Metformin as a potential therapeutic for neurological disease: mobilizing AMPK to repair the nervous system

ABSTRACT

Introduction: Metformin is currently first line therapy for type 2 diabetes (T2D). The mechanism of action of metformin involves activation of AMP-activated protein kinase (AMPK) to enhance mitochondrial function (for example, biogenesis, refurbishment and dynamics) and autophagy. Many neurodegenerative diseases of the central and peripheral nervous systems arise from metabolic failure and toxic protein aggregation where activated AMPK could prove protective.

Areas covered: The authors review literature on metformin treatment in Parkinson’s disease, Huntington’s disease and other neurological diseases of the CNS along with neuroprotective effects of AMPK activation and suppression of the mammalian target of rapamycin (mTOR) pathway on peripheral neuropathy and neuropathic pain. The authors compare the efficacy of metformin with the actions of resveratrol.

Expert opinion: Metformin, through activation of AMPK and autophagy, can enhance neuronal bioenergetics, promote nerve repair and reduce toxic protein aggregates in neurological diseases. A long history of safe use in humans should encourage development of metformin and other AMPK activators in preclinical and clinical research. Future studies in animal models of neurological disease should strive to further dissect in a mechanistic manner the pathways downstream from metformin-dependent AMPK activation, and to further investigate mTOR dependent and independent signaling pathways driving neuroprotection.

KEYWORDS:

• AMP-activated protein kinase (AMPK)
• autophagy
• axon regeneration
• diabetes
• mitochondria
• mTOR
• neurodegenerative disease
• neuropathic pain
• neuropathy
• PGC-1α

Article highlights

• In animal models of PD, metformin improved neurological symptoms, including lowering dyskinesias. The therapeutic pathways involved elevation of mitochondrial function and ROS scavenging, with evidence of AMPK-independent signaling

• In early HD and epilepsy, metformin-dependent suppression of the mTOR pathway was neuroprotective

• Metformin signaling via AMPK and associated elevation of PGC-1α activity can prevent disease in cuprizone and PTX-induced mouse models of MS

• In animal models of stroke and epilepsy, treatment with metformin raised AMPK activity and afforded protection

• Peripheral nerve regeneration is augmented by metformin acting via Schwann cells and also with direct neuronal effects that include optimization of autophagy

• In a variety of animal models of neuropathic pain, including CIPN, metformin prevented tactile and cold allodynia with suppression of mTOR signaling a major target

• The diabetic state depresses AMPK signaling in the DRG and thus treatment with metformin, or resveratrol, is protective against fiber loss and pain in multiple rodent models

• Metformin through subtle adjustment of the balance between AMPK activation and mTOR pathway suppression provides neuroprotection in a variety of neurological diseases

• Enhancing mitochondrial function, to surmount metabolic failure, combined with stimulation of autophagy are two major neuroprotective pathways mobilized by metformin to augment axonal/dendritic plasticity and suppress toxic protein aggregation

Box 1. The AMPK/PGC-1α signaling axis as a sentinel modulating the metabolic needs of the cell.

Table

Box 2. AMPK and the mTOR pathway interact to provide antagonistic and exquisite regulation of cellular growth and metabolism.

Table

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by grant # MOP-130282 from the Canadian Institutes of Health Research to P.F. and grant NS081082 from the National Institutes of Health to NA Calcutt. The authors are grateful to St Boniface Hospital Research for support. S Demaré was supported by a Natural Sciences and Engineering Research Council (NSERC) undergraduate research award. A Kothari was supported by an award from the Rady Faculty of Health Sciences BSc Med program.