A novel anti-Parkinsonian agent, zonisamide, attenuates MPTP-induced neurotoxicity in mice.
Zonisamide, an anti-convulsant drug, has recently been shown to exert beneficial effects in Parkinson's disease (PD). However, actual pathophysiological mechanism underlying the anti-parkinsonian effect of zonisamide remains uncertain. Here we tested exactly the neuroprotective effect of zonisamide against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice. We observed that zonisamide attenuated MPTP-induced dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) depletion in the striatum and reduced the loss of tyrosine hidroxylase (TH) positive neurons and the increase of glial fibrillary acidic protein (GFAP) positive astrocytes in the striatum and substantia nigra after 5 days. Our Western blot analysis study also showed that zonisamide can prevent the decrease of TH protein levels and increase of GFAP protein levels in the striatum 5 days after MPTP treatment. In the present study, on the other hand, zonisaimde treatment showed no significant changes of the striatal dopamine, DOPAC, and HVA content in the striatum of normal mice after 1 day, as compared to the vehicle-treated group. Furthermore, zonisamide produced a significant increase of the TH protein levels in the striatum after 1 day, as compared to vehicle-treated group. In contrast, zonisamide showed no significant changes of the GFAP protein levels in the striatum after 1 day, as compared to vehicle-treated group. These results show that anticonvulsant drug, zonisamide, has the neuroprotective effect in the MPTP model of PD in mice. Our study also demonstrates that the neuroprotective effect of zonisamide against dopaminergic cell damage may be mediated by the elevation of TH activity on dopaminergic system after MPTP treatment in mice. Our findings suggest that zonisamide may offer a new approach for the treatment of PD.
Yano
Ryohei
R
Department of Neurobiology and Therapeutics, Graduate School and Faculty of Pharmaceutical Sciences, The University of Tokushima, Tokushima 770-8505, Japan.
Yokoyama
Hironori
H
Kuroiwa
Hayato
H
Kato
Hiroyuki
H
Araki
Tsutomu
T
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D020267:MPTP Poisoning / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy*; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D000078305:Zonisamide
D000927:Anticonvulsants; D000978:Antiparkinson Agents; D005904:Glial Fibrillary Acidic Protein; D007555:Isoxazoles; D018696:Neuroprotective Agents; D000078305:Zonisamide; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D006719:Homovanillic Acid