NMDA-induced seizure intensity is enhanced in COX-2 deficient mice.
Pharmacological inhibition or genetic deletion of cyclooxygenase (COX)-2, but not COX-1, has been shown to increase susceptibility to kainic acid (KA)-induced excitotoxicity. However, it is unclear if susceptibility to excitotoxins that act through other neurotransmitter receptors is altered by COX-2 inhibition. To further understand the involvement of COX-2 in regulating susceptibility to excitotoxicity, we investigated the effect of COX-2 deletion on excitotoxicity induced by peripheral injection of N-methyl-d-aspartate (NMDA, a specific agonist of the NMDA receptors) or lindane (a GABA(A) receptor antagonist). COX-2(-/-) mice injected intraperitoneally with NMDA (50-100mg/kg) exhibited significantly increased median seizure intensity when compared to COX-2(+/+) mice. Further, COX-2(-/-) mice exposed to NMDA showed neuronal damage, detected by Fluoro Jade B (FJB) staining, in the CA3 region of the hippocampus. There was no FJB staining nor any significant difference in median or maximal seizure intensity in COX-2(+/+) and COX-2(-/-) mice exposed to lindane. LC-MS/MS analysis of brain prostaglandin profile in COX-2(-/-) mice demonstrated a significant increase in PGF(2alpha), TXB(2), PGE(2) and PGD(2) expression 1h after administration of an excitotoxic dose of KA, but not of NMDA. Our findings demonstrate that COX-2 regulates susceptibility to KA and NMDA excitotoxicity, which directly activate glutamatergic neurotransmission, but not to lindane, which indirectly alters glutamatergic neurotransmission. Furthermore, increased levels of prostaglandins after seizures are associated with consistent manifestation of neuronal damage.
Molecular Neuroscience Unit, Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Christopher D
CD
Toscano
Philip J
PJ
Kingsley
Lawrence J
LJ
Marnett
Francesca
F
Bosetti
D000818:Animals; D051546:Cyclooxygenase 2 / Q000172:deficiency*; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005452:Fluoresceins; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D001556:Hexachlorocyclohexane / Q000008:administration & dosage; D007306:Insecticides / Q000008:administration & dosage; D007608:Kainic Acid / Q000008:administration & dosage; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000633:toxicity*; D009930:Organic Chemicals / Q000378:metabolism; D011453:Prostaglandins / Q000032:analysis; D012640:Seizures / Q000139:chemically induced* / Q000235:genetics*
D018690:Excitatory Amino Acid Agonists; D005452:Fluoresceins; D007306:Insecticides; D009930:Organic Chemicals; D011453:Prostaglandins; C435731:fluoro jade; D001556:Hexachlorocyclohexane; D016202:N-Methylaspartate; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D007608:Kainic Acid