Efficacy of a benzothiazole-based LRRK2 inhibitor in oligodendrocyte precursor cells and in a murine model of multiple sclerosis.

Autor: Benítez-Fernández R; Centro de Investigaciones Biológicas Margarita Salas-CSIC, Madrid, Spain.; Instituto Cajal-CSIC, Madrid, Spain., Josa-Prado F; Instituto Cajal-CSIC, Madrid, Spain., Sánchez E; Instituto Cajal-CSIC, Madrid, Spain., Lao Y; Instituto Cajal-CSIC, Madrid, Spain., García-Rubia A; Centro de Investigaciones Biológicas Margarita Salas-CSIC, Madrid, Spain., Cumella J; Instituto de Química Médica, IQM-CSIC, Madrid, Spain., Martínez A; Centro de Investigaciones Biológicas Margarita Salas-CSIC, Madrid, Spain.; Centro de Investigaciones Biomédicas en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain., Palomo V; Centro de Investigaciones Biomédicas en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.; Instituto Madrileño de Estudios Avanzados, IMDEA Nanociencia, Madrid, Spain.; Unidad de Nanobiotecnología Asociada al Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain., de Castro F; Instituto Cajal-CSIC, Madrid, Spain.
Jazyk: angličtina
Zdroj: CNS neuroscience & therapeutics [CNS Neurosci Ther] 2024 Jan; Vol. 30 (1), pp. e14552.
DOI: 10.1111/cns.14552
Abstrakt: Aims: Multiple sclerosis (MS) is a chronic neurological disease that currently lacks effective curative treatments. There is a need to find effective therapies, especially to reverse the progressive demyelination and neuronal damage. Oligodendrocytes form the myelin sheath around axons in the central nervous system (CNS) and oligodendrocyte precursor cells (OPCs) undergo mechanisms that enable spontaneously the partial repair of damaged lesions. The aim of this study was to discover small molecules with potential effects in demyelinating diseases, including (re)myelinating properties.
Methods: Recently, it has been shown how LRRK2 inhibition promotes oligodendrogliogenesis and therefore an efficient repair or myelin damaged lesions. Here we explored small molecules inhibiting LRRK2 as potential enhancers of primary OPCs proliferation and differentiation, and their potential impact on the clinical score of experimental autoimmune encephalomyelitys (EAE) mice, a validated model of the most frequent clinical form of MS, relapsing-remitting MS.
Results: One of the LRRK2 inhibitors presented in this study promoted the proliferation and differentiation of OPC primary cultures. When tested in the EAE murine model of MS, it exerted a statistically significant reduction of the clinical burden of the animals, and histological evidence revealed how the treated animals presented a reduced lesion area in the spinal cord.
Conclusions: For the first time, a small molecule with LRRK2 inhibition properties presented (re)myelinating properties in primary OPCs cultures and potentially in the in vivo murine model. This study provides an in vivo proof of concept for a LRRK2 inhibitor, confirming its potential for the treatment of MS.
(© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje