Session Time: 1:45pm-3:15pm
Location: Exhibit Hall C
Objective: To evaluate the therapeutic potential of the Rho Kinase (ROCK) inhibitor Fasudil in translational models of Parkinson’s disease (PD).
Background: There is still a strong need for a disease-modifying treatment of PD because former neuroprotective approaches have all failed. ROCK has recently been identified as a novel molecular target for PD but also for other neurodegenerative disorders such as ALS and is strongly implicated in the regulation of neuronal cell survival, axonal outgrowth and neuroinflammation.
Methods: ROCK was inhibited with Fasudil in lesioned primary midbrain dopaminergic neurons and cellular survival, neurite outgrowth as well as neuroinflammation were evaluated. In the MPTP and 6-OHDA toxin-based and in the human alpha-Synuclein (A53T) overexpressing genetic animal model of PD Fasudil was orally applied and both motor behaviour as well as neuropathological alterations were examined.
Results: In different lesioning primary neuronal cell models of PD Fasudil increased dopaminergic cell survival and stimulated neurite outgrowth which could be attributed to an increased phosphorylation of Akt or recompartmentalization of alpha-Synuclein. Chronic oral administration of Fasudil in the systemic lesion MPTP-model enhanced dopaminergic cell survival and fostered the regeneration of dopaminergic axonal terminals together with a restoration of dopamine levels in the striatum. In the local striatal lesion 6-OHDA-model Fasudil elicited an improved axonal regenerative response while under genetic overexpression of human alpha-Synuclein (A53T) its midbrain pathology was significantly reduced. All animals tolerated Fasudil very well and exhibited an improved motor behavior as evaluated in the cylinder test or Catwalk gait analysis.
Conclusions: Since Fasudil is already licensed for human use for the treatment of subarachnoid hemorrhage-induced vasospasms and has a very favorable safety profile in humans, our data strongly support the large potential of Fasudil as a pharmacological agent for disease-modification in PD.
To cite this abstract in AMA style:L. Tönges, L. Tatenhorst, J. Koch, T. Outeiro, M. Zweckstetter, M. Bähr, P. Lingor. Disease-modification in Translational Models of Parkinson’s disease by the Rho Kinase Inhibitor Fasudil [abstract]. Mov Disord. 2017; 32 (suppl 2). https://www.mdsabstracts.org/abstract/disease-modification-in-translational-models-of-parkinsons-disease-by-the-rho-kinase-inhibitor-fasudil/. Accessed December 1, 2023.
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MDS Abstracts - https://www.mdsabstracts.org/abstract/disease-modification-in-translational-models-of-parkinsons-disease-by-the-rho-kinase-inhibitor-fasudil/