This is the first study to investigate the potential protective effects of the lipophilic kavapyrone (+/-)-
kavain in the experimental
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of
Parkinson's disease (PD). Male C57BL/6 mice were treated with (+/-)-
kavain (50, 100, or 200 mg/kg i.p.) or vehicle 60 min before and 60 min after a single administration of
MPTP (30 mg/kg s.c.) or saline, respectively. Mice were sacrificed after 7 days and the neostriatum was analyzed for
dopamine and its metabolites using HPLC with electrochemical detection. Furthermore, nigral sections were processed for
tyrosine hydroxylase (TH) immunocytochemistry. To determine the effects of (+/-)-
kavain (200 mg/kg) on
MPTP metabolism, HPLC analysis of striatal MPP(+) (1-methyl-4-phenylpyridinium) levels was performed.
MPTP treatment alone led to a significant depletion of striatal
dopamine levels to 12.61% of saline controls. The lower dosages of (+/-)-
kavain (50 and 100 mg/kg) showed only a nonsignificant attenuation of
MPTP-induced
dopamine depletion, but a high dosage of (+/-)-
kavain (200 mg/kg) significantly antagonized the
dopamine depletion to 58.93% of saline control values. Remarkably, the
MPTP-induced decrease of TH-immunoreactivity as well as the loss of nigral neurons was completely prevented by (+/-)-
kavain (200 mg/kg). Striatal MPP(+) levels were not altered by (+/-)-
kavain treatment. In conclusion, we found that
MPTP metabolism was not influenced by (+/-)-
kavain and postulate the antiglutamatergic effects of (+/-)-
kavain for its protective effects against
MPTP toxicity. (+/-)-
Kavain may be a novel candidate for further preclinical studies in animal models of PD and other disorders with glutamatergic overactivity.