Title : Preclinical in vivo study on selective cannabinoid receptor type 2 and donepezil combined therapy in Alzheimer’s disease
Abstract:
As one of the major healthcare challenges worldwide, Alzheimer’s disease (AD) is a detrimental brain disorder of a multifactorial nature, with an etiopathogenesis still not completely clear, influenced by epigenetic and genetic variants combined with environmental and lifestyle factors [1]. With over 50 million people afflicted by AD globally, and total worldwide payments of caring for these patients estimated at $1 trillion in 2020 [2], acetylcholinesterase (AChE) inhibitors remain the mainstay treatment option, providing only symptomatic relief without slowing the disease progression. The cholinesterase inhibitors that interact simultaneously with AChE (catalytic and peripheral sites) and amyloid-beta (Aβ) plaque deposition coupled with added properties such as antioxidant action, neuroprotective activity or endocannabinoidergic system display the potential of ameliorating the cognitive deficit in AD by restoring cholinergic activities [3]. The endocannabinoid system is composed of at least two well-described cannabinoid receptor 1 (CB1) and receptor 2 (CB2). CB1 receptors are widely expressed in the central nervous system, where they regulate the main functions of the brain [4]. Recent studies have suggested that CB1 receptor-specific agonists have potential therapeutic properties in AD at low non-psychotropic doses [5]. However, major attention in AD has been paid to specific CB2 receptor agonists due to their lack of psychoactive properties, even though CB2 receptors are mainly expressed in the immune system, with relatively low expression in neurons [6]. Interestingly, it has been found that CB2 receptors are selectively overexpressed in cells associated with Aβ enriched neuritic plaques in AD samples from postmortem human brains. In light of all these data, exogenous and endogenous cannabinoids represent an attractive and promising target for the treatment of AD. So far, no results have been published to determine the effects of donepezil and CB2 agonists’ co-administration on AD-relevant behaviors and brain pathology.
The aim of this study was to evaluate the effects of long-term donepezil- cannabinoids with CB2 selectivity co-treatment in AβPP/PS1 mice, a transgenic model of AD that mimics the progressive cognitive deficiency and neurodegenerative process, in pre-symptomatic and early stage of the symptomatic phase of the disease.
In vivo studies supported by cognitive performance evaluation, multimodal imaging, histology and immunohistochemistry analysis were used to meet the objectives of this study, investigate the preclinical efficacy of long-term co-treatment associations, evaluate the impact of therapy on cerebral metabolism, identify the acetylcholine-related changes and amyloid-β quantification in an animal model.
Translating the selective CB2 agonists into the clinic is not an easy challenge, but identifying innovative approaches for treating millions of AD people holds the promise of improving their daily life and CB2 agents might just prove to be effective, due to their modulation of the endocannabinoid system, as well as their effect on neuroinflammation, Aβ clearance, cell viability in the presence of Aβ, and glucose up take in brain.
Funding: This work was supported by a grant of the Ministry of Research, Innovation and Digitalization, CNCS-UEFISCDI, project number PN-III-P1-1.1-PD-2021-0466, within PNCDI III; and “Grigore T. Popa” University of Medicine and Pharmacy, grant number 4715/25.02.2021.
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[4] Wilson, R.I.; Nicoll, R.A. 2002. Neuroscience: Endocannabinoid signaling in the brain. Science, 296, 678-682.
[5] Bedse, G., Romano, A., Lavecchia, A.M., Cassano, T., Gaetani, S. 2014. The role of endocannabinoid signaling in the molecular mechanisms of neurodegeneration in Alzheimer’s disease. J. Alzheimer’s Dis. 43, 1115-1136.
[6] Le Boisselier, R., Alexandre, J., Lelong-Boulouard, V., Debruyne, D. 2017. Focus on cannabinoids and synthetic cannabinoids. Clin. Pharmacol. Ther. 101, 220-229.
What will audience learn from your presentation?
- identify important limitations of animal models in the investigation of cannabinoid effects in the Alzheimer’s disease, and focus future research in this area on specific, unanswered questions regarding the complexities of endocannabinoid system and its main receptors (CB1 and CB2);
- the role of age in determining the long-term effect of cannabinoid on cognition, highlighting possible detrimental consequences during brain development and beneficial outcomes in old age;
- a high degree of experimental control can be achieved by precisely controlling the animal's life experiences and history of drug exposure. This allows clear inferences to be made concerning the causality of effects observed in the experiment;
- the brain mechanisms that underlie addictive behaviour, procedures that can be conducted in humans are severely limited compared with the manipulations and measures that can be performed in animals.
