in the majority of tissues, it was thought to be theonly isoform responsible for propagating the inflammatory
response and thus, considered as the best target for antiinflammatory drugs [62]. In this regard, deficits in spatial
working memory in female but not male mice wereabolished by COX-2 inhibitor celecoxib with alteration ofAβpeptides [63]. Another animal study found that COX-2
inhibitor NS-398 protected memory deficit in mice [64].
According to another animal study, COX-2 inhibitors suchas rofecoxib (5 and 10 mg/kg, ip) or valdecoxib (5 and 10

Yui et al.

mg/kg, ip) improved memory deficit [65]. With regard toclinical effects of COX-2 inhibitor, a 52-week, multicenter,randomized, double-blind, placebo-controlled, parallel-groupstudy in patients aged 50 years or older reported that at the
final 52 weeks, change in Assesment Scale-Cognitive
Behavior scores from baseline was not significantly different
between placebo and celecoxib 200 mg treated groups (5.00
and 4.39, respectively) [66]. According to a randomized,
double-blind, multicenter clinical trial of naproxen orcelecoxib vs placebo (1:1:1.5 assignment ratio), which
conducted between 2001 and 2004 at six U.S.-based clinics in2528 people with age of 70 years or older, there was no
significant effects of celecoxib treatment in these elder
patients with AD [67]. In similar line of evidence, according
to a double-blinded, multicenter trial in 692 patients withmild or moderate AD aged 50 years or older treated with 25
mg/day COX-2 inhibitor rofecoxib or placebo for 12 months,
there is no significant improvement in the rofecoxib
treatment group compared with placebo control group [68]. In
another double-blind study to investigate whether rofecoxib
could delay a diagnosis of AD in patients with mild
cognitive impairment aged 65 years or older, rofecoxib 25
mg/day (n = 725) or placebo (n = 732) were treated for up to
4 years [69]. This study did not demonstrate differences
between treatment groups. This study reported no consistentevidence that rofecoxib differed from placebo in post hoc
analyses comparing the AD assessment scales [69]. Thus,
this study did not support the hypothesis that rofecoxib
would delay a diagnosis of AD [69]. In conjunction with thelack of effects observed in previous AD studies, the findings
suggest that inhibition of COX-2 is not a useful therapeutic
approach in AD [69]. Drawing these strands together, COX2 inhibitors improved memory deficits in animal model ofAD, however, several clinical studies did not support the
hypothesis that celecoxib prevent progress of adult AD
patients. Further precise clinical trial will be needed to study
the clinical effects of COX-2 inhibitors.
In regard to efficacy of COX-1 inhibitors, animal studies
reported preferential effects of COX-1inhibitors, rather than
COX-2 inhibitors [70, 71]. Mice with the lateral ventricle of
COX-1-deficient (COX-1(-/-)) induced by injection withbeta-amyloid (Abeta(1-42)) exhibited neurodegenerationcompared to their wild-type (WT) mice, indicating that
inhibition of COX-1 activity may be valid therapeutic strategy
to reduce brain inflammatory response and neurodegeneration[70]. Similarly, triple transgenic AD (3 × Tg-AD) micetreated with the COX-1 selective inhibitor SC-560 improved
spatial learning and memory, and reduced amyloid deposits
and tau hyperphosphorylation [71]. These findings may
demonstrate that selective COX-1 inhibition reduces
neuroinflammation and neuropathology, and improvescognitive function in 3 × Tg-AD mice [71]. Thus, selective
COX-1 inhibition might be a potential therapeutic approachfor AD. However, there is few clinical trial with COX-1
inhibitors. Further clinical trials will be needed todemonstrate the efficacy of COX-1 inhibitors in AD.
2.5.3. Differences in Action between COX-1 and COX-2
Inhibitors in Alzheimer’s Disease
The expression levels of COX-1 and COX-2 change inthe different stages of AD pathology. In an early stage,

Eicosanoids Derived From Arachidonic Acid and Their Family

COX-2 is increased in neurons with increased neuronal
COX-2 expression and with the expression of cell cycle
proteins [61]. COX-2 is found in post synaptic dendrites andexcitatory terminals, particularly in the cortex, hippocampus
and amygdala, with both neuronal and vascular associations[62]. Moreover, COX-2 has a compartmental distribution insomatosensory cortical neurons consistent with the local
neuronal synthesis of prostanoids that are involved inneurovascular coupling [72]. While, COX-1 plays antiinflammatory role [73] and primarily expressed in microglia[61]. Thus, COX-1 and COX-2 play each role in the different
stages of AD pathology [61]. Because COX-2 is typicallyinduced by inflammatory stimuli in the majority of tissues, it
was thought to be the only isoform responsible forpropagating the inflammatory response and thus, consideredas the best target for anti-inflammatory drugs [62].
2.6. Eicosanoids in Autism Spectrum Disorders
2.6.1. The Role of Eicosanoids in Autism Spectrum
Disorders
The COX/PEG2 pathway play an important role in synaptic
plasticity and also may be included in pathophysiology of
ASD [12]. Accumulating evidence indicated that PGE2
signalling interacts with another crucial developmental pathway
such as the Wnt (ewingless-related MMTV integration site)
signalling pathway [74]. The Wnt signalling also regulates
neuronal connectivity by controlling axon pathfinding, axon
remodelling, dendrite morphogenesis and synapse formation[75]. The canonical Wnt signaling pathway is composed of a
network of proteins that modify cell communication andinteraction with other cells [76]. The Wnt signaling pathway
therefore may be implicated for development of ASD [76].
In most previous studies, changes in families of eicosanoids
have reported alterations in antioxidant status in ASD patients[77, 78]. According to a previous study in 44 ASD children
aged 3.5-12 years and 44 age-matched healthy matchedchildren, elevated plasma F2-isoprostane, which is significant
risk for antineuronal positivity, was found in 54.5% of ASD
children [77]. Families of eicosanoids such as PGE2,
leukotrienes and isoprostanes have been reported to besignificantly elevated levels in 20 male ASD compared to 19
age and gender-matched controls [78]. Thus, pathophysiology
of ASD may be related to eicosanoid regulation [78].
2.6.2. Eicosanoids and AA-Derived Signaling Mediators inAutism Spectrum disorders: Ceruloplasmin
In most previous ASD studies, changes in bloodeicosanoid families such as superoxide dismutase (SOD),
transferrin (Tf) and ceruloplasmin (Cp) levels indicatedalterations in antioxidant status [79-81], vulnerability tooxidative stress [82, 83], and copper dyshomeostasis [84, 85]
in ASD patients. It was known that iron and copper canmodulates the synthesizing and catabolism of prostaglandins[86]. Furthermore, copper [87] and iron [88] mediators areclosely related to AA-derived eicosanoid signaling mediators[89]. In this regard, ceruloplasmin (Cp) is a major coppertransport protein in plasma in relation to neurodegenerative
conditions, including Alzheimer's disease [90]. Copper
supplementation (gycinat, 2 mg/day for 8 weeks) produced a
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781

isoprostanes in young adult women [91]. Superoxide
dismutase (SOD), which is a biomarker of copper status thatplays a role in signaling [92], play a role in controlling
prostaglandin F2 alpha [93]. Further, transferrin (Tf), which
carries iron throughout the systemic circulation of tissues[94], may relate to alteration of eicosanoid metabolism [95].
Tf has been reported to have association with COX-2 in livercancer [96], and COX2 invasion via NF-KB signaling [97].
It is therefore suggested that plasma Tf may be related toeicosanoid signaling. In this regard, a previous 16-weekdouble-blind, randomized placebo-controlled trial examined
the role of eicosanoid families estimated the efficacy of
supplementation with larger doses of ARA (240 mg/day)
added to DHA (240 mg/day) in individuals with ASD (n = 7)
(mean age = 14.6 ± 5.9 years) [98]. In this study, plasma
Tf levels in the 7 individuals with ASD treated with this
supplementation were significantly increased comparted to 6
placebo treated controls [98]. There was also a trend towards
significant difference (P = 0.08) in the change in plasma
SOD levels [98]. The supplementation significantly improved
the Aberrant Behavior Checklist-measured social withdrawal
and the Social Responsiveness Scale-measured communication.
Considering that mutual relationship between SOD and Tf
acts as a mediator in signaling pathways [99], these findings
regarding the plasma levels of TF, as well as SOD, suggestthat signal transduction was upregulated in the ARA plus
DHA supplementation group. Collectively, improvement ofsocial impairment induced by supplementation with larger
doses of ARA added to DHA may be related to upregulationof signal transduction [98].
SUMMARY
AA-derived eicosanoids belong to a complex family of
lipid signaling mediators that regulate a wide variety ofphysiological responses and pathological processes, and control
important cellular processes, including cell proliferation,
apoptosis, metabolism and migration. Moreover, eicosanoids
perform numerous regulatory functions in the brain andthroughout the rest of the body. AA can be converted into
biologically active compounds by COX. The COX pathway
are important lipid mediators involved in numerous homeostaticand pathophysiological processes, including neuropsychiatricconditions such as schizophrenia. Celecoxib, a selective
COX-2 inhibitor, has been known to have antipsychotic
effects in patients with schizophrenia. The main mechanismof action the efficacy of COX-2 inhibitors in early stage ofschizophrenia is inhibiting conversion of AA into active
prostatanoids such as PLE2, prostatanoids D2, prostatanoids
12 and others. This review summarized beneficial antipsychotic
effects of celecoxib add-on therapy compared to atypicalantipsychotics such as risperidone or amisulporide. Celecoxib
can be considered as an effective add-on treatment for refractory
major depression and bipolar depression. The COX/PEG2
pathway an important role in synaptic plasticity and may be
included in pathophysiology of ain ASD. In this regard,
plasma Tf, which is an iron mediator related to eicosanoid
signaling, may be related to social impairment of ASD.
COX-1 and COX-2 are involved in inflammatory andregenerating pathways respectively in AD pathology. COX-1
is typically induced by inflammatory stimuli in the majority

782 Current Neuropharmacology, 2015, Vol. 13, No. 6

of tissues, and the only isoform responsible for propagating
the inflammatory response and thus, considered as the best
target for AD. However, animal model studies and a few
clinical trials demonstrated efficacy of COX-2 inhibitors,
further precise clinical studies on efficacy of inhibitors of
COX-2 as well as COX-1 are needed to show definitive
efficacy of these inhibitors

Yui et al.
[13]

[14]

[15]

CONFICT OF INTEREST
The authors confirm that this article had no conflict ofinterest.

[16]

ACKNOWLEDGMENTS
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas (Grant No 21200017) (20092012) and a Grant-in-Aid For Scientific Research C (20142017) from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.

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Revised: February 25, 2015

Accepted: February 25, 2015