Oxidative stress induced by glutamate receptor agonists

Abstract

The effect of various selective glutamate agonists upon the rate of generation of reactive oxygen species (ROS), was examined in an isolated synaptoneurosomal (microsac) fraction derived from rat cerebral cortex. The rates of ROS generation were determined by a fluorescent probe. Agonists specific for each of the three major glutamate inotropic receptor sites (NMDA, kainic acid, a-amino-3-hydroxy-5-methyl-4-isoxalolpropionic acid, AMPA), were able to enhance rates of ROS generation. The metabotropic glutamate agonist trans-1-aminocyclopentane-1,3-dicarboxylic acid, (ACPD), was inactive in this regard. Stimulation of ROS was most pronounced in the case of kainate. Such results could not be replicated by use of ion-channel active agents, veratridine and A23817. Pretreatment with the kainate antagonist, 6-cyano-7-quinoxaline-2,3-dione (CNQX), was not able to block the kainate-induced elvation of ROS. Domoic acid, a kainate agonist, also enhanced microsac ROS generation. Neurological damage may result from generation of excess free radicals, and this may be effected by glutamate agonists acting by means independent of their ionotropic properties.

Oxidative and excitotoxic insults exert differential effects on spinal motoneurons and astrocytic glutamate transporters: Implications for the role of astrogliosis in amyotrophic lateral sclerosis

“…Previous theories suggested that oxidative inhibition of EAAT activity leads to increased levels of extracellular Glu, subsequent excitotoxicity, and neuronal degeneration (Trotti et al, 1998). Moreover, the disturbance of EAAT function would produce an amplifying cycle where excessive stimulation of Glu receptors resulted in further formation of ROS (Bondy and Lee, 1993). Our first major finding from investigations of the cellular responses to oxidative and excitotoxic insults was evidence of their preferential targeting of astrocytes and neurons, respectively.…”

“…Moreover, the detrimental effects of these processes can be perpetuated further through amplifying cycles (Trotti et al, 1998). For example, among various interdependent relationships between excitotoxicity and oxidative stress, free radicals can increase Glu release (Gilman et al, 1994;PellegriniGiampietro et al, 1990), and activation of Glu receptors produces reactive oxygen species (ROS; Bondy and Lee, 1993).…”

Neuronal life and death: an essential role for the p53 family

“…In this regard, glutamate receptor activation leads to the generation of reactive oxygen species. 112,113 Reactive oxygen species are known to induce DNA strand breaks, and exposure of neurons to reactive oxygen species leads to neuronal apoptosis. 114 ± 117 Enhancement of p53 expression has been observed in numerous cell types following exposure to reactive oxygen species.…”

Increased Cerebral Free Radical Production During Thiamine Deficiency

“…First, pathologic lesions in the pyrithiaminc-induced thiamine deficient (PTO) rat arc associated with increased levels of glutamate and activation of the NMDA receptor (Hazell et al, 1993;Langlais, 1995: Langlais and Mair, 1990: Langlais and Zhang, 1993. Activation of glutamate-NM DA receptors leads to free radical fonnation (Bondy and Lee, 1993) and NMDA agonists are particularly potent in stimulating the rate of generation of reactive oxygen species (ROS) in cerebral tissue (Bondy and Lee, 1993). Activation of the NMDA receptor has also been implicated in postischemic elevation of lipid peroxidation in hippocampus and transient ischemia elevates extracellular fluid (ECF) levels of both excitatory amino acids and rates of hydroxyl radical formation (Delbarre et al, 1991 (Halliwell and Gutteridge, 1985), are frequently observed in vulnerable brain regions of PTD treated rats (Collins, 1967;Zhang et al, 1995) and mice (Watanabe and Kanabe, 1978).…”