title: Inhibition of rho kinase enhances survival of dopaminergic neurons and attenuates axonal loss in a mouse model of Parkinson's disease.
abstract: Axonal degeneration is one of the earliest features of Parkinson's disease pathology, which is followed by neuronal death in the substantia nigra and other parts of the brain. Inhibition of axonal degeneration combined with cellular neuroprotection therefore seem key to targeting an early stage in Parkinson's disease progression. Based on our previous studies in traumatic and neurodegenerative disease models, we have identified rho kinase as a molecular target that can be manipulated to disinhibit axonal regeneration and improve survival of lesioned central nervous system neurons. In this study, we examined the neuroprotective potential of pharmacological rho kinase inhibition mediated by fasudil in the in vitro 1-methyl-4-phenylpyridinium cell culture model and in the subchronic in vivo 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Application of fasudil resulted in a significant attenuation of dopaminergic cell loss in both paradigms. Furthermore, dopaminergic terminals were preserved as demonstrated by analysis of neurite network in vitro, striatal fibre density and by neurochemical analysis of the levels of dopamine and its metabolites in the striatum. Behavioural tests demonstrated a clear improvement in motor performance after fasudil treatment. The Akt survival pathway was identified as an important molecular mediator for neuroprotective effects of rho kinase inhibition in our paradigm. We conclude that inhibition of rho kinase using the clinically approved small molecule inhibitor fasudil may be a promising new therapeutic strategy for Parkinson's disease.
authors.affiliation: Department of Neurology, University Medicine Göttingen, Robert-Koch-Str 40, 37075 Göttingen, Germany. ltoenge@gwdg.de
authors.forename: Lars
authors.initials: L
authors.lastname: Tönges
authors.forename: Tobias
authors.initials: T
authors.lastname: Frank
authors.forename: Lars
authors.initials: L
authors.lastname: Tatenhorst
authors.forename: Kim A
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: Szego
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
authors.forename: Jochen H
authors.initials: JH
authors.lastname: Weishaupt
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; D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000201:enzymology / Q000473:pathology / Q000502:physiology*; D020267:MPTP Poisoning / Q000188:drug therapy / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D016501:Neurites / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D018696:Neuroprotective Agents; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; C049347:fasudil; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine