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Excitatory amino acid antagonists protect mice against MPP+ seizures
1Research Laboratories of Schering AG, Berlin, Federal Republic of Germany.
Abstract:
Administration of 1-methyl-4-phenyl-pyridinium ion (MPP+) into the lateral ventricle of mice induced clonic convulsions and lethality in a dose- and age-dependent manner. MPP+ failed to induce seizures in 4-day-old mice, and the convulsant response to MPP+ was enhanced in aged mice. The seizures triggered by MPP+ in adult mice were blocked by coadministration of L-glutamate antagonists active at kainate/AMPA receptors such as gamma-D-glutamylaminomethylsulphonate and 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline. The N-methyl-D-aspartate (NMDA) antagonist 2-amino-7-phosphonoheptanoate, but not kynurenate, also protected mice against MPP+ convulsions. Similarly, the benzodiazepine midazolam and the adenosine A1 agonist 2-chloroadenosine, but not antiepileptic drugs such as phenobarbital, trimethadione, ethosuximide, or acetazolamide, showed a protective efficacy against seizures. Additionally, the excitatory amino acid antagonists as well as phenobarbital, midazolam and 2-chloroadenosine protected mice against MPP+ lethality. These data suggest that convulsant action of MPP+ and its lethality in rodents may be mediated by excitatory amino acids.
Insights
1-methyl-4-phenyl-pyridinium ion (MPP+) causes seizures and death in mice, with effects varying by age. Excitatory amino acid antagonists and certain drugs block these effects, suggesting a role for excitatory amino acids.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- 1-methyl-4-phenyl-pyridinium ion (MPP+) is a neurotoxin known to induce Parkinsonism-like symptoms.
- The precise mechanisms underlying MPP+-induced seizures and lethality are not fully understood.
Purpose of the Study:
- To investigate the role of excitatory amino acids in MPP+-induced convulsions and lethality in mice.
- To identify potential therapeutic targets for mitigating MPP+-induced neurotoxicity.
Main Methods:
- Administration of MPP+ into the lateral ventricle of mice of different ages.
- Assessment of seizure induction and lethality following MPP+ administration.
- Evaluation of the protective effects of various neurochemical agents, including glutamate receptor antagonists, benzodiazepines, and adenosine agonists.
Main Results:
- MPP+ induced dose- and age-dependent clonic convulsions and lethality in mice.
- The convulsant and lethal effects of MPP+ were significantly reduced by antagonists of kainate/AMPA and NMDA receptors.
- Midazolam (a benzodiazepine) and 2-chloroadenosine (an adenosine A1 agonist) also demonstrated protective efficacy against MPP+-induced seizures and lethality.
- Conventional antiepileptic drugs were largely ineffective in preventing MPP+-induced seizures.
Conclusions:
- The findings suggest that excitatory amino acids play a crucial role in the neurotoxic effects of MPP+.
- Targeting excitatory amino acid pathways may offer a therapeutic strategy for conditions involving MPP+-like neurotoxicity.