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NMDA-induced seizure intensity is enhanced in COX-2 deficient mice
Christopher D Toscano1, Philip J Kingsley, Lawrence J Marnett
1Molecular Neuroscience Unit, Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
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.
Insights
Cyclooxygenase (COX)-2 deletion enhances susceptibility to N-methyl-d-aspartate (NMDA) and kainic acid (KA) excitotoxicity, causing neuronal damage. However, COX-2 inhibition does not affect lindane-induced seizures, indicating COX-2
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Cyclooxygenase (COX)-2 inhibition or deletion increases susceptibility to kainic acid (KA)-induced excitotoxicity.
- The role of COX-2 in excitotoxicity mediated by other neurotransmitter receptors remains unclear.
- Understanding COX-2's role is crucial for developing targeted therapies for excitotoxic brain injury.
Purpose of the Study:
- To investigate the effect of COX-2 deletion on excitotoxicity induced by N-methyl-d-aspartate (NMDA) and lindane.
- To determine if COX-2 regulates susceptibility to excitotoxins acting through different neurotransmitter receptors.
Main Methods:
- Utilized COX-2 knockout (COX-2(-/-)) and wild-type (COX-2(+/+)) mice.
- Administered NMDA or lindane intraperitoneally to induce excitotoxicity.
- Assessed seizure intensity, neuronal damage using Fluoro Jade B (FJB) staining, and prostaglandin profiles via LC-MS/MS.
Main Results:
- COX-2(-/-) mice showed significantly increased seizure intensity and hippocampal CA3 neuronal damage after NMDA administration.
- No significant differences in seizure intensity or neuronal damage were observed between COX-2(-/-) and COX-2(+/+) mice after lindane exposure.
- LC-MS/MS analysis revealed increased prostaglandin levels (PGF(2alpha), TXB(2), PGE(2), PGD(2)) in COX-2(-/-) mice after KA, but not NMDA, administration.
Conclusions:
- COX-2 plays a critical role in regulating susceptibility to excitotoxicity mediated by direct activation of glutamatergic neurotransmission (KA, NMDA).
- COX-2 does not appear to influence excitotoxicity resulting from indirect alterations in glutamatergic neurotransmission (lindane).
- Elevated prostaglandin levels post-seizure correlate with neuronal damage, highlighting their involvement in excitotoxic injury.
