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Endocannabinoid signalling and the deteriorating brain

Key Points

  • Endocannabinoids are lipid mediators derived from arachidonic acid and produced on demand to restore homeostasis. By activating cannabinoid CB1 and CB2 receptors, they produce neuromodulatory and immune modulatory actions.

  • Endocannabinoid levels and CB1 and CB2 expression vary during ageing and neuroinflammatory and neurodegenerative disorders. CB1 loss or overactivation may affect cognition negatively in advanced or young age, respectively.

  • CB2 receptors control inflammatory cytochine production in brain-invading T lymphocytes during neuroinflammatory conditions. CB1 and CB2 receptors also control the cellular features of 'inflammaging', whereas, with age, CB1 may participate in the neuroinflammation accompanying a disrupted hypothalamic–pituitary–adrenal (HPA) axis in obesity.

  • The endocannabinoid system controls the activity of molecular and subcellular master regulators of cell metabolism, such as mammalian target of rapamycin (mTOR) and mitochondria, lysosomes and autophagosomes, which are also involved in the correct functioning of the CNS during ageing and neurological conditions. These effects might also be mediated by intracellular populations of CB1 receptors.

  • Endocannabinoids are accompanied in tissues by several metabolically related bioactive fatty acid amides and esters, which act at non-cannabinoid receptors. This renders the pharmacological manipulation of endocannabinoid levels, and hence the indirect modulation of cannabinoid receptor activity with inhibitors of endocannabinoid metabolic enzymes, more problematic.

  • Nevertheless, several preclinical studies indicate that CB1 and, particularly, CB2 agonists, as well as inhibitors of endocannabinoid inactivation, may be useful as disease-modifying agents for neurodegenerative and neuroinflammatory conditions such as multiple sclerosis. This, together with other mechanisms of action, may explain the recent clinical success of plant cannabinoids against spasticity and pain in multiple sclerosis.

Abstract

Ageing is characterized by the progressive impairment of physiological functions and increased risk of developing debilitating disorders, including chronic inflammation and neurodegenerative diseases. These disorders have common molecular mechanisms that can be targeted therapeutically. In the wake of the approval of the first cannabinoid-based drug for the symptomatic treatment of multiple sclerosis, we examine how endocannabinoid (eCB) signalling controls — and is affected by — normal ageing and neuroinflammatory and neurodegenerative disorders. We propose a conceptual framework linking eCB signalling to the control of the cellular and molecular hallmarks of these processes, and categorize the key components of endocannabinoid signalling that may serve as targets for novel therapeutics.

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Figure 1: Main biosynthetic and inactivating enzymes in endocannabinoid signalling.
Figure 2: Age-related changes at different system levels and their regulation by endocannabinoid signalling. Ageing is accompanied by changes in cellular processes, impairments in the integration of cellular activities, and deficits in physiological functions.
Figure 3: Effect of neuroinflammation on endocannabinoid signalling.
Figure 4: The endocannabinoidome in neurodegenerative diseases.

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Acknowledgements

Research in the laboratory of A.Z. was funded by the Deutsche Forschungsgemeinschaft (FOR926, SFB645) and is a member of Excellence Cluster Immunosensation. N.S. is funded by the US National Institutes of Health (NIH; DA014486 and DA026430). V.D. acknowledges Progetto Operativo Nazionale (PON01_02512) and FIRB-MERIT grant number RBNE08HWLZ_006, for funding, and is a recipient of unrestricted grants from GW Pharmaceuticals, UK, and Allergan, USA. The authors wish to thank L. De Petrocellis and E. Drews for their help during the preparation of this manuscript.

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VD acts as a consultant for GW Pharmaceuticals, UK, VD receives unrestricted grants from GW Pharmaceuticals, UK, and Allergan, USA

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Di Marzo, V., Stella, N. & Zimmer, A. Endocannabinoid signalling and the deteriorating brain. Nat Rev Neurosci 16, 30–42 (2015). https://doi.org/10.1038/nrn3876

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