Reduced susceptibility to ischemic brain injury and N -methyl- d -aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice

Abstract

Cyclooxygenase-2 (COX-2), a prostanoid-synthesizing enzyme that contributes to the toxicity associated with inflammation, has recently emerged as a promising therapeutic target for several illnesses, ranging from osteoarthritis to Alzheimer's disease. Although COX-2 has also been linked to ischemic stroke, its role in the mechanisms of ischemic brain injury remains controversial. We demonstrate that COX-2-deficient mice have a significant reduction in the brain injury produced by occlusion of the middle cerebral artery. The protection can be attributed to attenuation of glutamate neurotoxicity, a critical factor in the initiation of ischemic brain injury, and to abrogation of the deleterious effects of postischemic inflammation, a process contributing to the secondary progression of the damage. Thus, COX-2 is involved in pathogenic events occurring in both the early and late stages of cerebral ischemia and may be a valuable therapeutic target for treatment of human stroke.middle cerebral artery occlusion ͉ prostanoids ͉ cerebral blood flow ͉ NS398 ͉ stroke

Altered GABAergic neurotransmission is associated with increased kainate-induced seizure in prostaglandin-endoperoxide synthase-2 deficient mice

“…While abnormalities in the macula densa and juxtaglomerular apparatus have been previously described in adult PTGS-2 deficient mice [21], Iadecola and colleagues [21] have also reported that PTGS-2 deficient mice show creatinine levels in the normal range, suggesting normal renal function in adult PTGS-2 deficient mice. Further, since the dicarboxylate excitatory amino acid analogs are mainly eliminated by glomerular filtration [62] and no alterations in the glomeruli and renal tubules have been characterized [21], the renal clearance of KA is unlikely to be altered in PTGS-2 deficient mice.…”

“…Acute pretreatment with PTGS inhibitors such as celecoxib, nimesulide and flurbiprofen has been shown to increase seizure activity in response to excitotoxic doses of KA or pentylenetetrazole [4,61], supporting the suggested role for PTGS in regulation of neuronal excitability. Conversely, PTGS inhibition by genetic or pharmacological means after neuronal damage has been initiated results in neuroprotection [9,15,18,21,26,63]. While this dichotomy is well defined for the studies mentioned above, it has also been demonstrated that mice over expressing a human form of PTGS-2 solely in neurons, had increased KA induced mortality [27].…”

Wide therapeutic time window for nimesulide neuroprotection in a model of transient focal cerebral ischemia in the rat

“…In addition, recent investigations have found a potentiation of excitotoxicity in transgenic mice overexpressing neuronal COX-2 [37] and a significant reduction in ischemic brain injury in COX-2-deficient mice [36,62]. COX-2 expression by itself does not lead to neuronal death since a variety of healthy neuronal populations throughout the CNS express COX-2 mRNA and protein under normal conditions [5,77] and COX-2 expression can be experimentally induced without causing neuronal death [56].…”

Cannabinoid activation of PPARα; a novel neuroprotective mechanism

“…The expression of COX-2 is generally found to be upregulated after stroke (Miettinen et al, 1997;Nogawa et al, 1997), indicating a potential route for therapeutic intervention following such an insult. Although its role in cerebral ischaemic damage in man is unclear, inhibition of COX-2 expression can reduce the infarct volume and neuronal damage in stroke models (Iadecola et al, 2001). For example, selective inhibition of COX-2 has been shown to reduce markedly global ischaemiaevoked hippocampal neuronal death (Nakayama et al, 1998).…”