Up close: Cannabinoids in neurodegenerative disorders
September 30, 20222 min read
The reported incidence of Alzheimer's, Parkinson's, and Huntington's disease has risen during the last 50 years, but complete understanding of the etiology of each has remained elusive. Common molecular mechanisms are known, at least. These include neuroinflammation, excitotoxicity, and mitochondrial dysfunction. In these, directly or indirectly, endocannabinoid signaling has been found to be altered. The endocannabinoid system is part of the mammalian neural cell-signaling network. Cannabinoid receptors 1 and 2 (spoken of as ‘CB1’ and ‘CB2’) are involved in the regulation of glutamate homeostasis, Ca(2+) influx, mitochondrial action, trophic support, and inflammatory state, and other receptors, gated by cannabinoids, such as PPARγ, mediate in anti-inflammatory effects too. The up-regulation of CB2 receptors in particular has been found to be significant in neurodegenerative disorders. Thus, the modulation of cannabinoid receptor signaling, especially CB2, ought to represent a welcome therapeutic target.
Research data in cellular and animal models is beginning to suggest that this conjecture is warranted. Activation of CB1 receptors, abundant in the hippocampus, basal ganglia, and cerebellum, reduces intracellular Ca concentrations, inhibits glutamate release, and enhances neurotrophin expression and neurogenesis. [18F]FMPEP-d2 PET imaging shows age- and genotype-dependent impairments in the availability of cannabinoid receptor 1 in at least one model of Alzheimer's disease. Slowing this, if possible, would bode well for impeding deterioration of memory and cognitive function.
CB2 receptors, expressed in the central nervous system, particularly in microglia, and in immune system cells involved in the release of cytokines, have been shown to be upregulated in neuritic plaques in the hippocampus and entorhinal cortex of patients, which probably means that they play a role specifically in the inflammatory pathology of Alzheimer’s disease.
In the basal ganglia disorders, Parkinson's disease (PD) and Huntington's disease, there appear to be benefits with endocannabinoid modulation as well. These include alleviation of motor symptoms like choreic movements (with CB1 and TRPV1 agonists), with bradykinesia (with CB1 antagonists) and tremor (with CB1 agonists), and also delay of disease progression (because CB1 agonists reduce excitotoxicity, CB2 agonists limit the toxicity of reactive microglia, and antioxidant cannabinoids generally attenuate oxidative damage.
Cannabidiol (CBD) is an inverse agonist for GPR3, GPR6, and GPR12. It lacks psychoactive properties, and is characterized by antioxidative and anti-inflammatory features. Clinical studies have not shown promising results yet across the neurodegenerative diseases, but they are continuing.
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The foregoing is a report on trends and developments in the cannabinoid industry. No product described herein is intended to diagnose, treat, cure or prevent any disease or syndrome.
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