Delayed treatment with arundic acid reduces the MPTP-induced neurotoxicity in mice.
The authors investigated the protective effects of a novel astrocyte-modulating agent, arundic acid, in a 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP) mouse model of Parkinson's disease. Male mice received four intraperitoneal (i.p.) injections of MPTP (20 mg/kg) at 2 h intervals. The content of dopamine and its metabolites in the striatum was reduced markedly 7 days after MPTP treatment. The delayed treatment with arundic acid (30 mg/kg, i.p.) administered 3, 4, 5 and 6 days after MPTP treatment did not affect the depletion of dopamine and its metabolites in the striatum. Our immunohistochemical study with anti-tyrosine hydroxylase antibody, anti-neuronal nuclei antibody, anti-glial fibrillary acidic protein antibody, anti-S 100beta antibody and anti-nestin antibody showed that the delayed treatment with arundic acid had a protective effect against MPTP-induced neuronal damage in the striatum and the substantia nigra of mice. Furthermore, this agent ameliorated the severe reductions in number of isolectin reactive microglia in the striatum and the substantia nigra 7 days after MPTP treatment. These results demonstrate that the inhibition of S 100beta synthesis in astrocytes may be the major component of the beneficial effect of arundic acid. Thus, our present findings provide that the therapeutic strategies targeted to astrocytic modulation with arundic acid offers a great potential for restoring the functional capacity of the surviving dopaminergic neurons in individuals affected with Parkinson's disease.
Oki
Chie
C
Department of Neurobiology and Therapeutics, Graduate School and Faculty of Pharmaceutical Sciences, The University of Tokushima, 1-78 Sho-machi, Tokushima 770-8505, Japan.
Watanabe
Yu
Y
Yokoyama
Hironori
H
Shimoda
Taiji
T
Kato
Hiroyuki
H
Araki
Tsutomu
T
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D002210:Caprylates / Q000494:pharmacology / Q000627:therapeutic use*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins; D004298:Dopamine / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000378:metabolism; D037102:Lectins / Q000378:metabolism; D020267:MPTP Poisoning / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000378:metabolism; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D002210:Caprylates; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; D037102:Lectins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; C492380:NeuN protein, mouse; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; C459360:ONO2506; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine