Jadoon, K.A.
(2016)
An investigation into the metabolic and cardiovascular effects of phytocannabinoids using in vivo and in vitro techniques.
PhD thesis, University of Nottingham.
Abstract
Metabolic syndrome, first described as Syndrome X, includes a cluster of metabolic abnormalities including visceral obesity, insulin resistance, dyslipidaemia and hypertension. The pathophysiology of metabolic syndrome is complex, however, visceral adiposity and insulin resistance are thought to play a central role and both are implicated in the development of type 2 diabetes. Both metabolic syndrome and type 2 diabetes increase the risk of cardiovascular disease, by initiating and accelerating the progression of atherosclerosis, the hallmark of cardiovascular disease. Chronic low-grade inflammation of adipose tissue and vascular endothelium is well documented in type 2 diabetes and associated cardiovascular disease. In addition, stress has also been identified as one of the factors that increases the risk of cardiovascular disease.
The endocannabinoid system is a physiological system that includes cannabinoid (CB1/CB2) receptors, their endogenous ligands and the enzymes responsible for their biosynthesis and degradation. Activation of the endocannabinoid system in the central nervous system leads to increased appetite and food intake while in the periphery it causes lipogenesis. Chronic over activation of the endocannabinoid system has been seen in both obesity and type 2 diabetes. Attempts to modulate the endocannabinoid system, by using CB1 antagonist/inverse agonist, rimonabant, led to positive metabolic and cardiovascular effects, but were associated with adverse psychiatric events. Cannabidiol (CBD) and delta 9 tetrahydrocannabivarin (Δ9 THCV or THCV), are two phytocannabinoids, obtained from Cannabis Sativa L. Both show a distinct pharmacological profile, separate from rimonabant and delta 9 tetrahydrocannabinol (Δ9 THC or THC), the parent compound obtained from Cannabis Sativa L. Both have potent anti-inflammatory and anti-oxidant properties and show multiple desirable cardiovascular and metabolic effects in preclinical studies. The aim of this project was to investigate the metabolic and cardiovascular effects of these two phytocannabinoids, by employing in vivo and in vitro techniques. Chapter 2 describes in detail the clinical study in type 2 diabetic subjects, where we used CBD and THCV, alone and in combination and studied their effects on various metabolic, cardiovascular and inflammatory parameters. Chapter 3 presents acute study of the cardiovascular effects of CBD in young healthy volunteers. Chapters 4 and 5 deal with the effects of CBD and THCV on mature human adipocytes and human aortic endothelial cells respectively. Last chapter includes work done on plasma samples and homogenised femoral arteries from Zucker Diabetic Fatty rats and their lean counterparts, treated with CBD. We found that THCV improves glycaemic parameters in type 2 diabetes, while CBD affects resting cardiovascular parameters and cardiovascular response to stress. CBD affects the release of leptin and IL-6 from adipocytes, while both CBD and THCV affect the release of endothelin-1 and vascular cell adhesion molecule-1 from aortic endothelial cells. CBD also shows positive impact on cytokines in diabetic rats.
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