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    Metformin Prevents Nigrostriatal Dopamine Degeneration Independent of AMPK Activation in Dopamine Neurons

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    Author
    Bayliss, JA; Lemus, MB; Santos, VV; Deo, M; Davies, JS; Kemp, BE; Elsworth, JD; Andrews, ZB
    Date
    2016-07-28
    Source Title
    PLoS One
    Publisher
    PUBLIC LIBRARY SCIENCE
    University of Melbourne Author/s
    Kemp, Bruce; Bayliss, Jacqueline
    Affiliation
    Medicine and Radiology
    Anatomy and Neuroscience
    Metadata
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    Document Type
    Journal Article
    Citations
    Bayliss, J. A., Lemus, M. B., Santos, V. V., Deo, M., Davies, J. S., Kemp, B. E., Elsworth, J. D. & Andrews, Z. B. (2016). Metformin Prevents Nigrostriatal Dopamine Degeneration Independent of AMPK Activation in Dopamine Neurons. PLOS ONE, 11 (7), https://doi.org/10.1371/journal.pone.0159381.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/259999
    DOI
    10.1371/journal.pone.0159381
    Abstract
    Metformin is a widely prescribed drug used to treat type-2 diabetes, although recent studies show it has wide ranging effects to treat other diseases. Animal and retrospective human studies indicate that Metformin treatment is neuroprotective in Parkinson's Disease (PD), although the neuroprotective mechanism is unknown, numerous studies suggest the beneficial effects on glucose homeostasis may be through AMPK activation. In this study we tested whether or not AMPK activation in dopamine neurons was required for the neuroprotective effects of Metformin in PD. We generated transgenic mice in which AMPK activity in dopamine neurons was ablated by removing AMPK beta 1 and beta 2 subunits from dopamine transporter expressing neurons. These AMPK WT and KO mice were then chronically exposed to Metformin in the drinking water then exposed to MPTP, the mouse model of PD. Chronic Metformin treatment significantly attenuated the MPTP-induced loss of Tyrosine Hydroxylase (TH) neuronal number and volume and TH protein concentration in the nigrostriatal pathway. Additionally, Metformin treatment prevented the MPTP-induced elevation of the DOPAC:DA ratio regardless of genotype. Metformin also prevented MPTP induced gliosis in the Substantia Nigra. These neuroprotective actions were independent of genotype and occurred in both AMPK WT and AMPK KO mice. Overall, our studies suggest that Metformin's neuroprotective effects are not due to AMPK activation in dopaminergic neurons and that more research is required to determine how metformin acts to restrict the development of PD.

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