title: Gabapentin's minimal action on markers of rat brain arachidonic acid metabolism agrees with its inefficacy against bipolar disorder.
abstract: In rats, FDA-approved mood stabilizers used for treating bipolar disorder (BD) selectively downregulate brain markers of the arachidonic acid (AA) cascade, which are upregulated in postmortem BD brain. Phase III clinical trials show that the anticonvulsant gabapentin (GBP) is ineffective in treating BD. We hypothesized that GBP would not alter the rat brain AA cascade. Chronic GBP (10 mg/kg body weight, injected i.p. for 30 days) compared to saline vehicle did not significantly alter brain expression or activity of AA-selective cytosolic phospholipase A(2) (cPLA(2)) IVA or secretory (s)PLA(2) IIA, activity of cyclooxygenase-2, or prostaglandin E(2) or thromboxane B(2) concentrations. Plasma esterified and unesterified AA concentration was unaffected. These results, taken with evidence of an upregulated AA cascade in the BD brain and that approved mood stabilizers downregulate the rat brain AA cascade, support the hypothesis that effective anti-BD drugs act by targeting the brain AA cascade whereas ineffective drugs (such as GBP) do not target this pathway, and suggest that the rat model might be used for screening new anti-BD drugs.
authors: Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Edmund A
authors: EA
authors: Reese
authors: Yewon
authors: Y
authors: Cheon
authors: Epolia
authors: E
authors: Ramadan
authors: Hyung-Wook
authors: HW
authors: Kim
authors: Lisa
authors: L
authors: Chang
authors: Jagadeesh S
authors: JS
authors: Rao
authors: Stanley I
authors: SI
authors: Rapoport
authors: Ameer Y
authors: AY
authors: Taha
mesh_terms: D000588:Amines / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001714:Bipolar Disorder / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005227:Fatty Acids / Q000097:blood; D005632:Fructose / Q000031:analogs & derivatives / Q000494:pharmacology; D000077206:Gabapentin; D015870:Gene Expression; D054522:Group VI Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D054510:Phospholipases A2, Cytosolic / Q000235:genetics / Q000378:metabolism; D054497:Phospholipases A2, Secretory / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013929:Thromboxane B2 / Q000378:metabolism; D000077236:Topiramate; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D000588:Amines; D014151:Anti-Anxiety Agents; D015415:Biomarkers; D003509:Cyclohexanecarboxylic Acids; D005227:Fatty Acids; D008565:Membrane Proteins; D000077236:Topiramate; D016718:Arachidonic Acid; D005632:Fructose; D013929:Thromboxane B2; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; D054522:Group VI Phospholipases A2; D054510:Phospholipases A2, Cytosolic; D054497:Phospholipases A2, Secretory; D015232:Dinoprostone