Targeting dysfunctional cholinergic transmission in Huntington’s disease

Abstract

Huntington’s disease (HD) is a fatal, inherited neurodegenerative disorder for which there is no cure at present. Previous studies have shown that dysfunctional cholinergic transmission may be a significant contributing factor in the neuropathology of HD. Further, the literature suggests that enhancing cholinergic transmission and nicotinic activity, through the activation of nicotinic acetylcholine receptors, may be an effective therapeutic strategy for the treatment of HD. This thesis assesses the ability of varenicline, a nicotinic acetylcholine receptor ligand, to reverse the symptoms and neuropathology of HD in symptomatic YAC128 mice, and to delay the onset of HD symptoms in pre-symptomatic YAC128 mice. Mice were assessed using behavioural tests including those for motor coordination (rotarod and accelerod), cognitive function (rewarded T-maze test and novel object recognition task), and psychiatric function (novelty suppressed feeding test and modified Porsolt test), as well as immunohistochemical staining to detect morphological changes and other assays to measure the levels of neurochemicals such as trophic factors and cytokines. The results showed that varenicline, administered at 5 mg/kg/day for 28 days, improved motor coordination, cognitive performance and psychiatric function. Varenicline also improved the underlying neuropathology of YAC128 mice through a number of interdependent mechanisms, such as huntingtin protein aggregation, which is postulated to be neuroprotective, as well as increased medium spiny neuron survival and progenitor cell proliferation. Varenicline improved motor coordination in symptomatic YAC128 mice, as well as WT mice, when administered at a lower dosage of 1 mg/kg/day for 14 days. The beneficial effects of varenicline persisted for eight and ten weeks in YAC128 and WT mice respectively after the drug had been eliminated from circulation. Tissue analysis showed that varenicline increased the concentration of neurotrophic factors and modulated neuroinflammation. To test whether varenicline was able to cross the blood-brain-barrier and enter the brain, a high performance liquid chromatography assay was carried out. The results of this assay showed that the concentration of varenicline was significantly higher in the brain than in plasma. Further, the concentration of varenicline was not altered by HD. Varenicline, administered for 28 days at 1 mg/kg/day, failed to prevent the onset of motor coordination or motor learning deficits in pre-symptomatic YAC128 mice. However, varenicline delayed the onset of deficits in T-maze acquisition by over four months, and the onset of deficits in working memory by one month. Varenicline also showed antidepressant effects. In an open-label pilot study, patients with HD were able to carry out tests of neurocognitive function and psychiatric function with no difficulty, which suggests that it is feasible to carry out a large-scale clinical trial for varenicline. Further, varenicline was well tolerated in both patients. In conclusion, the research conducted in this thesis has identified a potential therapy for HD which was well tolerated in humans, and improved motor, cognitive and psychiatric function, as well as the underlying neuropathology in a clinically-relevant mouse model of HD. This research has also identified future potential therapeutic targets for HD, and provided new information on the YAC128 model. Future studies will be required to determine the efficacy of varenicline in the clinic, and to confirm the pathways identified in this thesis through which varenicline mediates its beneficial effects.