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Antioxidants attenuate MK-801-induced cortical neurotoxicity in the rat
1MRC Applied Neuroscience Group, School of Biomedical Sciences, Queen's Medical Centre, University of Nottingham, NG7 2UH, UK. colin.willis@nottingham.ac.uk
Abstract:
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.
Insights
Antioxidants like DMSO significantly reduce neurodegeneration caused by N-methyl-D-aspartate (NMDA) antagonists, suggesting oxidative stress is key. This neuroprotective effect persists even when treatment is delayed, offering therapeutic potential for brain injury.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- Oxidative stress is linked to neurodegenerative diseases and can stem from increased local brain metabolism.
- NMDA antagonists like MK-801 elevate glucose metabolism and cause neuronal damage in specific rat brain regions.
Purpose of the Study:
- To investigate the neuroprotective effects of various antioxidants against MK-801-induced neuronal loss.
- To explore the role of oxidative stress in NMDA antagonist-induced neurotoxicity.
Main Methods:
- Administration of MK-801 to rats to induce neuronal necrosis.
- Treatment with different antioxidants: free radical scavengers (DMSO, alpha-tocopherol) and spin traps (S-PBN, DEPMPO).
- Assessment of neuronal loss, cytoplasmic vacuoles, heat shock protein expression, and regional cerebral blood flow.
Main Results:
- Free radical scavengers and spin traps significantly attenuated MK-801-induced neuronal necrosis.
- Dimethyl sulfoxide (DMSO) provided substantial neuroprotection (80-86% reduction) even when administered up to 4 hours post-MK-801.
- MK-801 caused a rapid, prolonged increase in posterior cingulate blood flow, which DMSO only transiently reduced.
Conclusions:
- Oxidative stress is implicated in MK-801-induced neuronal necrosis.
- Antioxidants demonstrate significant neuroprotective potential against NMDA antagonist toxicity.
- The findings support the therapeutic utility of antioxidants in conditions involving oxidative stress-induced brain damage.
