Cannabinoids in neurodegenerative disorders: an overview
July 29, 20224 min read
The endocannabinoid system, part of the body’s onboard cell signaling network, plays a widely modulatory role in important functions in neurodegenerative disorders. These functions are known to include neurotransmission, glial activation, oxidative stress, and protein homeostasis. There is evidence that cannabinoids slow the progression of multiple sclerosis in particular, and offer some symptomatic relief as well, notably in spasticity. Data suggest that multiple targets in MS can be modulated all at once, opening the way to better disease management through interdiction of more than one mechanism of action simultaneously. There is also evidence for disease delay in amyotrophic lateral sclerosis (or ‘ALS’, or ‘Lou Gehrig’s disease’ or ‘motor neuron disease’). Here, cannabinoids are clearly active across the whole range of abnormal physiological processes, and they may even modulate the gene expression that drives the whole syndrome. In glaucoma and diabetic retinopathy, too, endocannabinoids and their synthetic cousins are turning out to have the right pharmacological profile not only to lower intraocular pressure, a critical part of treatment, but to target the associated neurodegenerative processes that underlie these diseases.
In separate posts we give you detailed examinations of the state of cannabinoid research in each of MS, ALS, and glaucoma. Here, as background, is an overview of what is broadly known at this point about whether and why cannabinoids work in neurodegenerative disorders in general.
At the fundamental level, several lines of evidence have suggested that the endocannabinoid system plays an important role in early neuronal development. For example, natural cannabinoids improve dopamine neurotransmission and tau and amyloid pathology in parkin-null, human tau overexpressing (PK-/-/TauVLW) mice, a model of complex frontotemporal dementia, Parkinsonism, and lower motor neuron disease. It is clear that both of the inhibitory G protein-coupled receptors CB1 and CB2 play central mediating roles, and also that additional receptors may be involved as well. Collectively, CB1 and CB2 receptor signaling contributes to the control of Ca2+ homeostasis, trophic support, mitochondrial activity, and inflammatory conditions. The level of expression of these receptors, and of downstream enzymes controlling endocannabinoid levels, undergo time- and brain region-specific changes during neurodegenerative and neuroinflammatory disorders.
CB1 receptors are mostly expressed in neurons, where they regulate neurotransmitter release and synaptic strength, and CB2 receptors are found mostly in glial cells and microglia, where they activate and over-express in disease. At CB1, anandamide and 2-arachidonoylglycerol are the two most studied agents in counteracting neurochemical imbalances. At CB2, lipophilic mediators regulate the activity and function of glia and microglia. The release of potentially neurotoxic compounds through astroglial hemichannels and pannexons has been implicated as one of the functional alterations that negatively affect the progression of multiple brain diseases. Recent insights have suggested that regulating the opening and closing of these channels specifically is where endocannabinoids could play an important role. In the normal brain, because they apparently elicit the Ca2+-activation of astrocyte hemichannels, these endocannabinoids may be of significant consequence in synaptic plasticity. Endocannabinoids also eem to counteract the activation of inflammatory pathways that lead to glia-mediated production of TNF-α and IL-1β, both well-known triggers of astroglial hemichannel opening.
Thus it is that research is focussing most on activity at the CB2 receptor site at the moment, recognizing also that the actions of agonists of CB1 receptors are psychotropic, and that there are as well serious side effects that accompany selective antagonists of this same receptor. Differential localization of CB2 receptors in neural cell types and upregulation in neuroinflammation are clearly keys to therapeutic potential, then. This is an important insight. Because of their wide expression in immune cells, CB2 receptors have traditionally been thought to act as peripheral receptors, so to speak. Their recent identification in brain areas and in distinct neuronal cells has made it reasonable to examine CB2 signaling in the context of brain pathophysiology, synaptic plasticity and neuroprotection.
Applied study of specific candidates for cannabinoid treatment in neurodegenerative disorders is still in its infancy. Cannabigerol (CBG) may emerge as a treatment against neuroinflammation and oxidative stress. CBG pre-treatment has been able to reduce the loss of cell viability induced by the medium of LPS-stimulated macrophages in NSC-34 cells. Pre-treatment with CBG also inhibits apoptosis, or cell death, demonstrated by the reduction of caspase 3 activation and Bax expression, while Bcl-2 levels at the same time increases. CBG pre-treatment has also counteracted inflammation, as shown by the reduction of IL-1&beta, TNF-&alpha, IFN-&gamma, and PPAR&gamma, and also oxidative stress in NSC-34 cells treated with the medium of LPS-stimulated RAW 264.7. Immunocytochemistry has shown, finally, that CBG pre-treatment also reduces nitrotyrosine, SOD1 and iNOS protein levels and restored Nrf-2 levels.
PureForm CBD™ is bioidentical to CBD extracted from hemp and cannabis but without residual cannabinoids like THC or any of the impurities or chemicals associated with plant-derived production processes. Our molecular assembly technique, that synthesizes CBD from aromatic terpenes instead of cannabis, assures you the food and pharmaceutical-grade quality that you need for quality-conscious customers. If you are interested in PureForm CBD™ or want to partner on any other of the 140+ known cannabinoids, please contact Damian Peters at310-666-4869, or firstname.lastname@example.org.
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.
Promotions, new products and sales. Directly to your inbox.