The Therapeutic Potential of Metformin in Neurodegenerative Diseases

Abstract

The search for treatments for neurodegenerative diseases is a major concern in light of today's aging population and an increasing burden on individuals, families, and society. Although great advances have been made in the last decades to understand the underlying genetic and biological cause of these diseases, only some symptomatic treatments are available. Metformin has long since been used to treat Type 2 Diabetes and has been shown to be beneficial in several other conditions. Metformin is well-tested in vitro and in vivo and an approved compound that targets diverse pathways including mitochondrial energy production and insulin signaling. There is growing evidence for the benefits of metformin to counteract age-related diseases such as cancer, cardiovascular disease, and neurodegenerative diseases. We will discuss evidence showing that certain neurodegenerative diseases and diabetes are explicitly linked and that metformin along with other diabetes drugs can reduce neurological symptoms in some patients and reduce disease phenotypes in animal and cell models. An interesting therapeutic factor might be how metformin is able to balance survival and death signaling in cells through pathways that are commonly associated with neurodegenerative diseases. In healthy neurons, these overarching signals keep energy metabolism, oxidative stress, and proteostasis in check, avoiding the dysfunction and neuronal death that defines neurodegenerative disease. We will discuss the biological mechanisms involved and the relevance of neuronal vulnerability and potential difficulties for future trials and development of therapies.

Metformin limits osteoarthritis development and progression through activation of AMPK signalling

“…Metformin has been shown to activate AMP-activated protein kinase (AMPK), a master regulator of energy balance and metabolism. Dysregulation of AMPK is linked to multiple age-related diseases including diabetes, atherosclerosis, cardiovascular disease, cancer, neurodegenerative diseases and osteoarthritis (OA) 8–12. Reduced AMPK activity, assessed by phosphorylation of a specific threonine in the catalytic alpha subunit of AMPK (AMPKα1), is observed in both human and mouse knee OA cartilage 12–14.…”

Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus

“…• Neurodegenerative diseases: There is growing evidence in preclinical and clinical studies for the benefits of metformin to counteract neurodegenerative diseases 247 . The rationale is based on the potential of the drug to act as a neuroprotective agent by targeting neuronal oxidative stress, inflammation and cell death.…”

Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

“…Apart from its glucose-lowering effect, metformin was studied for its cardioprotective and vasculo-protective effects and more recently for its effects as a cancer preventive and anti-cancer/anti-tumor agent in different cancers (Figure 1) [5,20,21]. Depending on patient prolife and various disease conditions or stages, metformin treatment-associated beneficial effects in the treatment of hepatic diseases [22][23][24][25], renal damage and disorders [26], neurodegenerative diseases [27][28][29], and bone disorders [30] were reported. In addition, metformin treatment-related antiaging effects, delay in the onset of age-related disorders, and improvement in longevity (lifespan) were reported in C. elegans, insects, and rodents [31][32][33][34].Interest has grown in studying the possible use of metformin as an anti-cancer/anti-tumor agent individually or in combination with frequently used chemotherapeutic agents and/or radiation.…”