Postischemic blockade of AMPA but not NMDA receptors mitigates neuronal damage in the rat brain following transient severe cerebral ischemia.
Glutamatergic transmission is an important factor in the development of neuronal death following transient cerebral ischemia. In this investigation the effects of N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists on neuronal damage were studied in rats exposed to 10 min of transient cerebral ischemia induced by bilateral common carotid occlusion combined with hypotension. The animals were treated with a blocker of the ionotropic quisqualate or alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptor, 2.3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX), given postischemia as an intraperitoneal bolus dose of 30 mg kg-1 followed by an intravenous infusion of 75 micrograms min-1 for 6 h, or with the noncompetitive NMDA receptor blocker dizocilpine (MK-801) given 1 mg kg-1 i.p. at recirculation and 3 h postischemia, or with the competitive NMDA receptor antagonist DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116), 5 mg kg-1, given intraperitoneally at recirculation. Treatment with NBQX provided a significant reduction of neuronal damage in the hippocampal CA1 area by 44-69%, with the largest relative decrease in the temporal part of the hippocampus. In neocortex a significant decrease in the number of necrotic neurons was also noted. No protection could be seen following postischemic treatment with dizocilpine or CGP 40116. Our data demonstrate that AMPA but not NMDA receptor antagonists decrease neuronal damage following transient severe cerebral ischemia in the rat and that the protection by NBQX may be dependent on the severity of the ischemic insult. We propose that the AMPA receptor-mediated neurotoxicity could be due to ischemia-induced changes in the control mechanisms of AMPA receptor-coupled processes or to changes of AMPA receptor characteristics.
Laboratory for Experimental Brain Research, University Hospital, Lund University, Sweden.
B
B
Nellgård
T
T
Wieloch
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure; D001831:Body Temperature; D016923:Cell Death / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*
D001786:Blood Glucose; D011810:Quinoxalines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C064539:2-amino-4-methyl-5-phosphono-3-pentenoic acid; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate