In vitro and in vivo models of Huntington's disease, an inherited condition in which nerve cells in the brain break down over time, show disease-related alterations in the endocannabinoid system, part of the body’s neural cell-signaling network, and the dopamine regulatory system downstream. In animal models, for example, there have been found reductions in N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D activity, diacylglycerol lipase activity, and cannabinoid receptor binding, mostly associated with changes in the striatum. Endocannabinoid degradation also rectifies dopaminergic deficits in these models, and dopaminergic drive, which declines with age, is restored by targeting this enzymatic degradation by elevating tissue levels of the endocannabinoid 2-arachidonoylglycerol (2-AG).
Chronic cannabinoid receptor stimulation selectively prevents motor impairments. A 2018 study showed improvements in gait and fine motor skills, and concomitant weight gain. Improvements were also observed in irritability and apathy, and in hypersalivation. Another 2018 study showed a selective deficit in synaptic plasticity modulated by anandamide, though not 2-arachidonoylglycerol, which was ameliorated by administration of the latter. There is preclinical evidence the cannabis-based medicine Sativex is a neuroprotective agent capable of delaying disease progression.
The endocannabinoid pathways
Experimental evidence suggests an important role of the type 1 cannabinoid (CB1) neural receptor in multiple domains in Huntington’s disease, that include motor, cognitive, and behavioral features. Loss of striatal type 1 receptors is described even in premanifest disease. The CB1 receptor mediates neuroprotection via a PI3K/Akt/mTORC1/BDNF pathway. CB1R knockout worsens motor performances in mice and increases susceptibility to 3-nitropropionic intoxication. Delayed disease onset in an enriched environment correlates with delayed loss of these receptors. Animal data suggests that preservation and activation of CB1 receptors may be protective against progression.
Thus, elevating CB1 levels and/or signaling may be beneficial for human patients. CB1 functions through G-protein alpha subtype i/o (G(i/o))-linked, ERK-dependent signal transduction. However its protective potential may be limited by over-coupling to G(s), stimulation of cAMP, or increased aggregate formation. These could explain the poor therapeutic efficacy of cannabinoids in more complex models, and imply that therapies selective for the G(i/o), ERK pathway may be of most beneficial.
Cannabinoid receptor 2 signaling in peripheral immune cells also modulates disease onset and severity in animal models. CB2 agonists protect the striatum against malonate toxicity, and function generally in defense against neuroinflammation. CB2 receptors are also expressed on vascular cells, though not astroglial cells, contrasting with early rodent studies that seemed to show glial cell localisation. This finding, with increased CD31 co-localisation, may represent a new context for CB2 therapeutic approaches to neurodegeneration. Microglial CB2 receptors are nevertheless neuroprotective in excitotoxicity. They promote progenitor cell proliferation via mTORC1 signaling.
Toward a therapeutic strategy
The fact that CB1 receptors are reduced in the basal ganglia during the progression of Huntington’s disease supports the usefulness of enhancing CB1 receptor signaling in therapy, and offers a convincing explanation for the hyperkinesia typical of the disease. Further studies have revealed that the property that enables certain cannabinoid agonists to reduce hyperkinesia is actually their capability to directly activate vanilloid TRPV(1) receptors. It may be that here is the mechanism by which cannabinoids may protect striatal projection neurons.
Several cannabinoid agonists have been tested for this purpose in various animal models, and these studies revealed that the major characteristics that enable cannabinoids to provide neuroprotection in general are by reduction in inflammatory events, exerted through glial CB2 receptors, normalization of glutamate homeostasis, then limiting excitotoxicity, through CB1 receptors, and exerting an antioxidant effect by means other than cannabinoid receptors. The changes in the endocannabinoid signaling system during striatal degeneration support this neuroprotective effect, particularly the up-regulatory responses in CB2 receptors in glial cells recruited at lesioned sites.
Cannabigerol is neuroprotective R6/2 and 3-nitropropionate-lesioned mouse models Huntington's disease, and VCE-003.2, a novel cannabigerol derivative, enhances neuronal progenitor cell survival, and alleviates symptomatology in other mouse models.
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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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