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Biochem Pharmacol. 2018 Nov;157:67-84. doi: 10.1016/j.bcp.2018.08.016. Epub 2018 Aug 17.

Cannabinoid pharmacology/therapeutics in chronic degenerative disorders affecting the central nervous system.

Author information

1
Universidad de Navarra, Facultad de Ciencias, Departamento de Bioquímica y Genética, Pamplona, Spain; Universidad de Navarra, CIMA, Programa de Neurociencias, Pamplona, Spain; IdiSNA, Instituto de Investigación Sanitaria de Navarra, Spain. Electronic address: maymerich@unav.es.
2
Departamento de Patología y Terapéutica Experimental, Universidad de Barcelona, L'Hospitalet de Llobregat, Spain; CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain.
3
Universidad de Navarra, Facultad de Ciencias, Departamento de Bioquímica y Genética, Pamplona, Spain; Universidad de Navarra, CIMA, Programa de Neurociencias, Pamplona, Spain.
4
Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Spain.
5
CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain; Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; IRYCIS, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.

Abstract

The endocannabinoid system (ECS) exerts a modulatory effect of important functions such as neurotransmission, glial activation, oxidative stress, or protein homeostasis. Dysregulation of these cellular processes is a common neuropathological hallmark in aging and in neurodegenerative diseases of the central nervous system (CNS). The broad spectrum of actions of cannabinoids allows targeting different aspects of these multifactorial diseases. In this review, we examine the therapeutic potential of the ECS for the treatment of chronic neurodegenerative diseases of the CNS focusing on Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. First, we describe the localization of the molecular components of the ECS and how they are altered under neurodegenerative conditions, either contributing to or protecting cells from degeneration. Second, we address recent advances in the modulation of the ECS using experimental models through different strategies including the direct targeting of cannabinoid receptors with agonists or antagonists, increasing the endocannabinoid tone by the inhibition of endocannabinoid hydrolysis, and activation of cannabinoid receptor-independent effects. Preclinical evidence indicates that cannabinoid pharmacology is complex but supports the therapeutic potential of targeting the ECS. Third, we review the clinical evidence and discuss the future perspectives on how to bridge human and animal studies to develop cannabinoid-based therapies for each neurodegenerative disorder. Finally, we summarize the most relevant opportunities of cannabinoid pharmacology related to each disease and the multiple unexplored pathways in cannabinoid pharmacology that could be useful for the treatment of neurodegenerative diseases.

KEYWORDS:

Cannabinoid receptors; Cannabinoids; Endocannabinoid system; Neurodegenerative diseases; Neuroprotection

PMID:
30121249
DOI:
10.1016/j.bcp.2018.08.016
[Indexed for MEDLINE]
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