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J Neuropathol Exp Neurol. 2014 Aug;73(8):770-9. doi: 10.1097/NEN.0000000000000095.

Rho kinase inhibition by fasudil in the striatal 6-hydroxydopamine lesion mouse model of Parkinson disease.

Author information

1
From the Department of Neurology, University Medicine Göttingen (LTa, LTö, K-AS, JCK, MB, PL); Department of Neurodegeneration and Restorative Research, University of Göttingen (ÉMS); and Center Nanoscale Microscopy and Molecular Physiology of the Brain (MB, PL), Göttingen, Germany.

Abstract

Chronic degeneration of nigrostriatal projections, followed by nigral dopaminergic cell death, is a key feature of Parkinson disease (PD). This study examines the neuroprotective potential of the rho kinase inhibitor fasudil in the 6-hydroxydopamine (6-OHDA) mouse model of PD in vivo. C57Bl/6 mice were lesioned by striatal stereotactic injections with 4 μg of 6-OHDA and treated with fasudil 30 or 100 mg/kg body weight via drinking water. Motor behavior was tested biweekly; histologic and biochemical analyses were performed at 4 and 12 weeks after lesion. Motor behavior was severely impaired after 6-OHDA lesion and was not improved by fasudil treatment. Fasudil 100 mg/kg did not significantly increase the number of dopaminergic cells in the substantia nigra after 12 weeks versus lesion controls. Interestingly, however, high-performance liquid chromatography analysis of dopamine metabolites revealed that striatal levels of 3,4-dihydroxyphenylacetic acid were significantly increased after 12 weeks, suggesting a regenerative response. In contrast to recent findings in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin model, fasudil effects seem limited in this severe 6-OHDA model of PD. Nevertheless, high therapeutic concentrations of fasudil are suggestive of a proregenerative potential for dopaminergic neurons, making further evaluations of rho kinase inhibition as a proregenerative therapeutic strategy in PD promising.

PMID:
25003236
DOI:
10.1097/NEN.0000000000000095
[Indexed for MEDLINE]

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