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

Abstract

Metformin is a drug in the family of biguanide compounds that is widely used in the treatment of type 2 diabetes (T2D). Interestingly, the therapeutic potential of metformin expands its prescribed use as an anti-diabetic drug. In this sense, it has been described that metformin administration has beneficial effects on different neurological conditions. In this work, we review the beneficial effects of this drug as a neuroprotective agent in different neurological diseases, with a special focus on epileptic disorders and Lafora disease, a particular type of progressive myoclonus epilepsy. In addition, we review the different proposed mechanisms of action of metformin to understand its function at the neurological level.

Keywords: AMPK; GPD2; Lafora disease; epilepsy; mechanism of action; metformin; neurological disorders.

Figure 1

Metabolic pathways affected by metformin. A diagram of the main pathways related to glycolysis and gluconeogenesis is depicted. Gluconeogenic substrates are highlighted in grey, and enzymes directly affected by metformin are highlighted in orange. Specific enzyme isoforms present in neurons are in red, and those present in astrocytes are in blue. See text for details. AldoA: aldolase; Alt: Alanine aminotransferase; AMPK: AMP-activated protein kinase; NADH: ubiquinone oxidoreductase; Fbp: fructose bisphosphatase; Gapdh: glyceraldehyde-3P dehydrogenase; G6pc: glucose 6-phosphatase; G6pd: glucose-6P dehydrogenase; Gck: glucokinase; Glctk: glycerate kinase; GLUT: glucose transporter; Gpd: glycerol-3P dehydrogenase; Gph: glycogen phosphorylase; Gs: glycogen synthase; Ldh: lactate dehydrogenase; LKB1: liver protein kinase; MCT: monocarboxylic transporter; OCT: organic cation transporter; Pc: pyruvate carboxylase; Pdh: pyruvate dehydrogenase; Pdk: pyruvate dehydrogenase kinase; Pepck1: phosphoenolpyruvate carboxykinase; Pfk: phosphofructokinase; Pfkfb3: phosphofructokinase 2,6-bisphosphatase; Pkm: pyruvate kinase; TCA cycle: tricarboxylic acid cycle; Tpi: triosephosphate isomerase.

Figure 2

Mechanisms of action of metformin and cellular outcomes. Proteins affected by metformin, either via AMPK-dependent and AMPK-independent pathways, are indicated. In red are outcomes that are inhibited by metformin. In blue are those that are enhanced by metformin.