title: Effects of chronic clozapine administration on markers of arachidonic acid cascade and synaptic integrity in rat brain.
abstract: BACKGROUND
  The mode of action of clozapine, an atypical antipsychotic approved for treating schizophrenia (SZ) and used for bipolar disorder (BD) mania, remains unclear. We tested for overlap with the actions of the mood stabilizers, lithium, carbamazepine and valproate, which downregulate arachidonic acid (AA) cascade markers in rat brain and upregulate BDNF. AA cascade markers are upregulated in BD and SZ postmortem BD brain in association with neuroinflammation and synaptic loss, while BDNF is decreased.
  
  
  METHODS
  Rats were injected intraperitoneally with a therapeutically relevant dose of clozapine (10 mg/kg/day) or with saline for 30 days, and AA cascade and synaptic markers and BDNF were measured in the brain.
  
  
  RESULTS
  Compared with saline-injected rats, chronic clozapine increased brain activity, mRNA and protein levels of docosahexaenoic acid (DHA)-selective calcium-independent phospholipase A₂ type VIA (iPLA₂), mRNA and protein levels of BDNF and of the postsynaptic marker, drebrin, while decreasing cyclooxygenase (COX) activity and concentration of prostaglandin E₂ (PGE₂), a proinflammatory AA metabolite. Activity and expression of AA-selective calcium-dependent cytosolic cPLA₂ type IVA and of secretory sPLA₂ Type II were unchanged.
  
  
  CONCLUSIONS
  These results show overlap with effects of mood stabilizers with regard to downregulation of COX activity and PGE₂ and to increased BDNF and suggest a common action against the reported neuropathology of BD and SZ. The increased iPLA₂ expression following clozapine suggests increased production of anti-inflammatory DHA metabolites, and, with increased BDNF and drebrin, clear neuroprotective action.
authors.affiliation: Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. peterkhw@gmail.com
authors.forename: Hyung-Wook
authors.initials: HW
authors.lastname: Kim
authors.forename: Yewon
authors.initials: Y
authors.lastname: Cheon
authors.forename: Hiren R
authors.initials: HR
authors.lastname: Modi
authors.forename: Stanley I
authors.initials: SI
authors.lastname: Rapoport
authors.forename: Jagadeesh S
authors.initials: JS
authors.lastname: Rao
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003024:Clozapine / Q000008:administration & dosage / Q000494:pharmacology*; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D004334:Drug Administration Schedule; D008297:Male; D009479:Neuropeptides / Q000378:metabolism; D054467:Phospholipases A2 / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000187:drug effects*; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D014150:Antipsychotic Agents; D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor; D009479:Neuropeptides; C053386:drebrins; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D011451:Prostaglandin-Endoperoxide Synthases; D054467:Phospholipases A2; D003024:Clozapine; D015232:Dinoprostone