An dieser Stelle möchten wir Ihnen einen kurzen Überblick über die aktuellen wissenschaftlichen Publikationen zum Einsatz von Fasudil bei der Parkinsonerkrankung geben.

Bitte beachten Sie, dass die hier vorgestellte Literatur lediglich als Einleitung dienen soll und keinen Anspruch auf Vollständigkeit hat. 

 

Publikationen zur ROCK-PD Studie

Wolff, AW; Bidner, H; Remane, Y; Zimmer, J; Aarsland, D; Rascol, O; Wyse, RK; Hapfelmeier, A; and Lingor, P (2024) Protocol for a randomized, placebo-controlled, double-blind phase IIa study of the safety, tolerability, and symptomatic efficacy of the ROCK-inhibitor Fasudil in patients with Parkinson’s disease (ROCK-PD). Front. Aging Neurosci. 16:1308577. https://doi.org/10.3389/fnagi.2024.1308577

Rho-Kinase (ROCK)
 

Li, Z.; Dong, X.; Dong, X.; Wang, Z.; Liu, W.; Deng, N.; Ding, Y.; Tang, L.; Hla, T.; Zeng, R.; et al. Regulation of PTEN by Rho small GTPases. Nat. Cell Biol. 2005, 7, 399–404. https://doi.org/10.1038/ncb1236

Park, J.; Arakawa-Takeuchi, S.; Jinno, S.; Okayama, H. Rho-associated kinase connects a cell cycle-controlling anchorage signal to the mammalian target of rapamycin pathway. J. Biol. Chem. 2011, 286, 23132-23141. https://doi.org/10.1074/jbc.M110.209114

Zhang, H.; Li, Y.; Yu, J.; Guo, M.; Meng, J.; Liu, C.; Xie, Y.; Feng, L.; Xiao, B.; Ma, C. Rho kinase inhibitor fasudil regulates microglia polarization and function. Neuroimmunomodulation 2013, 20, 313-322. https://doi.org/10.1159/000351221

Fasudil und die Parkinsonerkrankung

Koch, J. C., Tatenhorst, L., Roser, A. E., Saal, K. A., Tönges, L., & Lingor, P. (2018). ROCK inhibition in models of neurodegeneration and its potential for clinical translation. Pharmacology & therapeutics, 189, 1–21. https://doi.org/10.1016/j.pharmthera.2018.03.008

Roser, A. E., Tönges, L., & Lingor, P. (2017). Modulation of Microglial Activity by Rho-Kinase (ROCK) Inhibition as Therapeutic Strategy in Parkinson's Disease and Amyotrophic Lateral Sclerosis. Frontiers in aging neuroscience, 9, 94. https://doi.org/10.3389/fnagi.2017.00094

Tatenhorst, L., Eckermann, K., Dambeck, V., Fonseca-Ornelas, L., Walle, H., Lopes da Fonseca, T., Koch, J. C., Becker, S., Tönges, L., Bähr, M., Outeiro, T. F., Zweckstetter, M., & Lingor, P. (2016). Fasudil attenuates aggregation of α-synuclein in models of Parkinson's disease. Acta neuropathologica communications, 4, 39. https://doi.org/10.1186/s40478-016-0310-y

Saal, K. A., Galter, D., Roeber, S., Bähr, M., Tönges, L., & Lingor, P. (2017). Altered Expression of Growth Associated Protein-43 and Rho Kinase in Human Patients with Parkinson's Disease. Brain pathology (Zurich, Switzerland), 27(1), 13–25. https://doi.org/10.1111/bpa.12346

Tönges, L., Frank, T., Tatenhorst, L., Saal, K. A., Koch, J. C., Szego, É. M., Bähr, M., Weishaupt, J. H., & Lingor, P. (2012). Inhibition of rho kinase enhances survival of dopaminergic neurons and attenuates axonal loss in a mouse model of Parkinson's disease. Brain : a journal of neurology, 135(Pt 11), 3355–3370. https://doi.org/10.1093/brain/aws254

Robustelli, P., Ibanez-de-Opakua, A., Campbell-Bezat, C., Giordanetto, F., Becker, S., Zweckstetter, M., Pan, A. C., & Shaw, D. E. (2022). Molecular Basis of Small-Molecule Binding to α-Synuclein. Journal of the American Chemical Society, 144(6), 2501–2510. https://doi.org/10.1021/jacs.1c07591

Yang, Y. J., Bu, L. L., Shen, C., Ge, J. J., He, S. J., Yu, H. L., Tang, Y. L., Jue, Z., Sun, Y. M., Yu, W. B., Zuo, C. T., Wu, J. J., Wang, J., & Liu, F. T. (2020). Fasudil Promotes α-Synuclein Clearance in an AAV-Mediated α-Synuclein Rat Model of Parkinson's Disease by Autophagy Activation. Journal of Parkinson's disease, 10(3), 969–979. https://doi.org/10.3233/JPD-191909

Liu, F. T., Yang, Y. J., Wu, J. J., Li, S., Tang, Y. L., Zhao, J., Liu, Z. Y., Xiao, B. G., Zuo, J., Liu, W., & Wang, J. (2016). Fasudil, a Rho kinase inhibitor, promotes the autophagic degradation of A53T α-synuclein by activating the JNK 1/Bcl-2/beclin 1 pathway. Brain research, 1632, 9–18. https://doi.org/10.1016/j.brainres.2015.12.002

Lopez-Lopez, A.; Labandeira, C.M.; Labandeira-Garcia, J.L.; Muñoz, A. Rho kinase inhibitor fasudil reduces l-DOPA-induced dyskinesia in a rat model of Parkinson's disease. Br. J. Pharmacol. 2020, 177, 5622-5641. https://doi.org/10.1111/bph.15275

Sortwell CE, Manfredsson FP, Kemp C, Gombashlampe S, Kuhn N, Paumier K, et al. Nigral neuroprotection against alpha- synuclein toxicity is provided by oral fasudil administration. San Diego, CA; p. online.

Fasudil und die Amyotrophe Lateralsklerose
 

Koch, J. C., Kuttler, J., Maass, F., Lengenfeld, T., Zielke, E., Bähr, M., & Lingor, P. (2020). Compassionate Use of the ROCK Inhibitor Fasudil in Three Patients With Amyotrophic Lateral Sclerosis. Frontiers in neurology, 11, 173. https://doi.org/10.3389/fneur.2020.00173

Lingor, P., Weber, M., Camu, W., Friede, T., Hilgers, R., Leha, A., Neuwirth, C., Günther, R., Benatar, M., Kuzma-Kozakiewicz, M., Bidner, H., Blankenstein, C., Frontini, R., Ludolph, A., Koch, J. C., & ROCK-ALS Investigators (2019). ROCK-ALS: Protocol for a Randomized, Placebo-Controlled, Double-Blind Phase IIa Trial of Safety, Tolerability and Efficacy of the Rho Kinase (ROCK) Inhibitor Fasudil in Amyotrophic Lateral Sclerosis. Frontiers in neurology, 10, 293. https://doi.org/10.3389/fneur.2019.00293

Günther, R.; Balck, A.; Koch, J.C.; Nientiedt, T.; Sereda, M.; Bähr, M.; Lingor, P.; Tönges, L. Rho Kinase Inhibition with Fasudil in the SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis-Symptomatic Treatment Potential after Disease Onset. Front. Pharmacol. 2017, 8, 17. https://doi.org/10.3389/fphar.2017.00017

Fasduil und andere Erkrankungen

Ruan, H.; Zhang, Y.; Liu, R.; Yang, X. The acute effects of 30 mg vs 60 mg of intravenous Fasudil on patients with congenital heart defects and severe pulmonary arterial hypertension. Congenit. Heart Dis. 2019, 14, 645-650. https://doi.org/10.1111/chd.12764

Hou, H.-T.; Wang, Z.-Q.; Wang, J.; Yang, Q.; He, G.-W. Antispastic Effect of Fasudil and Cocktail of Fasudil and Nitroglycerin in Internal Thoracic Artery. Ann. Thorac. Surg. 2022. https://doi.org/10.1016/j.athoracsur.2021.11.079

Shibuya, M.; Hirai, S.; Seto, M.; Satoh, S.; Ohtomo, E. Effects of fasudil in acute ischemic stroke: results of a prospective placebo-controlled double-blind trial. J. Neurol. Sci. 2005, 238, 31-39. https://doi.org/10.1016/j.jns.2005.06.003

Suzuki, Y.; Shibuya, M.; Satoh, S.; Sugimoto, Y.; Takakura, K. A postmarketing surveillance study of fasudil treatment after aneurysmal subarachnoid hemorrhage. Surg. Neurol. 2007, 68, 126-31; discussion 131-2. https://doi.org/10.1016/j.surneu.2006.10.037

Suzuki, Y.; Shibuya, M.; Satoh, S.; Sugiyama, H.; Seto, M.; Takakura, K. Safety and efficacy of fasudil monotherapy and fasudil-ozagrel combination therapy in patients with subarachnoid hemorrhage: sub-analysis of the post-marketing surveillance study. Neurol. Med. Chir. (Tokyo) 2008, 48, 241-7; discussion 247-8. https://doi.org/10.2176/nmc.48.241

Vicari, R.M.; Chaitman, B.; Keefe, D.; Smith, W.B.; Chrysant, S.G.; Tonkon, M.J.; Bittar, N.; Weiss, R.J.; Morales-Ballejo, H.; Thadani, U. Efficacy and safety of fasudil in patients with stable angina: a double-blind, placebo-controlled, phase 2 trial. J. Am. Coll. Cardiol. 2005, 46, 1803-1811. https://doi.org/10.1016/j.jacc.2005.07.047

Fukumoto, Y.; Yamada, N.; Matsubara, H.; Mizoguchi, M.; Uchino, K.; Yao, A.; Kihara, Y.; Kawano, M.; Watanabe, H.; Takeda, Y.; et al. Double-blind, placebo-controlled clinical trial with a rho-kinase inhibitor in pulmonary arterial hypertension. Circ. J. 2013, 77, 2619-2625. https://doi.org/10.1253/circj.cj-13-0443