5-HT1F receptor-mediated mitochondrial biogenesis for the treatment of Parkinson's disease
AffiliationUniv Arizona, Dept Pharmacol & Toxicol, Coll Pharm
MetadataShow full item record
CitationScholpa, N. E., Lynn, M. K., Corum, D., Boger, H. A., and Schnellmann, R. G. (2018) 5‐HT1F receptor‐mediated mitochondrial biogenesis for the treatment of Parkinson's disease. British Journal of Pharmacology, 175: 348–358. doi: 10.1111/bph.14076.
JournalBRITISH JOURNAL OF PHARMACOLOGY
Rights© 2017 The British Pharmacological Society
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractBackground and PurposeParkinson's disease is characterized by progressive decline in motor function due to degeneration of nigrostriatal dopaminergic neurons, as well as other deficits including cognitive impairment and behavioural abnormalities. Mitochondrial dysfunction, leading to loss of ATP-dependent cellular functions, calcium overload, excitotoxicity and oxidative stress, is implicated in the pathophysiology of Parkinson's disease. Using the 5-HT1F receptor agonist LY344864, a known inducer of mitochondrial biogenesis (MB), we investigated the therapeutic efficacy of stimulating MB on dopaminergic neuron loss in a mouse model of Parkinson's disease. Experimental ApproachMale C57BL/6 mice underwent bilateral intrastriatal 6-hydroxydopamine or saline injections and daily treatment with 2mgkg(-1) LY344864 or vehicle for 14days beginning 7days post-lesion. Tyrosine hydroxylase immunoreactivity (TH-ir) and MB were assessed in the brains of all groups following treatment, and locomotor activity was evaluated prior to lesioning, 7days post-lesion and after treatment. Key ResultsIncreased mitochondrial DNA content and nuclear- and mitochondrial-encoded mRNA and protein expression was observed in specific brain regions of LY344864-treated naive and lesioned mice, indicating augmented MB. LY344864 attenuated TH-ir loss in the striatum and substantia nigra compared to vehicle-treated lesioned animals. LY344864 treatment also increased locomotor activity in 6-hydroxydopamine lesioned mice, while vehicle treatment had no effect. Conclusions and ImplicationsThese data revealed that LY344864-induced MB attenuates dopaminergic neuron loss and improves behavioural endpoints in this model. We suggest that stimulating MB may be beneficial for the treatment of Parkinson's disease and that the 5-HT1F receptor may be an effective therapeutic target.
Note12 month embargo; published online: 22 October 2017
VersionFinal accepted manuscript
SponsorsMUSC Barmore Foundation; National Institute of General Medical Sciences [GM084147]; Biomedical Laboratory Research and Development, VA Office of Research and Development [BX: 000851]
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