Pharmaceutica Analytica Acta

Abstract

Endocannabinoid Stimulated Release of Nitric Oxide and its Mitochondrial Influence Triggering Vascular Pathology

George B Stefano, Erin Quinn and Richard M Kream

Endocannabinoids, and their respective receptors, are involved in a host of cellular regulatory activities. In part, some of these mediated effects occur by way of stimulating constitutive nitric oxide release. This occurs in endothelia, certain white blood cells, microglia, and in similar invertebrate tissues, demonstrating that this is a conserved chemical messenger system. This endocannabinoid chemical messenger system, coupled to constitutive nitric oxide release, also appears to exert regulatory effects on mitochondrial energy associated processes, further substantiating its primordial history. In this regard, it appears to offer some beneficial actions in the occurrence of reperfusion injury and stroke. The mechanism envisioned is one initiated via a hypoxic event, which does not restore normalcy, then progresses to a pro-inflammatory state, and the resultant chronic condition manifests itself in a specific disorder. This fits nicely into a vascular-associated origin for Alzheimer’s Disease, whereby the proinflammatory state encompasses vessels that have endothelial gaps, providing for a compromised blood brain barrier, beta amyloid deposition, and enhanced white blood cell trafficking. In time, due to the physical progression of the events, Alzheimer’s Disease occurs.