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Rho kinase inhibitor fasudil reduces l ‐DOPA‐induced dyskinesia in a rat model of Parkinson's disease
Author(s) -
LopezLopez Andrea,
Labandeira Carmen M.,
LabandeiraGarcia Jose L.,
Muñoz Ana
Publication year - 2020
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15275
Subject(s) - fasudil , rhoa , rho associated protein kinase , rho kinase inhibitor , pharmacology , dopaminergic , medicine , chemistry , kinase , dopamine , signal transduction , biochemistry
Background and Purpose Rho kinase (ROCK) activation is involved in neuroinflammatory processes leading to progression of neurodegenerative diseases such as Parkinson's disease. Furthermore, ROCK plays a major role in angiogenesis. Neuroinflammation and angiogenesis are mechanisms involved in developing l ‐DOPA‐induced dyskinesias (LID). However, it is not known whether ROCK plays a role in LID and whether ROCK inhibitors may be useful against LID. Experimental Approach In rats, we performed short‐ and long‐term dopaminergic lesions using 6‐hydroxydopamine and developed a LID model. Effects of dopaminergic lesions and LID on the RhoA/ROCK levels were studied by western blot, real‐time PCR analyses and ROCK activity assays in the substantia nigra and striatum. The effects of the ROCK inhibitor fasudil on LID were particularly investigated. Key Results Short‐term 6‐hydroxydopamine lesions increased nigrostriatal RhoA/ROCK expression, apparently related to the active neuroinflammatory process. However, long‐term dopaminergic denervation (completed and stabilized lesions) led to a decrease in RhoA/ROCK levels. Rats with LID showed a significant increase of RhoA and ROCK expression. The development of LID was reduced by the ROCK inhibitor fasudil (10 and 40 mg·kg −1 ), without interfering with the therapeutic effect of l ‐DOPA. Interestingly, treatment of 40 mg·kg −1 of fasudil also induced a significant reduction of dyskinesia in rats with previously established LID. Conclusion and Implications The present results suggest that ROCK is involved in the pathophysiology of LID and that ROCK inhibitors such as fasudil may be a novel target for preventing or treating LID. Furthermore, previous studies have revealed neuroprotective effects of ROCK inhibitors.