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

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.

Metformin treatment ameliorates diabetes‐associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1

“…Our study demonstrates that long-term therapy with oral metformin enhances hippocampal neurogenesis and spatial memory accompanied by the inhibition of chronic microglial activation and increased phosphorylation of AMPK/aPKC f/k/IRS1 serine residues in the hippocampus of middle-aged diabetic mice independently of a glucose-lowering effect. These results are consistent with previous studies describing that chronic oral metformin administration has neuroprotective effects on HFD-induced decline in hippocampal neurogenesis and neurological disorders including dementia in animals and humans [10,12,14,15,[55][56][57][58]. Similarly, in animal disease models, chronic or acute IP injection of metformin improves neurodegeneration, cognitive decline, and neuroinflammation [45,49,57].…”

Metformin Protects against Experimental Acrylamide Neuropathy in Rats

“…It has been reported that MET might protect Schwann cells and stimulate nerve regeneration [Ma et al, 2015]. The neuroprotective effect of MET against various nervous disorders has been reported by Salminen et al [2011], Ashabi et al [2014], Patil et al [2014], Bayliss et al [2016], and Zhang et al [2017].…”

“…MET can cross blood brain barrier (BBB) [Takata et al, 2013], distribute in various brain regions and accumulate in the brain [Towler and Hardie, 2007]. It has neuroprotective effects in Alzheimer's disease [Salminen et al, 2011], cerebral ischemia [Ashabi et al, 2014], spinal cord injury [Zhang et al, 2017] and Parkinson's disease [Patil et al, 2014;Bayliss et al, 2016]. The neuroprotective effect of MET is frequently linked to activation of adenosine monophosphateactivated protein kinase (AMPK) which decreases glucogenesis and enhances neuronal glucose uptake [Amato and Man, 2011].…”

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…Metformin, which has been prescribed for diabetes for decades, inhibits liver glucose production, but also activates multiple cellular pathways that counteract aging processes, including activation of AMPK and inhibition of mTOR and inflammatory pathways (Barzilai et al, 2016). Metformin treatment ameliorates neurodegenerative and behavioral phenotypes in animal models of PD and AD (Bayliss et al, 2016; Niccoli et al, 2016). Such findings support the potential application of pharmacological agents that target metabolism to counteract brain aging and associated neurodegenerative disorders.…”