“Over the course of the last decade, Peroxisome Proliferator-Activated Receptors (PPARs) have been identified as part of the cannabinoid signaling system: both phytocannabinoids and endocannabinoids are capable of binding and activating these nuclear receptors. Fatty Acid Amide Hydrolase (FAAH) hydrolyzes the endocannabinoid Anandamide and other N-Acylethanolamines. These substances have been shown to have numerous anti-cancer effects, and indeed the inhibition of FAAH has multiple beneficial effects that are mediated by PPARα subtype and by PPARγ subtype, especially antiproliferation and activation of apoptosis. The substrates of FAAH are also PPAR agonists, which explains the PPAR-mediated effects of FAAH inhibitors. Much like cannabinoid ligands and FAAH inhibitors, PPARγ agonists show antiproliferative effects on cancer cells, suggesting that additive or synergistic effects may be achieved through the positive modulation of both signaling systems. In this perspective, we discuss the development of novel FAAH inhibitors able to directly act as PPAR agonists and their promising utilization as leads for the discovery of highly effective anti-cancer compounds.”
“Multiple sclerosis (MS) is characterized by a combination of inflammatory and neurodegenerative processes variously dominant in different stages of the disease. Thus, immunosuppression is the goal standard for the inflammatory stage, and novel remyelination therapies are pursued to restore lost function.
Cannabinoids such as 9Δ-THC and CBD are multi-target compounds already introduced in the clinical practice for multiple sclerosis (MS). Semisynthetic cannabinoids are designed to improve bioactivities and druggability of their natural precursors. VCE-004.8, an aminoquinone derivative of cannabidiol (CBD), is a dual PPARγ and CB2agonist with potent anti-inflammatory activity.
Activation of the hypoxia-inducible factor (HIF) can have a beneficial role in MS by modulating the immune response and favoring neuroprotection and axonal regeneration.
We investigated the effects of VCE-004.8 on the HIF pathway in different cell types.
This study provides new significant insights about the potential role of VCE-004.8 for MS treatment by ameliorating neuroinflammation and demyelination.”
“Phytocannabinoids are produced in Cannabis sativa L. in acidic form and are decarboxylated upon heating, processing, and storage. While the biological effects of decarboxylated cannabinoids such as Δ9 -tetrahydrocannabinol (Δ9 -THC) have been extensively investigated, the bioactivity of Δ9 -THCA is largely unknown, despite its occurrence in different Cannabis preparations. The aim of this study was to determine whether Δ9 -THCA modulates the PPARγ pathway and has neuroprotective activity.
The effects of six phytocannabinoids on PPARγ binding and transcriptional activity were investigated. The effect of Δ9 -THCA on mitochondrial biogenesis and PGC-1α expression was investigated in N2a cells. The neuroprotective effect was analysed in STHdhQ111/Q111 cells expressing a mutated form of the huntingtin protein, and in N2a cells infected with an adenovirus carrying human huntingtin containing 94 polyQ repeats (mHtt-q94). In vivo neuroprotective activity of Δ9 -THCA was investigated in mice intoxicated with the mitochondrial toxin 3-nitropropionic acid (3-NP).
Cannabinoid acids bind and activate PPARγ with higher potency than their decarboxylated products. Δ9 -THCA increases mitochondrial mass in neuroblastoma N2a cells, and prevents cytotoxicity induced by serum deprivation in STHdhQ111/Q111cells and by mutHtt-q94 in N2a cells. Δ9 -THCA, through a PPARγ-dependent pathway, was neuroprotectant in mice intoxicated with 3-NP, improving motor deficits and preventing striatal degeneration. In addition, Δ9 -THCA attenuated microgliosis, astrogliosis and the upregulation of proinflammatory markers induced by 3-NP.
CONCLUSION AND IMPLICATIONS:
Δ9 -THCA shows potent neuroprotective activity, worth consideration for the treatment of Huntington´s Disease and possibly other neurodegenerative and neuroinflammatory diseases.”
“Some cannabinoids activate the different isoforms of peroxisome proliferator-activated receptors (PPARs; α, β and γ), as shown through the use of reporter gene assays, binding studies, selective antagonists and knockout studies.
Activation of all isoforms, but primarily PPARα and γ, mediate some (but not all) of the analgesic, neuroprotective, neuronal function modulation, anti-inflammatory, metabolic, anti-tumoral, gastrointestinal and cardiovascular effects of some cannabinoids, often in conjunction with activation of the more traditional target sites of action such as CB1 , CB2 and TRPV1.
PPARs also mediate some of the effects of inhibitors of endocannabinoid degradation or transport. Cannabinoids may be chaperoned to the PPARs by fatty acid binding proteins (FABPs).
The aim of this review is to update the evidence supporting PPAR activation by cannabinoids, and review the physiological responses to cannabinoids that are mediated, and not mediated, by PPAR activation.”