Recurrent glutamate stimulations potentiate the hydroxyl radicals response to glutamate

Abstract

Neurotoxicity induced by hydroxyl radicals (OH) release is thought to be involved in a number of acute and chronical neuropathologies of the central nervous system. As far as neurodegenerative processes are concerned, the possible mechanisms giving rise to such OH releases remain poorly understood. In the present study, unanesthetized rats were perfused with a low salicylate solution through a chronic microdialysis cannula implanted into the striatum, and the OH responses to glutamate were analyzed. A single bolus of 3 mM glutamate elicited only minute releases of OH in naive rats. By contrast, recurrent infusions at 1-week intervals of the same glutamate concentration induced a robust OH response. Similar potentiation of the initial response also occurred for a larger glutamate concentration (30 mM). Oppositely, multiple injections of a high (300 mM) glutamate concentration resulted in a slow down of the initial OH response recorded in naive animals. The mechanisms giving rise to such effects are presently unknown. It is, however, clear that repetitive dysfunctions of the glutamate neurotransmission may be sufficient to promote the release of significant amounts of hydroxyl radicals, resulting in a progressive impairment of the astrocytic glutamate transporter, leading to neurodegenerative processes.

Prenatal infection obliterates glutamate‐related protection against free hydroxyl radicals in neonatal rat brain

“…Hydroxyl radicals reacted with salicylate in the perfusion medium and their formation was evaluated by measuring the resulting stable 2,3‐DHBA (2,3 dihydroxybenzoic acid) in each fraction. The high‐performance liquid chromatography (HPLC)/electrochemical detection method was similar to that already reported, using a mobile phase (0.07 M citric acid, 20% acetonitrile and 10% methanol) allowing a fast (<15 min) and accurate detection of 2,3‐DHBA (Cauquil‐Caubere et al, 1999; Laplanche et al, 2000). Results are expressed for each animal as the ratio between the actual 2,3‐DHBA level of each sample and the baseline (mean of the 3 samples preceding the stimulation).…”

N-methyl-D-aspartate but not glutamate induces the release of hydroxyl radicals in the neonatal rat: Modulation by group I metabotropic glutamate receptors

“…Hydroxyl radicals reacted with the salicylate of the perfusion medium, and their formation was evaluated by measuring the resulting stable 2,3-DHBA in each fraction by HPLC, followed by an electrochemical detection using previously reported methods (Cauquil-Caubère et al, 1999;Laplanche et al, 2000). Results are expressed for each animal as the ratio between the actual 2,3-DHBA level of each sample and the baseline (mean of the three samples preceding the stimulation).…”

“…On the other hand, breakdown of energy metabolism together with an excessive increase in intracellular calcium enhanced the production of toxic oxygen-derived free radicals. Accordingly, glutamate infusion in adult animals always results in the release of cytotoxic hydroxyl radicals (⅐OH; Lancelot et al, 1998;Cauquil-Caubère et al, 1999;Laplanche et al, 2000). In the extracellular space, ⅐OH inhibited the astrocytic glutamate transporter (Volterra et al, 1994;Cauquil-Caubère and Kamenka, 1998), the major effector of the clearance of glutamate from nerve terminals (Rothstein et al, 1996), resulting in the increase of glutamate into the synaptic cleft and, through a vicious cycle, in oxidative excitotoxicity.…”

“…Blocking the NMDA receptors might therefore represent a possible protective strategy against glutamate-induced neurotoxicity (Drian et al, 1999). However, most noncompetitive NMDA receptor antagonists, and particularly dizocilpine (MK-801), produced numerous neuronal injuries, manifested by vacuolization of the neuronal cytoplasm (Olney et al, 1991), Another possibility is to reduce the synaptic glutamate concentration, either by protecting the astrocytic glutamate transporter with antiradical drugs (Cauquil-Caubère et al, 1999) or more directly by reducing the glutamate release.…”

A Mouse Model of Acute Ischemic Spinal Cord Injury

“…Among different species, rats have been widely used as the model of choice to investigate the molecular and cellular mechanisms of changes in the basic neurochemistry after neurotrauma and the efficacy of pharmacological treatments, in order to attenuate the neuronal and glial damage leading to permanent functional impairment Brewer et al, 1999;Faden et al, 1988;Gaviria et al, 2000a,b;Pencalet et al, 1993;Ray et al, 1999;Rosenberg et al, 1999;Wrathall et al, 1994Wrathall et al, , 1996. Pharmacological intervention for neuroprotection soon after injury presents a promising therapeutic strategy, and some of the principal biochemical targets of the secondary injury mechanism have been identified in experimental models Cauquil-Caubere et al, 1999;Gaviria et al, 2000a,b;Rosenberg et al, 1999;Wrathall et al, 1994). Nevertheless, given the complexity and diverse response of the nervous system to injury, it is unlikely that a single approach, that is, pharmacological therapy, will be satisfactory, especially in chronic lesions (Gimenez y Ribotta and .…”