title: Rho kinase inhibition by fasudil in the striatal 6-hydroxydopamine lesion mouse model of Parkinson disease.
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.
authors.affiliation: 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.
authors.forename: Lars
authors.initials: L
authors.lastname: Tatenhorst
authors.forename: Lars
authors.initials: L
authors.lastname: Tönges
authors.forename: Kim-Ann
authors.initials: KA
authors.lastname: Saal
authors.forename: Jan C
authors.initials: JC
authors.lastname: Koch
authors.forename: Éva M
authors.initials: ÉM
authors.lastname: Szegő
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
authors.forename: Paul
authors.initials: P
authors.lastname: Lingor
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D001058:Apomorphine; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D053580:Muscle Strength / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D013378:Substantia Nigra / Q000473:pathology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018663:Adrenergic Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine; C049347:fasudil; D004298:Dopamine