Effect of the noncompetitive NMDA antagonists MK-801 and ketamine on the spastic Han-Wistar mutant: a rat model of excitotoxicity.
The neuroprotective effects of the NMDA antagonists MK-801 and ketamine were analyzed in a mutant strain of Han-Wistar rats which develop neurodegeneration in the hippocampus and cerebellum. Previous experiments have shown that the progressive neuronal degeneration observed in this mutant may be the result of a dysfunctional glutamatergic system. For MK-801 studies, mutants were injected in a chronic paradigm with (+)MK-801 or its weaker acting isomer (-)MK-801 at a dose of 1 mg/kg. Ketamine studies consisted of both acute (50 mg/kg once) and chronic (10 mg/kg multiple times) injection paradigms. MK-801-treated mutants exhibited longer life spans (8-23%) compared to saline-injected mutants. Ketamine-injected mutants in both paradigms also lived slightly longer (6-9%) than the saline mutants. Motor skill deterioration was monitored in an open-field test, and after 50 days of age the MK-801 and ketamine mutants displayed over 20% greater motor skill activity than the saline mutants. In the cerebellum, mutants treated with ketamine and both forms of MK-801 had 10-20% more Purkinje cells surviving at 55 days than the saline mutants. Further, the density of CA3c pyramidal hippocampal neurons in ketamine and MK-801-treated mutants as compared to saline mutants appeared to be greater upon qualitative analysis. This study shows that these mutants derive some protective effects from the NMDA antagonists MK-801 and ketamine, confirming glutamate-induced excitotoxicity as a possible cause of neuronal degeneration in this mutant strain of rat.
Brunson
K L
KL
Department of Biology, California State University at Northridge, Calif. 91330, USA.
Khanna
A
A
Cromwell
H C
HC
Cohen
R W
RW
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000502:physiology; D006624:Hippocampus / Q000166:cytology; D007649:Ketamine / Q000494:pharmacology*; D008136:Longevity / Q000187:drug effects; D009128:Muscle Spasticity / Q000188:drug therapy; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins; D011689:Purkinje Cells / Q000166:cytology; D017966:Pyramidal Cells / Q000166:cytology; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D007649:Ketamine; D016291:Dizocilpine Maleate