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.

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

“…The endocannabinoid system (ECS) has the ability to modulate these common traits in neurodegeneration, thus emerging as a viable target for symptom alleviation or disease progression based on pharmacological modulation of endocannabinoid signaling [5]. Cannabinoids provide a broad-spectrum profile, which is particularly interesting when dealing with complex pathologies of multifactorial origin [6]. The pleiotropic properties of cannabinoids confer the cannabinoids as important molecules for the development of neuroprotective strategies.…”

Cannabinoid Actions on Neural Stem Cells: Implications for Pathophysiology

“…They are characterized by the progressive loss of specific neuronal subpopulations in the CNS, with different clinical features being exhibited and can result from the natural process of brain aging or brain injury/trauma. Available treatments usually act on transient symptomatic relief, being poorly active at fighting the cellular events occurring as brain damage advances [253]. Therefore, it is essential to seek for molecules with disease-modifying activity that take into consideration the mechanisms that underlie disease progression and enable the repair of neuronal loss.…”

“…The neuroprotective potential of ECS-targeting compounds (e.g., cannabinoid agonists or antagonists, inhibitors of eCB degradation or biosynthesis or other modulators) has been extensively investigated over the last 20 years [253]. This neuroprotective nature of cannabinoids arises not only from their pleiotropic profile, i.e., the capacity to interact with neuromodulatory systems not directly related with the eCB signaling, but also from the presence of these targets in key cellular components of the CNS (i.e., neurons, astrocytes, microglia, oligodendrocytes and neural progenitor cells) and brain structures like the blood–brain barrier [58].…”

“…This neuroprotective nature of cannabinoids arises not only from their pleiotropic profile, i.e., the capacity to interact with neuromodulatory systems not directly related with the eCB signaling, but also from the presence of these targets in key cellular components of the CNS (i.e., neurons, astrocytes, microglia, oligodendrocytes and neural progenitor cells) and brain structures like the blood–brain barrier [58]. These features then translate into an ability to restore the CNS to a physiological homeostatic state after an acute or chronic perturbation, by fighting an array of cellular processes caused by brain insults or damage, like excitotoxicity, increased state of neuroinflammation, oxidative stress and protein aggregation, as well as other processes that interfere with neuronal homeostasis and integrity [253]. Given the relationship between all these pathological cellular hallmarks, the protection of CNS components must act on all or most of these targets in a multifaceted manner.…”

Cannabinoids and their actions: An update

“…The review articles underline the breadth of action of cannabinoids/endocannabinoids, encompassing examples of cell determination (Garcia‐Arencibia, Molina‐Holgado, & Molina‐Holgado, ) to cell death (Fernandez‐Ruiz, ). There are reviews on more translational aspects of cannabinoids.…”