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.

Abstract

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.

• Authors: Hiroyuki Kato, Tsutomu Araki, Yutaka Imai, Akira Takahashi, Yasuto Itoyama
• Journal: Journal of the neurological sciences (J Neurol Sci) Vol. 208 Issue 1-2 Pg. 9-15 (Apr 15 2003) ISSN: 0022-510X [Print] Netherlands
• PMID: 12639719 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Caprylates
• Glial Fibrillary Acidic Protein
• Neuroprotective Agents
• ONO2506
• 3,4-Dihydroxyphenylacetic Acid
• Tyrosine 3-Monooxygenase
• Dopamine

Topics

• 3,4-Dihydroxyphenylacetic Acid (metabolism)
• Animals
• Astrocytes (drug effects, pathology)
• Caprylates (therapeutic use)
• Corpus Striatum (injuries, metabolism)
• Disease Models, Animal
• Dopamine (metabolism)
• Dose-Response Relationship, Drug
• Drug Interactions
• Glial Fibrillary Acidic Protein (metabolism)
• Immunohistochemistry
• Male
• Mice
• Mice, Inbred C57BL
• Neuroprotective Agents (therapeutic use)
• Parkinson Disease (drug therapy, metabolism)
• Parkinsonian Disorders (drug therapy)
• Substantia Nigra (cytology, pathology)
• Time Factors
• Tyrosine 3-Monooxygenase (metabolism)