Investigation in the cannabigerol derivative VCE-003.2 as a disease-modifying agent in a mouse model of experimental synucleinopathy.

Autor: Burgaz S; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, Madrid, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain., Navarro E; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, Madrid, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain., Rodríguez-Carreiro S; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, Madrid, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain., Navarrete C; Emerald Health Pharmaceuticals, San Diego, USA., Garrido-Rodríguez M; Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain.; Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain.; Hospital Universitario Reina Sofía, Córdoba, Spain., Lastres-Becker I; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.; Instituto de Investigaciones Biomédicas Sols-Morreale (IIBSM), UAM-CSIC, Madrid, Spain.; Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Madrid, Spain.; Instituto de Investigación del Hospital Universitario de La Paz (IdiPAZ), Madrid, Spain.; Institute Teófilo Hernando for Drug Discovery, Universidad Autónoma de Madrid, Madrid, Spain., Chocarro J; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.; CNS Gene Therapy Department, Center for Applied Medical Research (CIMA), Universidad de Navarra, Pamplona, Spain., Lanciego JL; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.; CNS Gene Therapy Department, Center for Applied Medical Research (CIMA), Universidad de Navarra, Pamplona, Spain., Muñoz E; Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain. fi1muble@uco.es.; Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain. fi1muble@uco.es.; Hospital Universitario Reina Sofía, Córdoba, Spain. fi1muble@uco.es., Fernández-Ruiz J; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, Madrid, Spain. jjfr@med.ucm.es.; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. jjfr@med.ucm.es.; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain. jjfr@med.ucm.es.
Jazyk: angličtina
Zdroj: Behavioral and brain functions : BBF [Behav Brain Funct] 2024 Nov 01; Vol. 20 (1), pp. 28. Date of Electronic Publication: 2024 Nov 01.
DOI: 10.1186/s12993-024-00256-9
Abstrakt: Background: The cannabigerol derivative VCE-003.2, which has activity at the peroxisome proliferator-activated receptor-γ has afforded neuroprotection in experimental models of Parkinson's disease (PD) based on mitochondrial dysfunction (6-hydroxydopamine-lesioned mice) and neuroinflammation (LPS-lesioned mice). Now, we aim to explore VCE-003.2 neuroprotective properties in a PD model that also involves protein dysregulation, other key event in PD pathogenesis.
Methods: To this end, an adeno-associated viral vector serotype 9 coding for a mutated form of the α-synuclein gene (AAV9-SynA53T) was unilaterally delivered in the substantia nigra pars compacta (SNpc) of mice. This model leads to motor impairment and progressive loss of tyrosine hydroxylase-labelled neurons in the SNpc.
Results: Oral administration of VCE-003.2 at 20 mg/kg for 14 days improved the performance of mice injected with AAV9-SynA53T in various motor tests, correlating with the preservation of tyrosine hydroxylase-labelled neurons in the SNpc. VCE-003.2 also reduced reactive microgliosis and astrogliosis in the SNpc. Furthermore, we conducted a transcriptomic analysis in the striatum of mice injected with AAV9-SynA53T and treated with either VCE-003.2 or vehicle, as well as control animals. This analysis aimed to identify gene families specifically altered by the pathology and/or VCE-003.2 treatment. Our data revealed pathology-induced changes in genes related to mitochondrial function, lysosomal cell pathways, immune responses, and lipid metabolism. In contrast, VCE-003.2 treatment predominantly affected the immune response through interferon signaling.
Conclusion: Our study broadens the neuroprotective potential of VCE-003.2, previously described against mitochondrial dysfunction, oxidative stress, glial reactivity and neuroinflammation in PD. We now demonstrate its efficacy against another key pathogenic event in PD as α-synuclein dysregulation. Furthermore, our investigation sheds light on the molecular mechanisms underlying VCE-003.2 revealing its role in regulating interferon signaling. These findings, together with a favorable ADMET profile, enhance the preclinical interest of VCE-003.2 towards its future clinical development in PD.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje