Protection of dopaminergic neurons with a novel astrocyte modulating agent (R)-(-)-2-propyloctanoic acid (ONO-2506) in an MPTP-mouse model of Parkinson's disease.
We examined the neuroprotective effects of a novel astrocyte-modulating agent, (R)-(-)-2-propyloctanoic acid (ONO-2506), in a mouse model of Parkinson's disease. Male C57BL/6 mice received four intraperitoneal injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (10 mg/kg) at 1-h intervals. Dopamine content in the striatum, measured with HPLC 3 days after MPTP injection, was reduced to 23% of control. But this dopamine depletion was dose-dependently prevented by repeated treatments with ONO-2506 (3, 10 and 30 mg/kg, i.p.) administered 1, 6, 24 and 48 h after MPTP injection (51% of control in 30 mg/kg group, p<0.01). ONO-2506 treatment (30 mg/kg) started after 6 h, followed by treatments at 24 and 48 h, also prevented the reduction of dopamine content (42% of control vs. 11% of control in the saline-treated group, p<0.01). We also performed immunohistochemistry for tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP). The MPTP injection resulted in a loss of TH-positive dopaminergic neurons (42% of control, p<0.01) in the substantia nigra after 7 days, but ONO-2506 treatment prevented this neuronal loss (70% of control, p<0.01). The MPTP injection led to reactive astrocytosis in the striatum after 7 days, but ONO-2506 induced earlier, moderate astrocytic activation after 3-7 days. These findings show that ONO-2506 protects dopaminergic neurons against MPTP neurotoxicity probably through facilitating astrocytic support for neuronal recovery from injury. Pharmacological modulation of astrocytes may offer a novel therapeutic strategy for Parkinson's disease.
Kato
Hiroyuki
H
Department of Neurology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku,Sendai 980-8574, Japan. katoh@mail.cc.tohoku.ac.jp
Araki
Tsutomu
T
Imai
Yutaka
Y
Takahashi
Akira
A
Itoyama
Yasuto
Y
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D002210:Caprylates / Q000627:therapeutic use*; D003342:Corpus Striatum / Q000293:injuries / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000188:drug therapy; D013378:Substantia Nigra / Q000166:cytology / Q000473:pathology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D002210:Caprylates; D005904:Glial Fibrillary Acidic Protein; D018696:Neuroprotective Agents; C459360:ONO2506; D015102:3,4-Dihydroxyphenylacetic Acid; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine