Abstract
Kainic acid (KA) binds to the AMPA/KA receptors and induces seizures that result in inflammation, oxidative damage and neuronal death. We previously showed that cyclooxygenase-2 deficient (COX-2−/−) mice are more vulnerable to KA-induced excitotoxicity. Here, we investigated whether the increased susceptibility of COX-2−/− mice to KA is associated with altered mRNA expression and editing of glutamate receptors. The expression of AMPA GluR2, GluR3 and KA GluR6 was increased in vehicle-injected COX-2−/− mice compared to wild type (WT) mice in hippocampus and cortex, whereas gene expression of NMDA receptors was decreased. KA treatment decreased the expression of AMPA, KA and NMDA receptors in the hippocampus, with a significant effect in COX-2−/− mice. Furthermore, we analyzed RNA editing levels and found that the level of GluR3 R/G editing site was selectively increased in the hippocampus and decreased in the cortex in COX-2−/− compared with WT mice. After KA, GluR4 R/G editing site, flip form, was increased in the hippocampus of COX-2−/− mice. Treatment of WT mice with the COX-2 inhibitor celecoxib for two weeks decreased the expression of AMPA/KA and NMDAR subunits after KA, as observed in COX-2−/− mice. After KA exposure, COX-2−/− mice showed increased mRNA expression of markers of inflammation and oxidative stress, such as cytokines (TNF-α, IL-1β and IL-6), inducible nitric oxide synthase (iNOS), microglia (CD11b) and astrocyte (GFAP). Thus, COX-2 gene deletion can exacerbate the inflammatory response to KA. We suggest that COX-2 plays a role in attenuating glutamate excitotoxicity by modulating RNA editing of AMPA/KA and mRNA expression of all ionotropic glutamate receptor subunits and, in turn, neuronal excitability. These changes may contribute to the increased vulnerability of COX-2−/− mice to KA. The overstimulation of glutamate receptors as a consequence of COX-2 gene deletion suggests a functional coupling between COX-2 and the glutamatergic system.
Highlights
Cyclooxygenases (COX-1 and COX-2) convert arachidonic acid to bioactive prostaglandins (PG) and tromboxanes (TX), which have been implicated in important physiological functions [1,2], as well as in the pathophysiology of several neurological and neurodegenerative diseases, such as stroke, epilepsy, and Alzheimer’s disease [3]
We showed that pretreatment with celecoxib for 2 weeks recapitulated the effects on gene expression of some AMPA, KA and most of the N-methyl-D-aspartic acid (NMDA) receptor subunits observed in COX-22/2 mice, after KA treatment
Using qRT-PCR, we examined the relative changes in the mRNA expression pattern of the AMPA (GluR1–4) and KA (GluR5–7, KA1 and KA2) glutamate receptors subunits in the hippocampus and cortex of vehicle-injected COX-22/2 mice (n = 9) compared with vehicle-injected wild type (WT) mice (n = 9)
Summary
Cyclooxygenases (COX-1 and COX-2) convert arachidonic acid to bioactive prostaglandins (PG) and tromboxanes (TX), which have been implicated in important physiological functions [1,2], as well as in the pathophysiology of several neurological and neurodegenerative diseases, such as stroke, epilepsy, and Alzheimer’s disease [3]. We have previously demonstrated that COX-2 deficient (COX22/2), but not COX-12/2 mice, are more susceptible to kainicacid (KA)-induced seizure intensity and neuronal damage [6]. Kainate (AMPA/KA) and N-methyl-D-aspartic acid (NMDA) receptors (AMPAR, KAR and NMDAR), which are subtypes of the ionotropic glutamate receptors (iGluRs) in the brain [7], inducing seizures that result in inflammation, oxidative damage and neuronal death. These processes have been implicated in neurological, neurodegenerative, and psychiatric diseases [6,8,9, 10,11,12,13,14,15]. Neurodegeneration caused by systemic injection of KA has been widely used to investigate mechanisms of excitotoxicity mediated by excitatory neurotransmitter agonists and possible pharmacological neuroprotective interventions [6,21]
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