Rhodiola Rosea L.- An Evaluation of Safety and Efficacy in the Context of a Neurological Disorder, Alzheimer Disease

This thesis examined the safety and efficacy of Rhodiola rosea L. (Crassulaceae), a medicinal plant used traditionally by the Inuit of Nunavik, Québec, for the maintenance of mental and physical health. To assess the effects of Nunavik R. rosea on the central nervous system, a phytochemically characterized extract was tested in behavioural assays of anxiety with rats. Significant changes in behaviour were observed, particularly in the conditioned emotional response test. R. rosea was not a potent modulator of the benzodiazepine site of the GABAA receptor, indicating possible involvement of other neurotransmitters implicated in the neurobiology of anxiety.\ud Safety of Nunavik R. rosea, its marker phytochemicals, and additional R. rosea products was assessed by evaluating the risk of drug interaction potential. Inhibitory capacity was tested on major human drug metabolizing enzymes, the cytochrome P450s. Further, effects on the metabolism of repaglinide, an anti-diabetic drug, were examined in human liver microsomes. While the overall risk of interactions was low, variable impacts of R. rosea products on the formation of glucuronide metabolites of repaglinide necessitate caution.\ud In the TgCRND8 model of Alzheimer disease, R. rosea chronic administration led to modest improvements in the survival of male transgenic mice, which exhibit accelerated rates of mortality. Effects on learning and memory performance in the Morris water maze were limited to alterations in the patterns of use of search strategies as determined by our automated scoring algorithm, MWM Visual; changes in escape latencies were not observed.\ud Nunavik R. rosea administration resulted in elevated plasma levels of anandamide (20:1, n-9), a member of the endocannabinoid family, tentatively identified using an untargeted metabolomics approach via ultra-performance liquid chromatography-quadrupole-time-of-flight-mass spectrometry. R. rosea phytochemicals were either eliminated via the renal pathway, or transformed into potential metabolites.\ud Collectively, the anxiolytic activity of Nunavik R. rosea in rats, its protective effects on high background mortality in an aggressive Alzheimer disease model, low risk of inhibition of major enzymes involved in drug metabolism, and its ability to induce detectable changes in in vivo metabolic pathways are supportive scientific evidence for the use of this traditional medicine for general well-being by the Inuit