Potentiation of Excitotoxicity in Transgenic Mice Overexpressing Neuronal Cyclooxygenase-2

Abstract

In this study we describe the generation of a transgenic mouse model with neuronal overexpression of the human cyclooxygenase-2 , h(COX)-2 , to explore its role in excitotoxicity. We report that overexpression of neuronal hCOX-2 potentiates the intensity and lethality of kainic acid excitotoxicity in coincidence with potentiation of expression of the immediate early genes c-fos and zif-268. In vitro studies extended the in vivo findings and revealed that glutamate excitotoxicity is potentiated in primary cortico-hippocampal neurons derived from hCOX-2 transgenic mice , possibly through potentiation of mitochondrial impairment. This study is the first to demonstrate a cause-effect relationship between neuronal COX-2 expression and excitotoxicity. This model system will allow the systematic examination of the role of COX-2 in mechanisms of neurodegeneration that involve excitatory amino acid pathways. (Am J Pathol 1999, 155:995-1004) Cyclooxygenase (COX) is the rate-limiting enzyme in the production of prostaglandins and, as such, a key target for anti-inflammatory drugs. Indeed, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are COX inhibitors.

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

“…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]. These results described by Kelley et al are difficult to reconcile with the observation described in our study since the only endpoint measured in their study was mortality as opposed to ours which measured seizure intensity and neuronal damage.…”

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].…”

Chronic Lithium Administration to Rats Selectively Modifies 5-HT2A/2C Receptor-Mediated Brain Signaling Via Arachidonic Acid

“…An increased availability of unesterified AA and some of its eicosanoid products could promote neuronal excitability, glutamatergic neurotransmission, and seizure propagation (Bazán, 1989;Kelley et al, 1999;Kolko et al, 1996;Kunz and Oliw, 2001;Li et al, 1997;Lysz et al, 1987;Strauss and Marini, 2002;Wallenstein and Mauss, 1984). In contrast to its effect on PLA 2 signaling via AA, LiCl feeding is reported to reduce brain phospholipase C activation by cholinomimetics (Casebolt and Jope, 1989;Ormandy et al, 1991;Song and Jope, 1992).…”