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Altered arachidonic acid cascade enzymes in postmortem brain from bipolar disorder patients

Molecular Psychiatry volume 16, pages 419–428 (2011)Cite this article

Subjects

Abstract

Mood stabilizers that are approved for treating bipolar disorder (BD), when given chronically to rats, decrease expression of markers of the brain arachidonic metabolic cascade, and reduce excitotoxicity and neuroinflammation-induced upregulation of these markers. These observations, plus evidence for neuroinflammation and excitotoxicity in BD, suggest that arachidonic acid (AA) cascade markers are upregulated in the BD brain. To test this hypothesis, these markers were measured in postmortem frontal cortex from 10 BD patients and 10 age-matched controls. Mean protein and mRNA levels of AA-selective cytosolic phospholipase A2 (cPLA2) IVA, secretory sPLA2 IIA, cyclooxygenase (COX)-2 and membrane prostaglandin E synthase (mPGES) were significantly elevated in the BD cortex. Levels of COX-1 and cytosolic PGES (cPGES) were significantly reduced relative to controls, whereas Ca2+-independent iPLA2VIA, 5-, 12-, and 15-lipoxygenase, thromboxane synthase and cytochrome p450 epoxygenase protein and mRNA levels were not significantly different. These results confirm that the brain AA cascade is disturbed in BD, and that certain enzymes associated with AA release from membrane phospholipid and with its downstream metabolism are upregulated. As mood stabilizers downregulate many of these brain enzymes in animal models, their clinical efficacy may depend on suppressing a pathologically upregulated cascade in BD. An upregulated cascade should be considered as a target for drug development and for neuroimaging in BD.

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Introduction

Bipolar disorder (BD) is characterized by recurrent depressive and manic episodes. It afflicts about 1.5% of the US population,1 increases the risk of suicide approximately 5- to 17-fold,2 and has multiple risk alleles consistent with a polygenic inheritance.3 Recent studies suggest progressive brain atrophy and neuronal loss in BD patients, with increased brain levels of proinflammatory cytokines, and increased glutamatergic function and excitotoxicity.4, 5, 6 Some of these features are also found in psychiatric and neurodegenerative diseases including schizophrenia and Alzheimer's disease (AD). However, patients with BD have many more features that overlap with those of schizophrenic patients,7, 8 than with AD patients,9, 10 such as an early-onset, genetic association and drug therapy.

Inflammation and excitotoxicity can activate many brain signaling pathways, including the arachidonic acid (AA, 20:4n-6) metabolic cascade.11, 12, 13 For example, activation of the interleukin (IL)-1 receptor cascade can increase expression of AA metabolizing enzymes, including AA-selective cytosolic phospholipase A2 (cPLA2),14, 15, 16 secretory sPLA216 and cyclooxygenase (COX)-2,17 as well as of transcription factors that regulate transcription of these enzymes, particularly activator protein (AP)-2 and/or nuclear factor-κB. With regard to excitotoxicity, rats chronically administered a subconvulsant dose of N-methyl-D-aspartate (NMDA) showed an increase in brain AA turnover, protein and mRNA levels of cPLA2 IVA, AP-2 DNA binding activity, AP-2α and AP-2β protein, and cytokine levels.13, 18

AA is a nutritionally essential polyunsaturated fatty acid found mainly in the stereospecifically numbered (sn)-2 position of membrane phospholipids, from which it can be hydrolyzed by cPLA2 or sPLA2.19 A portion of the AA released can be metabolized into bioactive prostaglandin H2 (PGH2) by COX-1 or COX-2, to cytoprotective epoxyeicosatrienoic acids by cytochrome p450 epoxygenase, or to cytotoxic leukotrienes by lipoxygenase (LOX) subtypes 5, 12 and 15.20 PGH2 is converted into prostaglandin E2 (PGE2) by membrane prostaglandin synthase-1 (mPGES-1) or cytosolic prostaglandin synthase (cPGES). PGH2 also can be converted into thromboxane A2 (TXA2) by thromboxane synthase (TXS)21 (Figure 1). Of the two COX isoenzymes, COX-1 is constitutively expressed, whereas COX-2 is inducible.22, 23 cPGES uses PGH2 produced by COX-1, whereas mPGES-1 uses COX-2-derived endoperoxide.24 AA and its metabolites can modulate signal transduction, transcription, neuronal activity, apoptosis and many other processes within the brain.25, 26, 27

Figure 1
figure 1

Schematic diagram of arachidonic acid cascade.

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Lithium, valproate, carbamazepine and lamotrigine are approved by the FDA as ‘mood stabilizers’ for treating BD. Each of these agents, when given chronically to rats to produce a therapeutically relevant plasma concentration, downregulate parts of the brain AA cascade, including AA turnover in brain phospholipids (lithium, valproate, carbamazepine), cPLA2 IVA and its transcription factor AP-2 (lithium and carbamazepine), acyl-CoA synthetase (valproate), COX-1 (valproate), COX-2 (all four) and nuclear factor-κB (valproate).28, 29, 30, 31, 32, 33 Chronic lithium and carbamazepine also prevent elevations of brain AA cascade markers in rat models of neuroinflammation and excitotoxicity.34, 35

In view of evidence linking excitotoxicity and neuroinflammation to BD (see above),11 and the inhibition of rat brain AA metabolism by mood stabilizers, we hypothesized that the AA cascade is upregulated in the BD brain. To test this hypothesis, protein and mRNA levels of AA cascade enzymes (see above) were compared between postmortem frontal cortex from 10 BD patients and 10 unaffected controls. We also compared expression of Ca2+-independent iPLA2, which is selective for docosahexaenoic acid (22:6n-3) in membrane phospholipid,36 and of neuron-specific enolase (NSE), a marker of postmortem tissue integrity in the absence of acute injury.37, 38 The frontal cortex (Brodmann area 9) was chosen for this study because functional and structural abnormalities have been reported in this region in BD patients,5 and because relevant data on this region have been published.11, 38 Preliminary data on the subjects have been published in abstract form.39

Materials and methods

Postmortem brain samples

The protocol was approved by the Institutional Review Board of McLean Hospital, and by the Office of Human Subjects Research (OHSR) of the NIH (# 4380). Frozen postmortem human frontal cortex from 10 BD patients and 10 age-matched controls was provided by the Harvard Brain Tissue Resource Center (McLean Hospital, Belmont, MA, USA) under PHS Grant number R24MH068855 to JS Rao. Age (years, control: 43±3.5 (s.e.m.) vs BD: 49±7.2), postmortem interval (hours, control: 27±1.5 vs BD: 21±3.0) and brain pH (control: 6.6±0.16 vs BD: 6.7±0.09) did not differ significantly between the two groups, whereas the BD patients were exposed to various psychotropic medications as reported (Table 1).38

Table 1 Characteristics of control and bipolar disorder subjects
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Preparation of cytosolic and membrane fraction

Cytosolic and membrane extracts were prepared from postmortem frontal cortex of BD and control subjects as previously reported.40 Tissue was homogenized in a homogenizing buffer containing 20 mM Tris-HCl (pH 7.4), 2 mM ethylene glycol tetraacetic acid, 5 mM EDTA, 1.5 mM pepstatin, 2 mM leupeptin, 0.5 mM phenylmethylsulfonyl fluoride, 0.2 U ml−1 aprotinin and 2 mM dithiothreitol, using a Teflon homogenizer. The homogenate was centrifuged at 100 000 g for 60 min at 4 °C. The resulting supernatant-1 (S1) was the cytosolic fraction, and the pellet was resuspended in the homogenizing buffer containing 0.2% (w/v) Triton X-100. The suspension was kept at 4 °C for 60 min with occasional stirring and then centrifuged at 100 000 g for 60 min at 4 °C. The resulting supernatant-2 (S2) was the membrane fraction. Protein concentrations in membrane and cytosolic fractions were determined with Bio-Rad Protein Reagent (Bio-Rad, Hercules, CA, USA). The membrane and cytosolic fractions were confirmed using the specific markers, cadherin and tubulin, respectively.

Western blot analysis

Proteins (50 μg) from the cytoplasmic and membrane extracts were separated on 4–20% SDS-polyacrylamide gels (Bio-Rad). Following electrophoresis, the proteins were transferred to a polyvinylidene difluoride membrane (Bio-Rad). Protein blots were incubated overnight in tris-buffered-saline buffer, containing 5% nonfat dried milk and 0.1% Tween-20, with specific primary antibodies (1:200 dilution) for the group IVA cPLA2, group IIA sPLA2, group VIA iPLA2, COX-1 (1:1000), COX-2 (1:500), cytochrome P450 epoxygenase, TXS, 5-, 12-, and 15-LOX (Cell Signaling, Beverly, MA, USA) and NSE (1:10 000) (Abcam, Cambridge, MA, USA). mPGES-1 was determined using a specific (1:200) primary antibody (Abcam). Cytoplasmic and membrane protein blots were incubated with appropriate horseradish peroxidase-conjugated secondary antibodies (Bio-Rad) and visualized (Kodak, Rochester, NY, USA). Optical densities of immunoblot bands were measured using Alpha Innotech Software (Alpha Innotech, San Leandro, CA, USA) and were normalized to β-actin (Sigma-Aldrich, St Louis, MO, USA) to correct for unequal loading. All experiments were carried out twice with 10 controls and 10 postmortem brain samples from BD patients. Values were expressed as percent of control.

Total RNA isolation and real time reverse transcription-PCR

Total RNA was isolated from the frontal cortex using an RNeasy mini kit (Qiagen, Valencia, CA, USA). RNA integrity number was measured using a Bioanalyzer (Agilent 2100 Bioanalyzer, Santa Clara, CA, USA). RNA integrity numbers for control and BD were 6.9±0.4 and 7.1±0.5, respectively (mean±s.e.m.). Complementary DNA was prepared from total RNA using a high-capacity complementary DNA Archive kit (Applied Biosystems, Foster City, CA, USA). mRNA levels of cPLA2, sPLA2, iPLA2, COX-1, COX-2, mPGES-1, cPGES, LOX-5, 12, 15, TXS, cytochrome P450 epoxygenase and NSE were measured by quantitative reverse transcription-PCR, using an ABI PRISM 7000 sequence detection system (Applied Biosystems). Specific primers and probes for cPLA2, sPLA2, iPLA2, COX-1, COX-2, mPGES-1, cPGES, LOX-5, 12, 15, TXS and cytochrome P450 epoxygenase were purchased from TaqManP gene expression assays (Applied Biosystems), and consisted of a 20 × mix of unlabeled PCR primers and Taqman minor groove binder (MGB) probe (FAM dye-labeled). The fold-change in gene expression was determined by the ΔΔCt method.41 Data were expressed as the relative level of the target gene (cPLA2, sPLA2, iPLA2, COX-1, COX-2, mPGES-1, cPGES, LOX-5, 12, 15, TXS, cytochrome P450 epoxygenase and NSE) in the postmortem BD brain normalized to the endogenous control (β-globulin) and relative to the control (calibrator), as described.42 All experiments were carried out twice in triplicate with 10 control and 10 BD postmortem brain samples. The data were expressed as relative expression of control.

Statistical analysis

Data are presented as mean±s.e.m. Statistical significance of means was calculated using a two-tailed unpaired t-test. Power analysis was performed and α, the threshold for significance for two-tailed distribution, was set to 0.05 and β, the power index, to 20%. Pearson correlations were made between age, postmortem interval and pH of the frontal cortex, and mRNA levels of cPLA2, sPLA2, iPLA2, COX-1, COX-2, mPGES-1 and cPGES in postmortem brain from controls and BD patients combined. A subgroup statistical comparison was performed on control, all BD subjects and BD subjects that were on lithium medication using Bonferroni's multiple comparison test, to assess the effects of lithium on the molecular markers analyzed. A separate Bonferroni's multiple comparison test was performed between control, all BD and BD subjects who died by suicide, to determine whether suicide was a factor affecting gene or protein expression. Statistical significance was set at P<0.05.

Results

Upregulated protein and mRNA levels of cPLA2, sPLA2 and COX-2

Mean protein levels of cPLA2 IVA and sPLA2 IIA were increased significantly (P<0.01), by 87 and 92%. respectively (Figures 2a and b), in BD compared with control frontal cortex, whereas the mean iPLA2 protein level did not differ significantly between the groups (Figure 2c). Mean mRNA levels of cPLA2 and sPLA2 were increased significantly in BD compared with control brain by threefold (P<0.001) and sixfold (P<0.01), respectively (Figures 2d and e), but iPLA2 mRNA was not significantly different (Figure 2f). COX-2 protein and mRNA levels were increased significantly by 82% (Figure 3a, P<0.01) and 3.4-fold (Figure 3b, P<0.01), respectively, whereas COX-1 protein and mRNA were significantly decreased in the BD cortex by 40% (P<0.01, Figure 3c) and 0.6-fold (P<0.05, Figure 3d), respectively.

Figure 2
figure 2

Protein and mRNA levels of PLA2 enzymes. Mean cPLA2 (a), sPLA2 (b) and iPLA2 (c) protein (with representative immunoblots) as percent of control in frontal cortex, from control (n=10) and BD (n=10) subjects. Data are optical densities relative to that of β-actin. Mean mRNA as percent of control of cPLA2 (d), sPLA2 (e) and iPLA2 (f) in frontal cortex from control (n=10) and BD (n=10) subjects, measured using RT-PCR. Data are normalized to the endogenous control (β-globulin) and expressed relative to the control (calibrator), using the ΔΔCt method. Mean±s.e.m., **P<0.01, ***P<0.001.

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Figure 3
figure 3

Protein and mRNA levels of COX enzymes. Mean COX-2 (a) and COX-1 (c) protein (with representative immunoblots) as percent of control in frontal cortex, from control (n=10) and BD (n=10) subjects. Data are optical densities relative to that of β-actin. COX-2 (b) and COX-1 (d) mRNA levels in the frontal cortex from controls (n=10) and BD patients (n=10), measured using RT-PCR. Data are normalized to the endogenous control (β-globulin) and expressed relative to the control (calibrator), using the ΔΔCt method. Mean±s.e.m., *P<0.05, **P<0.01.

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Increased protein and mRNA levels of mPGES-1

Statistically significant increases were found in mPGES-1 protein (by 71%, P<0.01, Figure 4a) and mRNA (by 3.6-fold, P<0.01, Figure 4c) in samples from BD patients relative to controls. cPGES was significantly decreased with regard to protein (by 54%, P<0.01, Figure 4b) and mRNA (by 0.76-fold, P<0.01, Figure 4c). There was no significant difference in either the protein (Figures 5a–c) or mRNA (Figure 5d) level for LOX 5, 12, 15, TXS (Figures 6a and d) or cytochrome P450 (Figures 6b and e) between groups.

Figure 4
figure 4

Protein and mRNA levels of PGES enzymes. Mean mPGES-1 (a) and cPGES-1 (b) protein (with representative immunoblots) in control (n=10) and BD (n=10) frontal cortex. Data are optical densities of PGES protein to β-actin, expressed as percent of control. mRNA levels of mPGES-1 and cPGES-1 (c) in postmortem control (n=10) and BD (n=10) frontal cortex, measured using RT-PCR. Data are levels of PGES in the BD patients normalized to the endogenous control (β-globulin) and relative to control level (calibrator), using the ΔΔCt method. Mean±s.e.m., **P<0.01.

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Figure 5
figure 5

Protein and mRNA levels of lipoxygenases. Mean 5 LOX (a), 12 LOX (b) and 15 LOX (c) protein levels (with representative immunoblots) in frontal cortex from control (n=10) and BD (n=10) subjects. Bar graphs are ratios of optical densities of LOXs to that of β-actin, expressed as percent of control. LOX mRNA (d) in postmortem frontal cortex from the control (n=10) and BD (n=10) subjects, measured using RT-PCR. Data are levels of LOXs in BD normalized to the endogenous control (β-globulin) and relative to the control (calibrator), using the ΔΔCt method. Mean±s.e.m.

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Figure 6
figure 6

Protein and mRNA levels of thromboxane synthase, P450 epoxygenase and neuron specific enolase. Mean TXS (a), P450 epoxygenase (b) and neuronal-specific enolase (NSE) (c) protein in postmortem frontal cortex from control and BD subjects. Bar graph is ratio of optical density of each protein to that of β-actin, expressed as percent of control. TXS (d), P450 epoxygenase (e) and NSE mRNA (f) in postmortem frontal cortex from control (n=10) and BD (n=10) subjects, measured using RT-PCR. Data are level in the BD brain normalized to the endogenous control (β-globulin) and relative to control (calibrator), using the ΔΔCt method. Mean±s.e.m.

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Mean protein and mRNA levels of NSE did not differ significantly between BD and control brains (Figures 6c and e).

Power analysis and correlations with brain variables

Power analysis revealed that a sample size of 10 in each group was sufficient to detect a difference of 20%, on the basis of our estimated mean and s.d. values (as described in the Material and methods section). Pearson correlations between variables (age, PMI and pH) and mRNA levels across all 20 brain samples (control and BD patients combined) were not statistically significant (Table 2).

Table 2 Probabilities and Pearson's correlation r2 between brain mRNA levels and subject age, postmortem interval and brain pH
Full size table

Bonferroni's multiple comparison tests showed a significant decrease in AA cascade markers (protein and mRNA) between BD and control subjects, and BD subjects on lithium and controls (P<0.05). However, no significant change in an AA cascade marker was observed between all BD subjects and the subgroup of BD subjects treated with lithium. Similarly, both BD subjects and BD subjects who committed suicide showed reduced AA cascade markers (protein and mRNA) relative to controls (P<0.05). No significant difference was found between all BD subjects and the subgroup of BD subjects who committed suicide, in AA cascade marker levels.

Discussion

In this study, mean protein and mRNA levels of cPLA2 IVA, sPLA2 IIA, COX-2 and mPGES were significantly elevated in postmortem frontal cortex of BD patients compared with controls. Protein and mRNA levels of COX-1 and of cPGES were significantly reduced, whereas protein and mRNA levels of iPLA2, 5-, 12-, and 15-LOX, TXS, cytochrome p450 epoxygenase were not significantly altered. These results are consistent with the hypothesis that the brain AA cascade is upregulated in BD. The hypothesis is based on the observation that each of the four mood stabilizers approved for treating BD, when given chronically to rats, downregulate AA turnover in brain phospholipids and/or other markers of brain AA metabolism, and on evidence of neuroinflammation and excitotoxicity associated with disease progression in BD, including brain atrophy and cell loss, cognitive decline and symptom worsening.5, 43, 44, 45, 46

An upregulated AA cascade may contribute to disease progression in BD in many ways.47 For example, excess unesterified AA and lysophospholipids formed following AA hydrolysis can induce apoptosis by damaging mitochondria,48 activating caspases-3 and -9, releasing cytochrome c,49 decreasing expression of brain-derived neurotrophic factor,50 and reducing neuronal viability.51

The increased expression of cPLA2 IVA, sPLA2 IIA and COX-2 in the BD brain may be related to underlying excitotoxicity and/or neuroinflammation. An elevated brain glutamate/glutamine ratio, increased glutamate concentration and decreased levels of the NMDA receptor subunits, NR1, NR2A and NR3A, have been reported in the BD brain.41, 42, 52, 53 In this regard, chronic subconvulsive NMDA administration to rats reduced brain levels of NR1 and NR3A, increased AA turnover in brain membrane phospholipids and increased protein and mRNA levels of cPLA2 IVA and sPLA2 IIA.42 Increased Ca2+ entry into a cell through the glutamatergic NMDA receptor may directly activate Ca2+-dependent AA-selective cPLA2 to release AA from membrane phospholipids;34, 54 chronic lithium, carbamazepine or valproate can inhibit this process.34, 35

Neuroinflammation has been reported to activate AA cascade markers. For instance, exposure of rat astrocytes to bacterial lipopolysaccharide (LPS) is reported to increase cPLA2 transcription through an AP-2 and nuclear factor-κB-dependent manner.55 A rat model of inflammation, caused by chronic LPS infusion into the cerebroventricular system, showed increased AA incorporation and turnover within brain phospholipids, elevated concentrations of unesterified AA, PGE2 and other AA metabolites, and increased cPLA2 and sPLA2 activities.35, 56 LPS infusion also increased IL-1β, tumor necrosis factor-α and β-amyloid precursor protein in activated microglia and astrocytes, resulting in degeneration of hippocampal CA3 pyramidal neurons, and altered behavior.56, 57, 58 Cytokines formed during inflammation activate both cPLA2 and sPLA2 at astrocytic cytokine receptors.19, 59, 60, 61

Excitotoxicity and neuroinflammation have been associated with upregulation of mPGES-1, which is functionally coupled to COX-2.24, 62 Coupling is consistent with our finding of increased expression of both mPGES-1 and COX-2 in the BD frontal cortex. On the other hand, cPGES is coupled to COX-1, and the expression of both these enzymes was significantly reduced in the BD brain. This is consistent with evidence showing that products of COX-1 are selectively metabolized by cPGES.24, 62 Decreased expression of COX-1 and cPGES might be a compensatory response to increased expression of COX-2 and mPGES.

Consistent with an elevated AA metabolism in BD, studies have reported increased hydrolysis of serum phospholipids63, 64, 65 and increased levels of AA-derived prostaglandins in saliva,66 cerebrospinal fluid67 and serum64 from BD patients. AA cascade markers, including cPLA2 IVA, sPLA2 IIA and COX-2 protein and mRNA were elevated in frontal cortex of n-3 polyunsaturated fatty acid deprived rats,42 which exhibited BD-like behavioral symptoms.68 Expression of brain-derived neurotrophic factor and cyclic AMP response element binding protein also was reduced in the n-3 polyunsaturated fatty acid deprived animals.42

The absence of a significant difference in iPLA2 expression in the frontal cortex between BD patients and controls is consistent with unaltered iPLA2 activity in BD serum.69, 70 iPLA2 is thought to hydrolyze docosahexaenoic acid from membrane phospholipids,71 and its expression was not elevated in rat brain following either chronic NMDA administration or cerebroventricular LPS infusion.35, 42, 56 There was no significant difference in other AA and prostaglandin metabolic enzymes, such as P450 expoxygenease, 5-, 12- and 15-LOX, and TXS, between BD and control frontal cortex. These results suggest that increased AA signaling is channeled into prostanoid synthesis, and is selective only to parts of the AA cascade.

Similar to BD, studies in schizophrenic patients indicate an increase in brain calcium-dependent and -independent PLA2 activity, as well as iPLA2 IVA protein in red blood cells.72, 73 Similar AA cascade changes have been reported in postmortem brain from AD patients, where excitotoxicity and neuroinflammation are considered to have a role.74, 75 In AD postmortem brain tissue, cPLA2,76 sPLA259 and COX-2 expression is upregulated. Reduced cPLA2 expression ameliorated cognitive deficits in a mouse model of AD.78 Thus, the changes noted here may not be specific to BD, but may be related generally to excitotoxic and inflammatory processes that occur in multiple chronic and progressive neurodegenerative and neuropsychiatric disorders, including AD, Parkinson's disease, schizophrenia and unipolar depression.52, 69, 79

Many but not all of the differences between the BD and control brain were in an opposite direction to brain changes in rats chronically administered mood stabilizers. For example, chronic lithium and carbamazepine were shown to decrease mRNA and protein levels of cPLA2 IVA in rat brain, while this enzyme's expression was upregulated in the BD brain. sPLA2 expression also was upregulated in the BD brain; chronic lithium did not reduce sPLA2 expression in the normal rat brain,18 but prevented the upregulation that was caused by cerebroventricular LPS infusion (M Basselin et al., unpublished results). Increased expression of sPLA2 IIA in BD is consistent with reports of increased risk associated with alleles for pancreatic PLA280, 81 and for the sPLA2 receptor in BD.3 However, COX-1 was reduced in the BD brain as well as in the brain of rats given chronic valproate,32 whereas COX-2 was elevated in the BD brain but reduced by lithium, carbamazepine, valproate and lamotrigine.18 Opposite changes in AA cascade markers in the BD brain compared with the brain of rats treated with mood stabilizers may be the basis, in part, for their efficacy in BD.

Levels of mRNA in either BD or control brains did not correlate significantly with postmortem interval, brain pH, or subject age, and mean values of these parameters did not differ significantly between the two groups. Nevertheless, the BD patients were exposed to a variety of drugs not taken by the control subjects, which may have affected the results, as antipsychotics and mood stabilizers can have neurotoxic effects when given chronically.82, 83 No statistical difference was found in AA cascade genes in this study when the BD subjects were compared with the subgroup of BD subjects treated with lithium. Also, no statistical significance was found when the BD subjects were compared with BD subjects that died by suicide. This suggests that lithium or suicide does not affect the studied AA cascade markers.

A limitation of this study is lack of information about whether patients were manic or depressive at time of death. However, as several BD patients died by suicide, they may have been in a depressed phase of their illness. Future studies should examine AA cascade markers in brains from patients with schizophrenia (to control for comparable drug exposure), or with unipolar (primary major) depression or AD to test for disease specificity.84

In conclusion, many markers of the AA cascade were significantly upregulated in postmortem frontal cortex from BD patients. These changes may reflect neuroinflammation and excitotoxicity, associated with cell death or drug exposure, or may be intrinsic to the disease independent of these pathological processes. Some of upregulated AA cascade markers were downregulated in rat brain by chronically administered mood stabilizers, which may account for their efficacy in BD. Accordingly, new agents that are shown to downregulate the brain AA cascade in animal models could be considered for treating BD.

The results suggest that brain AA metabolism is elevated in BD, and this could be tested directly with the help of positron emission tomography and [1-11C]AA as a radioligand.85 If correct, an increased AA image would be a biological marker of disease progression and could be used to evaluate therapeutic efficacy. Increased brain AA metabolism has been imaged in patients with AD using positron emission tomography,86 and cPLA2, sPLA2 and COX-2 were also found to be elevated in postmortem brain.59, 76, 77

Conflict of interest

The authors declare no conflict of interest.

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Acknowledgements

We thank the Harvard Brain Bank, Boston, MA for providing the postmortem brain samples under PHS Grant number R24MH068855. This research was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. We also thank the Fellows' Editorial Board at NIH for reviewing the manuscript.

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  1. H-W Kim and J S Rao: These authors contributed equally to this work.

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  1. Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA

    H-W Kim, S I Rapoport & J S Rao

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  1. H-W Kim
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Kim, HW., Rapoport, S. & Rao, J. Altered arachidonic acid cascade enzymes in postmortem brain from bipolar disorder patients. Mol Psychiatry 16, 419–428 (2011). https://doi.org/10.1038/mp.2009.137

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Keywords

  • PLA2
  • inflammation
  • mood stabilizers
  • COX
  • PGES
  • excitotoxicity

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