The neuroprotective effects of cannabinoids were once thought to be mainly mediated by the G-protein coupled cannabinoid receptor CB1. However, recent insights into the endocannabinoid system have revealed a more complex series of interactions involving other receptors. Some cannabinoids have been found to have a particular affinity for the transcription factor nuclear receptor family of PPARs (peroxisome proliferator-activated receptors).
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In this review, the interactions of those cannabinoids with PPARs and the neuroprotective implications are explored. The conclusion of the authors is that some cannabinoids are in fact agonists of the PPAR family, in particular, PPAR-alpha and PPAR-gamma.
These receptors are known to be a part of the response to ischemic brain damage and it is probably through some immune system mediation effect that this is achieved. The implications of the study are that this is a potential mechanism for affecting neuroprotection and exploring the endocannabinoid system.
By altering the expression of genes vital for brain health, cannabinoids can exert neuroprotective (and potentially, in excess, neurodegenerative) effects through PPAR binding. This was unexpected but could produce a new understanding of the brain and new, novel ways of developing drugs to protect and heal the brain.
Instead of a relatively simple system using 2 cannabinoid receptors, the latest evidence is suggesting that the endocannabinoid system encompasses more and varied receptors than originally thought. In this case, the PPAR family, which are activated by peroxisome proliferators. It turns out that they are also activated by fenofibrate, THC, OEA, virodhamine, anandamide, WIN 55121-2, and noladin ether, most of the most common endocannabinoids.
Cannabinoids have been known to have anti-inflammatory effects for a long time. The main mechanism via the CB1 receptor is well known but incomplete. When PPARs are activated by cannabinoids, they increase the expression of some proteins involved in regulating genes involved in brain regulation.
When PPAR-alpha and PPAR-gamma are activated, they modulate the expression of genes that produce neuroprotective effects. The mechanism is not explored here and remains relatively unclear. However, it is known that NF-kB (the protein produced by PPAR expression interactions) is a part of the mechanism that produces iNOS, “neural cell adhesion molecules, theta-opioid receptor, amyloid precursor proteins, and a variety of other important neurological proteins and molecules.
The extent of this interaction is significant and implies that PPARs are very important for the healthy maintenance of the brain. These molecules are also very much involved in neuroprotection.
Further research will reveal these mechanisms more fully, but the extent of them detailed here suggest that interactions with PPARs via the endocannabinoid system offer an excellent method of precise and effective neuroprotective effects.
Dementia and brain damage are two of the biggest drains on society and the individual. The potential of the endocannabinoid system for mediating neuroprotective effects has been expanded by this study, which shows an alternative and more nuanced way of achieving some very positive effects.
The more nuanced understanding of the endocannabinoid and PPAR systems, and their interactions, will be very useful for understanding brain health, healing, and maintenance. When these interactions can be more fully understood, drugs that can exploit the neuroprotective effects. This could have implications for dementia patients, brain damage sufferers, and maintain brain health through life.