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 metformindependent AMPK activation, and to further investigate mTOR dependent and independent signaling pathways driving neuroprotection.

Beneficial Effects of Metformin on the Central Nervous System, with a Focus on Epilepsy and Lafora Disease

“…This is an indirect effect due to the inhibition of mitochondrial complex I by metformin (see below), leading to an increase in AMP levels, which inhibits adenylate cyclase and thus leads to a decrease in levels of cAMP, a mediator of CREB-dependent transcription. In addition, metformin has been proposed to activate AMP-activated protein kinase (AMPK), which has a negative effect on the transcriptional regulation of gluconeogenesis genes, among others [4] (see below); (b) Reducing the availability of gluconeogenic substrates: hepatic gluconeogenesis depends on the availability of appropriate substrates, such as glycerol, lactate, pyruvate, alanine, and dihydroxyacetone phosphate (DHAP), in order to convert them to glucose (Figure 1, grey boxes). Glycerol and DHAP are mutually interconnected, since glycerol is converted to glycerol 3-P (G3P) by glycerate kinase (Glctk) and then G3P is converted to DHAP by mitochondrial glycerol-3-phosphate dehydrogenase (GPD2).…”

“…High levels of NADH and low levels of ATP have a crucial negative impact on the gluconeogenesis pathway, as this process requires a large amount of energy and depends on a correct NADH/NAD + balance. Furthermore, as ATP production is reduced, the AMP/ATP ratio increases, and this leads to the activation of AMP-activated protein kinase (AMPK), a master regulator of energy homeostasis [2,4,21]. AMPK activation leads to the activation of catabolic pathways (e.g., glycolysis through the activation of Pfkfb3, an enzyme involved in the formation of 2,6-fructose bisphosphate, an allosteric activator of phosphofructokinase 1 (Pfk1)) and the inhibition of anabolic pathways (e.g., glycogen synthesis by inhibiting glycogen synthase; Gs), to restore energy balance (Figure 1) [4,21].…”

“…AMPK activation leads to the activation of catabolic pathways (e.g., glycolysis through the activation of Pfkfb3, an enzyme involved in the formation of 2,6-fructose bisphosphate, an allosteric activator of phosphofructokinase 1 (Pfk1)) and the inhibition of anabolic pathways (e.g., glycogen synthesis by inhibiting glycogen synthase; Gs), to restore energy balance (Figure 1) [4,21]. AMPK exerts this function both at the transcriptional level, regulating the activity of different transcriptional factors by phosphorylation (e.g., the downregulation of CREB, carbohydrate-responsive element binding protein (ChREBP), and sterol regulatory element binding protein (SREBP-1), which are involved in the expression of genes related to gluconeogenesis, the carbohydrate metabolism, and sterol biosynthesis, respectively; on the other hand, AMPK upregulates peroxisome proliferator-activated receptor γ co-activator 1 alpha (PGC1alpha), involved in mitochondrial biogenesis, and activates pro-health span molecules, such as the forkhead box O3 (FOXO3) transcription factor and sirtuin 1 (SIRT1) deacetylase, which in turn induce the expression of protective molecules [2,4,21,22]). AMPK also operates at the level of key metabolic enzyme activity (e.g., inhibition of acetyl-Co carboxylase (Acc1/2), an enzyme involved in the synthesis of malonyl-CoA, an intermediate in fatty acid synthesis, and an inhibitor of fatty acid oxidation; therefore, AMPK activation inhibits the synthesis of fatty acids and promotes their degradation) [21].…”

“…The effect of metformin on glucose metabolism occurs not only in hepatocytes, but also in other tissues, such as the brain [4]. Neurons and astrocytes are recognized to have different glucose metabolic profiles.…”

“…In some patients, it can produce lactic acidosis, gastrointestinal discomfort, and vitamin B12 deficiency. For this reason, metformin should be administered initially at low doses that are increased if side effects do not appear [4].…”