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Title: Phytocannabinoids and neuroprotection : mechanisms of action and in vitro models
Author: Ryan, Duncan
ISNI:       0000 0001 3542 7889
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2007
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Phytocannabinoids are unique to the herb Cannabis sativa and are structurally related to tetrahydrocannabinol (THC) which is psychoactive via activation of the endogenous cannabinoid system: Cannabidiol (CBD) has well-described pharmacological activities though is not a potent agonist within the classical endocannabinoid system. These compounds have been implicated as medicinally useful though their exact mechanisms of action are not yet fully established. The main aims ofthe present study were: I. To investigate the link between CBD and neuronal Ca2+homeostasis 2. To examine interactions between CBD..-and the endocannabinoid system 3. To characterise pharmacological differences between THC, CBD and whole Cannabis extracts rich in these cannabinoids 4. To assess the capacity of CBD (and other phytocannabinoids) as a neuroprotectant against mitochondrial stress (in SH-SY5Y cells) Work presented here utilised Fura-2 AM to monitor intracellular Ca2+ homeostasis and signalling mechanisms, as well as interactions between CBD and the endocannabinoid system, in primary rat hippocampal cultures. The Ca2+ indicator Rhod-FF was employed to investigate Ca2+signalling in mitochondria. Acute CBD application caused an increased [Ca2+]i in hippocampal cells. A clear interaction between CBD- and endocannabinoid-sigJ;lalling was established, with activation of the endocannabinoid system dampening CBD responses. Under basal conditions there is an apparent endocannabinoid tone which inhibits CBD responses. Mitochondrial Ca2 + stores were shown to be the source ofCa2+released by CBD, in close association with the mitochondrial Na+/Ca2+exchanger (NCX). Distinct pharmacoligcal profiles were observed between pure phytocannabinoids (CBD and THC) and whole Cannabis extracts rich in CBD or THC. Thus, broader pharmacological activity attributed to extracts is due to the presence of other compounds (or synergism between cannabinoids) and may agree with greater therapeutic efficacy for whole-plant extracts. These data present an important contribution to neuroscience, characterising CBD's actions in hippocampal cells. An interaction between CBD and the endocannabinoid system has been demonstrated as well as its potency as a neuroprotectant and modulator of Ca2 + homeostasis. CBD's therapeutic potential is underlined, especially against pathologies involving mitochondrial dysfunction. Keywords: calcium homeostasis, cannabidiol, endocannabinoid system, mitochondria, neuroprotection
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available