Excitatory amino acid antagonists protect mice against MPP + seizures

Adminstration 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 α‐D‐glutamylaminomethylsulphonate and 2,3‐dihydroxy‐6‐nitro‐7‐sulphamoyl‐benzo[f]quinoxaline. The N‐methyl‐D‐asparate (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‐chloradenosine 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.