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

Alquier, Thierry; Bayliss, Jacqueline A.; Lemus, Moyra B.; Santos, Vanessa V.; Deo, Minh; Davies, Jeffrey; Kemp, Bruce E.; Elsworth, John D.; Andrews, Zane B.

doi:10.1371/journal.pone.0159381

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

Thierry Alquier, Jacqueline A. Bayliss, Moyra B. Lemus, Vanessa V. Santos, Minh Deo, Jeffrey Davies

, Bruce E. Kemp, John D. Elsworth, Zane B. Andrews

PLOS ONE, Volume: 11, Issue: 7, Start page: e0159381

Swansea University Author: Jeffrey Davies

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DOI (Published version): 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...

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ISSN:	1932-6203
Published:	2016
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first_indexed	2016-08-18T18:43:26Z
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spelling	2020-06-25T15:24:43.7720326 v2 29599 2016-08-18 Metformin Prevents Nigrostriatal Dopamine Degeneration Independent of AMPK Activation in Dopamine Neurons 2cb3d1d96a7870a84d2f758e865172e6 0000-0002-4234-0033 Jeffrey Davies Jeffrey Davies true false 2016-08-18 BMS 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. Journal Article PLOS ONE 11 7 e0159381 1932-6203 Parkinson's disease, Metformin, AMPK, dopamine 31 12 2016 2016-12-31 10.1371/journal.pone.0159381 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 2020-06-25T15:24:43.7720326 2016-08-18T13:51:46.6724756 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Thierry Alquier 1 Jacqueline A. Bayliss 2 Moyra B. Lemus 3 Vanessa V. Santos 4 Minh Deo 5 Jeffrey Davies 0000-0002-4234-0033 6 Bruce E. Kemp 7 John D. Elsworth 8 Zane B. Andrews 9 0029599-16092016161823.PDF journal.pone.0159381.PDF 2016-09-16T16:18:23.7230000 Output 1725054 application/pdf Version of Record true 2016-09-16T00:00:00.0000000 © 2016 Bayliss et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. true https://creativecommons.org/licenses/by/4.0/
title	Metformin Prevents Nigrostriatal Dopamine Degeneration Independent of AMPK Activation in Dopamine Neurons
spellingShingle	Metformin Prevents Nigrostriatal Dopamine Degeneration Independent of AMPK Activation in Dopamine Neurons Jeffrey Davies
title_short	Metformin Prevents Nigrostriatal Dopamine Degeneration Independent of AMPK Activation in Dopamine Neurons
title_full	Metformin Prevents Nigrostriatal Dopamine Degeneration Independent of AMPK Activation in Dopamine Neurons
title_fullStr	Metformin Prevents Nigrostriatal Dopamine Degeneration Independent of AMPK Activation in Dopamine Neurons
title_full_unstemmed	Metformin Prevents Nigrostriatal Dopamine Degeneration Independent of AMPK Activation in Dopamine Neurons
title_sort	Metformin Prevents Nigrostriatal Dopamine Degeneration Independent of AMPK Activation in Dopamine Neurons
author_id_str_mv	2cb3d1d96a7870a84d2f758e865172e6
author_id_fullname_str_mv	2cb3d1d96a7870a84d2f758e865172e6_***_Jeffrey Davies
author	Jeffrey Davies
author2	Thierry Alquier Jacqueline A. Bayliss Moyra B. Lemus Vanessa V. Santos Minh Deo Jeffrey Davies Bruce E. Kemp John D. Elsworth Zane B. Andrews
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description	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.
published_date	2016-12-31T03:36:00Z
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Metformin Prevents Nigrostriatal Dopamine Degeneration Independent of AMPK Activation in Dopamine Neurons

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