The biomedical challenge of neurodegenerative disorders: an opportunity for cannabinoid-based therapies to improve on the poor current therapeutic outcomes

Abstract

At the beginning of the 21st century, the therapeutic management of neurodegenerative disorders remains a major biomedical challenge, particularly given the worldwide ageing of the population over the past 50 years that is expected to continue in the forthcoming years. This review will focus on the promise of cannabinoid-based therapies to address this challenge. This promise is based on the broad neuroprotective profile of cannabinoids, which may cooperate to combat excitotoxicity, oxidative stress, glia-driven inflammation and protein aggregation. Such effects may be produced by the activity of cannabinoids through their canonical targets (e.g. cannabinoid receptors and endocannabinoid enzymes) and also via non-canonical elements and activities in distinct cell types critical for cell survival or neuronal replacement (e.g. neurons, glia and neural precursor cells). Ultimately, the therapeutic events driven by endocannabinoid signalling reflect the activity of an endogenous system that regulates the preservation, rescue, repair and replacement of neurons and glia. LINKED ARTICLES: This article is part of a themed section on 8^th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc.

Figure 1

Progression of the incidence of AD, PD and HD in relation to age as a function of the rate of each disease per 100 subjects (source: Saba, 2015).

Figure 2

Comparison of life expectancy in 2015 and 2050 and the proportion of people over 65 years of age (predicted values), in different countries and geographical areas around the world (source: United Nations, 2015; World Health Organization, 2016; OECD, 2017). European countries, Japan, New Zealand, Australia, the USA and Canada will reach the highest life expectancies (close to or above 90 years), and the rate of people older than 65 will be at least 28% by 2050, with the highest incidence of neurodegenerative disorders (marked in red). Similarly, by 2050, the life expectancy and rates of people older than 65 will increase between 1.5‐fold and 3‐fold in Russia, China, Saudi Arabia, South Africa, Brazil, Argentina and particularly in Maghreb countries, Mexico, some countries in Central America and India, also in association with an important increase in the incidence of these disorders (marked in yellow).

Figure 3

Diagram showing the different research tools used to study neurodegenerative disorders.

Figure 4

Diagram showing a series of potential biomarkers that have been proposed to detect the progression of AD before its clinical diagnosis and the biological samples/methodological tools for their analysis (source: Frisoni et al., 2017). MMSE, mini‐mental state examination.

Figure 5

Diagram summarizing four important advantages of possible cannabinoid‐based therapies for the treatment of neurodegenerative disorders when compared with the other therapeutic strategies investigated to date. CB₂ receptor‐immunolabelled cells (in red and marked with arrows in the left bottom corner) are much more frequent in ALS tissue than in control tissue, corresponding to reactive microglia (in green and marked with arrows).

Figure 6

Summary of the different key targets and/or processes that are being investigated, and already showed some promise, for the development of cannabinoid‐based neuroprotective therapies in the four more representative chronic progressive neurodegenerative disorders (e.g. AD, PD, ALS and HD).