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by Kadek Sonia Piscayanti

Although the histological structure of the brain is largely preserved, intracellular signalling mechanisms undergo changes associated with the ageing process. Increasing concentrations of toxic metabolic end products, misfolded macromolecules and non-functional organelles characterize the ageing brain and are thought to significantly contribute to cognitive decline . The balance between the generation and clearance of toxic metabolic by-products and damaged macromolecules crucially influences the progression of ageing.

When THC was administered to the knockout mice it was shown that THC had no effect, proving THC works by activating cannabinoid receptors in the brain. Ageing is associated with a decline of cognitive performance in humans and animals.

Cannabinoids at physiological concentrations increase lysosomal stability and integrity , but high concentrations of THC actually increase lysosomal permeability via the CB1 receptor. An intriguing question is whether decreased CB1 receptor activity owing to genetic variation or epigenetic changes in humans influences lysosomal function and thus contributes to the development of neurodegenerative diseases. Further, CB1 receptors have been suggested to also be present on mitochondrial membranes and regulate mitochondrial activity . On the cellular level, the ECS regulates the expression of brain-derived neurotrophic factor and neurogenesis.

The ECS is found at the pre- and post-synaptic side of the nerve terminals in brain areas involved in learning and memory, such as the hippocampus, which modulates synaptic function . The widespread anatomical localization of CB1 receptors in the brain may explain its involvement in multiple memory stages that might require different neural substrates. In this context, several recent intriguing reports suggest the presence of CB1 receptors in astrocytes and mitochondria where they can also participate in the control of cognitive processes. In the brain, cannabinoids and endocannabinoids modulate a number of intracellular signalling pathways, some critically involved in the deleterious effect of cannabinoids on learning and memory processes. As well, there is emerging evidence for endocannabinoid roles in various forms of learning and memory outside the hippocampus, e.g. fear conditioning extinction and the amygdale , and habit learning and the basal ganglia .

Within this context, could the ECS modulate molecular and cellular processes influencing the ageing process? In this volume, Bilkei-Gorzo proposes that endocannabinoids indeed influence neuronal activity, exerting neuroprotective effects and regulating glial responses via the body’s homeostatic defence system. The ECS influences the amount of intracellular reactive oxygen species not only via an anti-oxidant buffering capacity, but also by influencing the removal of damaged macromolecules and by regulating mitochondrial activity . Most CB1 receptors do not reach the cell surface, but instead are localized intracellularly at the lysosomal and late endosomal levels .

The CB1 and CB2 receptors negatively regulate adenylyl cyclase activity through pertussis toxin-sensitive GTP-binding protein. Endocannabinoids have been well known to exhibit this property, which is considered to be an important mechanism of lymphocyte regulation .

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Endocannabinoids are able to suppress neuroinflammatory processes contributing to the progression of normal brain ageing and to the pathogenesis of neurodegenerative diseases. Animals lacking CB1 receptors exhibit early onset of learning deficits associated with age-related histological and molecular changes, which supports the hypothesized role of endocannabinoids against brain ageing. The task now falls to future clinical studies for confirmation of these preclinical findings.

  • The endocannabinoid system regulates many physiological responses of the body including pain, memory, appetite, and mood.
  • While both CBD and THC are used for medicinal purposes, they have different receptor activity, function, and physiological effects.
  • Mechanism of actionThe exact mechanism of action of CBD and THC is not currently fully understood.
  • However, it is known that CBD acts on cannabinoid receptors of the endocannabinoid system, which are found in numerous areas of the body, including the peripheral and central nervous systems, including the brain.

The effect of cannabinoids on immune functions appears to be transient which would allow the inhibitory effects to be overcome when the immune system needs to be activated during infections. This is supported by the downregulation of cannabinoid receptor expression when the immune cells are activated. Thus, the transient nature of cannabinoids on the immune system suggests that the side effects of the potential therapy may be minimal.

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