Protective effect of riluzole on MPTP-induced depletion of dopamine and its metabolite content in mice.
The neuroprotective effects of riluzole (2-amino-6-trifluoromethoxy benzothiazole), a Na+ channel blocker with antiglutamatergic activity, MK-801, a blocker of N-methyl-D-aspartate (NMDA) receptors and monoamine oxidase (MAO) inhibitor pargyline were compared in the model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced depletion of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) levels in mice. The mice received four intraperitoneal injections of MPTP (10 mg/kg) at 1-hr intervals and then the brains were analyzed at 1, 3 and 7 days after the treatments. Dopamine and DOPAC levels were significantly decreased in the striatum from 1 day after MPTP treatments. A severe depletion in dopamine and DOPAC levels was found in the striatum 3 and 7 days after MPTP treatments. Riluzole dose-dependently antagonized the MPTP-induced decrease in dopamine and DOPAC levels in the striatum. Pargyline also protected against MPTP-induced decrease in dopamine levels in the striatum. However, this drug showed no significant change in the striatal DOPAC levels. On the other hand, MK-801 failed to protect against MPTP-induced decrease in dopamine levels in the striatum. However, MK-801 reversed the MPTP-induced decrease in DOPAC levels. These results suggest that riluzole can protect against MPTP-induced striatal dopamine and DOPAC depletion in mice. This protective effect may be caused by inactivation of voltage-dependent Na+ channels by riluzole. Furthermore, the present study suggests that the activation of NMDA receptors does not mainly contribute to MPTP-induced neurodegeneration, whereas MAO, especially MAO type B(MAO-B) plays a crucial role in MPTP-induced degeneration of the nigrostriatal dopaminergic neuronal pathway.
Araki
T
T
Department of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Science and Medicine, Aoba-yama, Sendai, Japan. tsuaraki@mail.cc.tohoku.ac.jp
Kumagai
T
T
Matsubara
M
M
Ido
T
T
Imai
Y
Y
Itoyama
Y
Y
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010293:Pargyline / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D019782:Riluzole / Q000627:therapeutic use*; D015222:Sodium Channels / Q000187:drug effects; D013997:Time Factors
D015259:Dopamine Agents; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D015222:Sodium Channels; D015102:3,4-Dihydroxyphenylacetic Acid; D016291:Dizocilpine Maleate; D019782:Riluzole; D010293:Pargyline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine