Rho kinase inhibitor fasudil reduces l-DOPA-induced dyskinesia in a rat model of Parkinson's disease.
Br J Pharmacol
; 177(24): 5622-5641, 2020 12.
Article
em En
| MEDLINE
| ID: mdl-32986850
ABSTRACT
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. EXPERIMENTALAPPROACH:
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. KEYRESULTS:
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença de Parkinson
/
Discinesia Induzida por Medicamentos
Limite:
Animals
Idioma:
En
Revista:
Br J Pharmacol
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Espanha