It is simply yet again the suppressed cannabinoids system that is causing this.
Ca2+ homeostasis, overproduction of reactive oxygen species, mitochondrial defense and membrane permeability, mitochondrial DNA mutations. All these things are modulated by the cannabinoid system
This is why cannabis is helpful for everything basically. It is so far upstream of all the processes involved and has such wide involvement in all of them when you go over it all, many conditions are essentially caused by the same thing, perturbations of the cannabinoid system. The Cannabinoid system is the rest, sleep, digest and recover system to the HPA axis flight or fight, wake, alert system. The two are supposed to balance one another but can be disrupted in many ways.
Yes they both do, CB1 and CB2 activation by CBD indirectly by increase endogenous cannabinoids and CB2 by Caryophyllene as well as other affects mediated by other receptor systems they act on.
The Endocannabinoid System and PPARs: Focus on Their Signalling Crosstalk, Action and Transcriptional Regulation - PMC (nih.gov)
Abstract
Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors including PPARα, PPARγ, and PPARβ/δ, acting as transcription factors to regulate the expression of a plethora of target genes involved in metabolism, immune reaction, cell differentiation, and a variety of other cellular changes and adaptive responses. PPARs are activated by a large number of both endogenous and exogenous lipid molecules, including phyto- and endo-cannabinoids, as well as endocannabinoid-like compounds. In this view, they can be considered an extension of the endocannabinoid system. Besides being directly activated by cannabinoids, PPARs are also indirectly modulated by receptors and enzymes regulating the activity and metabolism of endocannabinoids, and, vice versa, the expression of these receptors and enzymes may be regulated by PPARs. In this review, we provide an overview of the crosstalk between cannabinoids and PPARs, and the importance of their reciprocal regulation and modulation by common ligands, including those belonging to the extended endocannabinoid system (or “endocannabinoidome”) in the control of major physiological and pathophysiological functions.
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Cannabinoids and Mitochondria | SpringerLink
Abstract
Mitochondria are key organelles providing energy supply and many other vital functions to cells.
Shortly after the discovery of plant-derived cannabinoid compounds, some studies indicated their impact onto mitochondrial functions. The later identification of cannabinoid receptors as classical seven-transmembrane G protein-coupled receptors suggested that these mitochondrial effects might be due to unspecific membrane-altering properties of cannabinoids. However, the recent discovery that brain mitochondria contain significant amounts of functional type-1 cannabinoid receptors (CB1) shed new light on cannabinoid physiology and pharmacology. In this chapter, we will summarize historical and recent evidence of the cannabinoid impact on mitochondrial functions in peripheral and central organs of the body.
Regulatory Effects of Cannabidiol on Mitochondrial Functions: A Review - PMC (nih.gov)
Abstract
Cannabidiol (CBD) is part of a group of phytocannabinoids derived from
Cannabis sativa. Initial work on CBD presumed the compound was inactive,
but it was later found to exhibit antipsychotic, anti-depressive, anxiolytic, and antiepileptic effects. In recent decades, evidence has indicated a role for CBD in the modulation of mitochondrial processes, including respiration and bioenergetics, mitochondrial DNA epigenetics, intrinsic apoptosis, the regulation of mitochondrial and intracellular calcium concentrations, mitochondrial fission, fusion and biogenesis, and mitochondrial ferritin concentration and mitochondrial monoamine oxidase activity regulation. Despite these advances, current data demonstrate contradictory findings with regard to not only the magnitude of effects mediated by CBD, but also to the direction of effects. For example, there are data indicating that CBD treatment can increase, decrease, or have no significant effect on intrinsic apoptosis. Differences between studies in cell type, cell-specific response to CBD, and, in some cases, dose of CBD may help to explain differences in outcomes. Most studies on CBD and mitochondria have utilized treatment concentrations that exceed the highest recorded plasma concentrations in humans, suggesting that future studies should focus on CBD treatments within a range observed in pharmacokinetic studies. This review focuses on understanding the mechanisms of CBD-mediated regulation of mitochondrial functions, with an emphasis on findings in neural cells and tissues and therapeutic relevance based on human pharmacokinetics.
Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications - PMC (nih.gov)
Abstract
Cannabinoids form a singular family of plant-derived compounds (phytocannabinoids), endogenous signaling lipids (endocannabinoids), and synthetic derivatives with multiple biological effects and therapeutic applications in the central and peripheral nervous systems.
One of these properties is the regulation of neuronal homeostasis and survival, which is the result of the combination of a myriad of effects addressed to preserve, rescue, repair, and/or replace neurons, and also glial cells against multiple insults that may potentially damage these cells. These effects are facilitated by the location of specific targets for the action of these compounds (e.g., cannabinoid type 1 and 2 receptors, endocannabinoid inactivating enzymes, and nonendocannabinoid targets) in key cellular substrates (e.g., neurons, glial cells, and neural progenitor cells). This potential is promising for acute and chronic neurodegenerative pathological conditions. In this review, we will collect all experimental evidence, mainly obtained at the preclinical level, supporting that different cannabinoid compounds may be neuroprotective in adult and neonatal ischemia, brain trauma, Alzheimer’s disease, Parkinson’s disease, Huntington’s chorea, and amyotrophic lateral sclerosis. This increasing experimental evidence demands a prompt clinical validation of cannabinoid-based medicines for the treatment of all these disorders, which, at present, lack efficacious treatments for delaying/arresting disease progression, despite the fact that the few clinical trials conducted so far with these medicines have failed to demonstrate beneficial effects.
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Cannabinoids Enhance NMDA-Elicited Ca2+ Signals in Cerebellar Granule Neurons in Culture | Journal of Neuroscience (jneurosci.org)
Abstract
A physiological role for cannabinoids in the CNS is indicated by the presence of endogenous cannabinoids and cannabinoid receptors. However, the cellular mechanisms of cannabinoid actions in the CNS have yet to be fully defined. In the current study, we identified a novel action of cannabinoids to enhance intracellular Ca2+responses in CNS neurons. Acute application of the cannabinoid receptor agonists
R(+)-methanandamide,
R(+)-WIN, and HU-210 (1–50 nm) dose-dependently enhanced the peak amplitude of the Ca2+ response elicited by stimulation of the NMDA subtype of glutamate receptors (NMDARs) in cerebellar granule neurons. The cannabinoid effect was blocked by the cannabinoid receptor antagonist SR141716A and the Gi/Go protein inhibitor pertussis toxin but was not mimicked by the inactive cannabinoid analog
S(−)-WIN, indicating the involvement of cannabinoid receptors. In current-clamp studies neither
R(+)-WIN nor
R(+)-methanandamide altered the membrane response to NMDA or passive membrane properties of granule neurons, suggesting that NMDARs are not the primary sites of cannabinoid action. Additional Ca2+ imaging studies showed that cannabinoid enhancement of the Ca2+ signal to NMDA did not involve N-, P-, or L-type Ca2+ channels but was dependent on Ca2+ release from intracellular stores. Moreover, the phospholipase C inhibitor U-73122 and the inositol 1,4,5-trisphosphate (IP3) receptor antagonist xestospongin C blocked the cannabinoid effect, suggesting that the cannabinoid enhancement of NMDA-evoked Ca2+ signals results from enhanced release from IP3-sensitive Ca2+ stores.
These data suggest that the CNS cannabinoid system could serve a critical modulatory role in CNS neurons through the regulation of intracellular Ca2+signaling.
