Oxidative stress in stroke pathophysiology validation of hydrogen peroxide metabolism as a pharmacological target to afford neuroprotection.
Reactive oxygen species (ROS) accumulation has been described in the brain following an ischemic insult. Superoxide anion is converted by superoxide dismutase into hydrogen peroxide (H2O2), and the latter is then transformed into the toxic hydroxyl radical, through the Haber-Weiss reaction, converted to water by glutathione peroxidase (GPx) or dismuted to water and oxygen through catalase. Accumulation of H2O2 has been suggested to exert neurotoxic effects, although recent in vitro studies have demonstrated either physiological or protective roles of this molecule in the brain. In particular, oxidative stress is critically involved in brain damage induced by transient cerebral ischemia. Here, we demonstrate that inhibition of GPx by systemic (i.p.) administration of mercaptosuccinate (MS, 1.5-150 mg/kg) dose-dependently reduces brain infarct damage produced by transient (2 h) middle cerebral artery occlusion (MCAo) in rat. Neuroprotection was observed when the drug was administered 15 min before the ischemic insult, whereas no effect was detected when the drug was injected 1h before MCAo or upon reperfusion. Furthermore, application of MS (1 mM) to corticostriatal slices limited the irreversible functional derangement of field potentials caused by a prolonged (12 min) oxygen-glucose deprivation. This effect was reverted by concomitant bath application of the catalase inhibitor 3-aminotriazole (20mM), suggesting the involvement of catalase in mediating the neuroprotective effects of MS. Thus, our findings demonstrate that MS is neuroprotective in both in vivo and in vitro ischemic conditions, through a mechanism which may involve increased endogenous levels of H2O2 and its consequent conversion to molecular oxygen by catalase.
Amantea
Diana
D
Department of Pharmacobiology, University of Calabria, Rende (CS), Italy.
Marrone
Maria Cristina
MC
Nisticò
Robert
R
Federici
Mauro
M
Bagetta
Giacinto
G
Bernardi
Giorgio
G
Mercuri
Nicola Biagio
NB
D000640:Amitrole / Q000494:pharmacology; D000818:Animals; D002374:Catalase / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000037:antagonists & inhibitors*; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy*; D008297:Male; D019579:Neocortex / Q000187:drug effects / Q000503:physiopathology; D017072:Neostriatum / Q000187:drug effects / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000188:drug therapy*; D013870:Thiomalates / Q000627:therapeutic use*
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D013870:Thiomalates; C046062:2-thiomalic acid; D006861:Hydrogen Peroxide; D002374:Catalase; D005979:Glutathione Peroxidase; D000640:Amitrole