Neuropharmacology
Department of Pharmacology & Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
Published: April 2017
Objective: Studies in the post mortem human brain and in genetic mouse model suggest that dysfunctional cholinergic neurotransmission, through a loss of agonist rather than receptors may be a significant contributing factor to HD pathology. If correct, pharmacological replacement may therefore be a potential treatment strategy. We have investigated whether chronic administration of the selective nicotinic partial agonist varenicline improved motor, cognitive and affective symptoms in a transgenic mouse model of Huntington's disease.
Method: The performance of 15 month old YAC128 mice and age-matched wild-type littermates was assessed in the rotarod, T-maze, novel object recognition, novelty suppressed feeding and forced swim tests prior to and after treatment with varenicline (5 mg/kg/day for 28 days via miniosmotic pump). Thymidine analogues, whilst DARPP32 and EM48 immunohistochemistry were used to assess the effect of varenicline on progenitor cell proliferation and survival, medium spiny neurons and aggregate formation respectively.
Results: Chronic treatment with varenicline significantly improved motor coordination, delay-dependent memory and reduced depressive-like behaviour in late stage YAC128 mice. Varenicline also produced genotype-independent improvements in recognition memory and reduced anxiety. In addition, varenicline displayed anxiolytic effects and improved spatial memory in the absence of compromised function. Functional improvements were accompanied by neuropathological changes including increased aggregate formation, neuroprotection and increased progenitor cell proliferation and survival.
Interpretation: Our findings provide evidence that administration of an exogenous nicotinic agonist may be of clinical benefit in the treatment of late-stage Huntington's disease.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1016/j.neuropharm.2016.12.021 | DOI Listing |
has been identified in human and mouse HD brain as the pathogenic exon 1 mRNA generated from aberrant splicing between exon 1 and 2 that contributes to aggregate formation and neuronal dysfunction (Sathasivam et al., 2013). Detection of the HTT exon 1 protein (HTTex1p) has been accomplished with surrogate antibodies in fluorescence-based reporter assays (MSD, HTRF), and immunoprecipitation assays, in HD postmortem cerebellum and knock-in mice but direct detection by SDS-PAGE and western blot assay has been lacking.
View Article and Find Full Text PDFFree Radic Biol Med
December 2024
Instituto de Bioquímica y Microbiología, UACh, Valdivia, Chile; Center for Interdisciplinary Studies on Nervous System (CISNe), UACh, Valdivia, Chile; Janelia Research Campus HHMI, Ashburn, VA, USA. Electronic address:
Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the first exon of the huntingtin gene. The huntingtin protein (Htt) is ubiquitously expressed and localized in several organelles, including endosomes, where it plays an essential role in intracellular trafficking. Presymptomatic HD is associated with a failure in energy metabolism and oxidative stress.
View Article and Find Full Text PDFTransl Neurodegener
October 2024
Centre for Molecular Medicine and Therapeutics, Vancouver, BC, V5Z 4H4, Canada.
J Neurochem
September 2024
Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
Huntington's disease (HD) is a monogenic disorder with autosomal dominant inheritance. In HD patients, neurons in the striatum and cortex degenerate, leading to motor, psychiatric and cognitive disorders. Dysregulated synaptic function and calcium handling are common in many neurodegenerative diseases, including HD.
View Article and Find Full Text PDFBrain Commun
February 2024
Huntington's Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, UCL, London WC1N 3BG, UK.
Huntington's disease is an inherited neurodegenerative disorder for which a wide range of disease-modifying therapies are in development and the availability of biomarkers to monitor treatment response is essential for the success of clinical trials. Baseline levels of neurofilament light chain in CSF and plasma have been shown to be effective in predicting clinical disease status, subsequent clinical progression and brain atrophy. The identification of further sensitive prognostic fluid biomarkers is an active research area, and total-Tau and levels have been shown to be increased in CSF from Huntington's disease mutation carriers.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!
© LitMetric 2025. All rights reserved.