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

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.

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

“…The retrograde endocannabinoid signalling system is a lipid-based neuromodulatory system with important roles in the CNS including in physiological and neurodegenerative processes [94,95]. It has been associated to pathogenesis of PD as well as AD and ischemia [95][96][97] and suggested as a therapeutic target for treatment of a range of neurodegenerative disorders including AD, PD, HD, multiple sclerosis (MS), and ALS [98][99][100]. Putative roles for its regulation via post-translational deimination have not been previously identified and therefore bring a novel angle of modulation of endocannabinoid signalling pathways in neurodegeneration, including in early disease stages.…”

Inhibition of fatty acid amide hydrolase prevents pathology in neurovisceral acid sphingomyelinase deficiency by rescuing defective endocannabinoid signaling

“…It has also been proposed that endogenous CB 1 receptor activation serves as a buffer against depression, while its downregulation results in depressive symptoms (Mangieri & Piomelli, 2007; Patel & Hillard, 2009; Fowler, 2015). In addition, the eCB system plays important prohomeostatic, anti‐inflammatory, and neuroprotective functions (Sarne & Mechoulam, 2005; van der Stelt & Di Marzo, 2005; Chiarlone et al , 2014; Gomez‐Galvez et al , 2016), and its possible involvement in different neurodegenerative diseases (van der Stelt et al , 2005; Blazquez et al , 2011; Aymerich et al , 2018) has stimulated the therapeutic interest of eCB modulation for the treatment of neurological disorders.…”

Distinctive Evidence Involved in the Role of Endocannabinoid Signalling in Parkinson’s Disease: A Perspective on Associated Therapeutic Interventions

“…In the study, it was explored for the first time if a low dose Δ9-THCV is also antidyskinetic, a relevant antiparkinsonian property [ 195 ]. Earlier studies involved modulation of the ECS, specifically targeting the CB1 receptor in deferring LID [ 95 , 199 ]. To investigate the antidyskinetic potential of Δ9-THCV, a Pitx3ak mutant mice model, a relevant parkinsonism animal model linked with dopaminergic deficiency, was utilized, given the polymorphisms of Pitx 3ak has in fact been related to PD [ 200 , 201 , 202 ].…”