Riluzole (2-amino-6-trifluoromethoxy benzothiazole) attenuates MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity in mice.
The protective effects of 2-amino-6-trifluoromethoxy benzothiazole (riluzole), a Na(+) channel blocker with antiglutamatergic activity were investigated in the model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced depletion of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in mice. The mice were injected intraperitoneally (i.p.) with four administrations of MPTP (10 mg/kg) at 1 h intervals and then the brains were analyzed at 3 and 7 days after the treatments. Dopamine, DOPAC and HVA levels were significantly decreased in the striatum 3 days after MPTP treatments. Riluzole dose-dependently antagonized the MPTP-induced decrease in dopamine, DOPAC and HVA levels in the striatum. MPTP treatment also caused a severe decrease in the amount of nigral tyrosine hydroxylase protein (TH) and microtuble-associated protein 2 (MAP 2) and produced a marked increase in the striatal glial fibrillary acidic protein (GFAP). Our immunohistochemical study with TH and MAP 2 staining showed that riluzole can protect against MPTP-induced neuronal damage in the substantia nigra. Furthermore, riluzole markedly increased the striatal GFAP-positive astrocytes 3 days after MPTP treatments. These results suggest that riluzole is effective against MPTP-induced neurodegeneration of the nigrostriatal dopaminergic neuronal pathway. Our findings also may provide a rationale for the identification of astrocytes as a prominent target for the development of new therapies of Parkinson's disease.
Araki
T
T
Department of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Science and Medicine, Aoba-yama, Sendai 980-8578, Japan. tsuaraki@mail.cc.tohuko.ac.jp
Muramatsu
Y
Y
Tanaka
K
K
Matsubara
M
M
Imai
Y
Y
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004347:Drug Interactions / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019782:Riluzole / Q000494:pharmacology*; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D005904:Glial Fibrillary Acidic Protein; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D015102:3,4-Dihydroxyphenylacetic Acid; D018698:Glutamic Acid; D019782:Riluzole; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D006719:Homovanillic Acid