Antioxidants attenuate MK-801-induced cortical neurotoxicity in the rat.
Oxidative stress has been implicated in the pathogenesis of several neurodegenerative diseases and may result from excessive free radical production due to increased local metabolism. Non-competitive N-methyl-D-aspartate (NMDA) antagonists (MK-801 and phencyclidine) increase glucose metabolism in many brain areas and induce cytoplasmic vacuoles, heat shock protein and necrotic cell death in neurones of the rodent posterior cingulate and retrosplenial cortex. We have investigated the effect of several antioxidants with differing properties on MK-801-induced neuronal loss. Free radical scavengers (dimethyl sulfoxide (DMSO) and alpha-tocopherol) and spin traps (N-tert-butyl-alpha-(2-sulfophenyl)-nitrone (S-PBN) and 5-(diethoxyphosphoryl)-5-methyl-1-pyrrole N-oxide (DEPMPO)), produced marked attenuation of MK-801-induced neuronal necrosis in the rat posterior cingulate and retrosplenial cortex. Further, administration of DMSO could be delayed by up to 4 h after MK-801 dosing and still achieve between 80 and 86% reduction in neuronal loss. We also show that MK-801 administration rapidly induced a four-fold and prolonged increase in cerebral blood flow in the posterior cingulate. This elevated regional blood flow was only transiently reduced by DMSO administration. The anterior cingulate, a region which undergoes no neuronal loss, showed only a two-fold increase in regional blood flow following MK-801 administration. These results support a hypothesis that oxidative stress plays a role in MK-801-induced neuronal necrosis since pathological changes can be attenuated by several antioxidants.
Willis
Colin L
CL
MRC Applied Neuroscience Group, School of Biomedical Sciences, Queen's Medical Centre, University of Nottingham, NG7 2UH, UK. colin.willis@nottingham.ac.uk
Ray
David E
DE
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002540:Cerebral Cortex / Q000473:pathology*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D009474:Neurons / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D014810:Vitamin E / Q000494:pharmacology
C510912:(diethoxyphosphoryl)-5-methylpyrroline N-oxide; D000975:Antioxidants; D003497:Cyclic N-Oxides; D018691:Excitatory Amino Acid Antagonists; D016166:Free Radical Scavengers; D011758:Pyrroles; D014810:Vitamin E; C029217:phenyl-N-tert-butylnitrone; D016291:Dizocilpine Maleate; D004121:Dimethyl Sulfoxide