Potential and Limits of Cannabinoids in Alzheimer’s Disease Therapy

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This review was aimed at exploring the potentiality of drugging the endocannabinoid system as a therapeutic option for Alzheimer’s disease (AD). Recent discoveries have demonstrated how the modulation of cannabinoid receptor 1 (CB1) and receptor 2 (CB2) can exert neuroprotective effects without the recreational and pharmacological properties of Cannabis sativa. Thus, this review explores the potential of cannabinoids in AD, also highlighting their limitations in perspective to point out the need for further research on cannabinoids in AD therapy.

Abstract

Alzheimer’s disease (AD) is a detrimental brain disorder characterized by a gradual cognitive decline and neuronal deterioration. To date, the treatments available are effective only in the early stage of the disease. The AD etiology has not been completely revealed, and investigating new pathological mechanisms is essential for developing effective and safe drugs. The recreational and pharmacological properties of marijuana are known for centuries, but only recently the scientific community started to investigate the potential use of cannabinoids in AD therapy—sometimes with contradictory outcomes. Since the endocannabinoid system (ECS) is highly expressed in the hippocampus and cortex, cannabis use/abuse has often been associated with memory and learning dysfunction in vulnerable individuals. However, the latest findings in AD rodent models have shown promising effects of cannabinoids in reducing amyloid plaque deposition and stimulating hippocampal neurogenesis. Beneficial effects on several dementia-related symptoms have also been reported in clinical trials after cannabinoid treatments. Accordingly, future studies should address identifying the correct therapeutic dosage and timing of treatment from the perspective of using cannabinoids in AD therapy. The present paper aims to summarize the potential and limitations of cannabinoids as therapeutics for AD, focusing on recent pre-clinical and clinical evidence.

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Molecular characterization of a peripheral receptor for cannabinoids.

S. MUNRO, K L Thomas, M. Abu-Shaar … (1993)

The major active ingredient of marijuana, delta 9-tetrahydrocannabinol (delta 9-THC), has been used as a psychoactive agent for thousands of years. Marijuana, and delta 9-THC, also exert a wide range of other effects including analgesia, anti-inflammation, immunosuppression, anticonvulsion, alleviation of intraocular pressure in glaucoma, and attenuation of vomiting. The clinical application of cannabinoids has, however, been limited by their psychoactive effects, and this has led to interest in the biochemical bases of their action. Progress stemmed initially from the synthesis of potent derivatives of delta 9-THC, and more recently from the cloning of a gene encoding a G-protein-coupled receptor for cannabinoids. This receptor is expressed in the brain but not in the periphery, except for a low level in testes. It has been proposed that the nonpsychoactive effects of cannabinoids are either mediated centrally or through direct interaction with other, non-receptor proteins. Here we report the cloning of a receptor for cannabinoids that is not expressed in the brain but rather in macrophages in the marginal zone of spleen.

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Structure of a cannabinoid receptor and functional expression of the cloned cDNA.

L Matsuda, S Lolait, M J Brownstein … (1990)

Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS) in a complex and dose-dependent manner. Although CNS depression and analgesia are well documented effects of the cannabinoids, the mechanisms responsible for these and other cannabinoid-induced effects are not so far known. The hydrophobic nature of these substances has suggested that cannabinoids resemble anaesthetic agents in their action, that is, they nonspecifically disrupt cellular membranes. Recent evidence, however, has supported a mechanism involving a G protein-coupled receptor found in brain and neural cell lines, and which inhibits adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. Also, the receptor is more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. Here we report the cloning and expression of a complementary DNA that encodes a G protein-coupled receptor with all of these properties. Its messenger RNA is found in cell lines and regions of the brain that have cannabinoid receptors. These findings suggest that this protein is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana.

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Global, regional, and national burden of Alzheimer's disease and other dementias, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

Emma Nichols, Cassandra E I Szoeke, Stein Emil Vollset … (2019)

Summary Background The number of individuals living with dementia is increasing, negatively affecting families, communities, and health-care systems around the world. A successful response to these challenges requires an accurate understanding of the dementia disease burden. We aimed to present the first detailed analysis of the global prevalence, mortality, and overall burden of dementia as captured by the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016, and highlight the most important messages for clinicians and neurologists. Methods GBD 2016 obtained data on dementia from vital registration systems, published scientific literature and surveys, and data from health-service encounters on deaths, excess mortality, prevalence, and incidence from 195 countries and territories from 1990 to 2016, through systematic review and additional data-seeking efforts. To correct for differences in cause of death coding across time and locations, we modelled mortality due to dementia using prevalence data and estimates of excess mortality derived from countries that were most likely to code deaths to dementia relative to prevalence. Data were analysed by standardised methods to estimate deaths, prevalence, years of life lost (YLLs), years of life lived with disability (YLDs), and disability-adjusted life-years (DALYs; computed as the sum of YLLs and YLDs), and the fractions of these metrics that were attributable to four risk factors that met GBD criteria for assessment (high body-mass index [BMI], high fasting plasma glucose, smoking, and a diet high in sugar-sweetened beverages). Findings In 2016, the global number of individuals who lived with dementia was 43·8 million (95% uncertainty interval [UI] 37·8–51·0), increased from 20.2 million (17·4–23·5) in 1990. This increase of 117% (95% UI 114–121) contrasted with a minor increase in age-standardised prevalence of 1·7% (1·0–2·4), from 701 cases (95% UI 602–815) per 100 000 population in 1990 to 712 cases (614–828) per 100 000 population in 2016. More women than men had dementia in 2016 (27·0 million, 95% UI 23·3–31·4, vs 16.8 million, 14.4–19.6), and dementia was the fifth leading cause of death globally, accounting for 2·4 million (95% UI 2·1–2·8) deaths. Overall, 28·8 million (95% UI 24·5–34·0) DALYs were attributed to dementia; 6·4 million (95% UI 3·4–10·5) of these could be attributed to the modifiable GBD risk factors of high BMI, high fasting plasma glucose, smoking, and a high intake of sugar-sweetened beverages. Interpretation The global number of people living with dementia more than doubled from 1990 to 2016, mainly due to increases in population ageing and growth. Although differences in coding for causes of death and the heterogeneity in case-ascertainment methods constitute major challenges to the estimation of the burden of dementia, future analyses should improve on the methods for the correction of these biases. Until breakthroughs are made in prevention or curative treatment, dementia will constitute an increasing challenge to health-care systems worldwide. Funding Bill & Melinda Gates Foundation.

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Annette Graham: Role: Academic Editor

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Journal ID (nlm-ta): Biology (Basel)

Journal ID (iso-abbrev): Biology (Basel)

Journal ID (publisher-id): biology

Title: Biology

Publisher: MDPI

ISSN (Electronic): 2079-7737

Publication date (Electronic): 17 June 2021

Publication date Collection: June 2021

Volume: 10

Issue: 6

Electronic Location Identifier: 542

Affiliations

[1 ]Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; giulia.abate@ 123456unibs.it (G.A.); daniela.uberti@ 123456unibs.it (D.U.)

[2 ]Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, 171 64 Solna, Sweden

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[* ]Correspondence: simone.tambaro@ 123456ki.se

Author information

Giulia Abate https://orcid.org/0000-0001-9161-3475

Daniela Uberti https://orcid.org/0000-0002-5926-9122

Simone Tambaro https://orcid.org/0000-0001-7000-7556

Article

Publisher ID: biology-10-00542

DOI: 10.3390/biology10060542

PMC ID: 8234911

PubMed ID: 34204237

SO-VID: 144f9f55-dc92-4584-b5db-b4fcd56d258c

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

Potential and Limits of Cannabinoids in Alzheimer’s Disease Therapy

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Most cited references 195

Molecular characterization of a peripheral receptor for cannabinoids.

Structure of a cannabinoid receptor and functional expression of the cloned cDNA.

Global, regional, and national burden of Alzheimer's disease and other dementias, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

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