Overview of Metformin and Neurodegeneration: A Comprehensive Review

Abstract

This comprehensive review examines the therapeutic potential of metformin, a well-established diabetes medication, in treating neurodegenerative disorders. Originally used as a first-line treatment for type 2 diabetes, recent studies have begun investigating metformin's effects beyond metabolic disorders, particularly its neuroprotective capabilities against conditions like Parkinson's disease, Alzheimer's disease, Huntington's disease, and multiple sclerosis. Key findings demonstrate that metformin's neuroprotective effects operate through multiple pathways: AMPK activation enhancing cellular energy metabolism and autophagy; upregulation of antioxidant defenses; suppression of inflammation; inhibition of protein aggregation; and improvement of mitochondrial function. These mechanisms collectively address common pathological features in neurodegeneration and neuroinflammation, including oxidative stress, protein accumulation, and mitochondrial dysfunction. Clinical and preclinical evidence supporting metformin's association with improved cognitive performance, reduced risk of dementia, and modulation of pathological hallmarks of neurodegenerative diseases is critically evaluated. While metformin shows promise as a therapeutic agent, this review emphasizes the need for further investigation to fully understand its mechanisms and optimal therapeutic applications in neurodegenerative diseases.

Keywords: metformin; neurodegeneration; type 2 diabetes.

Figure 1

Structural and botanical characterization of metformin (C₄H₁₁N₅). Galega officinalis (Fabaceae), the plant from which metformin was originally derived, is characterized by palmately compound leaves and racemose inflorescences. The molecular structure of metformin shows a structural pattern that highlights the biguanide scaffold with terminal N-methylation. Image by rawpixel.com on Freepik. Created in BioRender. Kciuk, M. (2025) https://BioRender.com/o18q303 (accessed on 9 March 2025).

Figure 2

A cascade of progressive protein aggregation in neurodegenerative pathogenesis. The process initiates in the healthy brain with native protein monomers, which undergo conformational changes leading to oligomerization. These oligomeric intermediates further aggregate into protofibrils, ultimately assembling into highly ordered amyloid fibrils. This terminal aggregation state correlates with observable neuropathology, characterized by distinct patterns of brain damage. The downstream of cellular consequences of protein aggregation, includes disruption of essential neuronal functions: protein quality control mechanisms, mitochondrial homeostasis, axonal transport efficiency, and synaptic transmission integrity. This cascade represents a crucial mechanistic framework in understanding the molecular basis of neurodegenerative disorders and identifies potential therapeutic intervention points along the aggregation pathway. Created in BioRender. Kciuk, M. (2025) https://BioRender.com/g29m614 (accessed on 19 February 2025).

Figure 3

Molecular mechanisms of neuroinflammatory signaling cascades in neurodegeneration. Converging molecular pathways mediating neuroinflammatory responses in neurodegenerative conditions have two primary inflammatory triggers: pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), which initiate distinct but interconnected signaling cascades across the cellular membrane. PAMPs (pathogen-associated molecular patterns), including LPS, viral RNA/DNA, flagellin, and peptidoglycans, initiate inflammation through TLR-mediated signaling. This process branches into two main cascades: TIRAP–MyD88-MAP3K–MAP2K–MAPK and TRIF–TBL1–IRF3. Both pathways converge to activate NF-κB, triggering the expression of pro-inflammatory genes. These include critical cytokines (TNF-α, IL-1β, IL-6, IL-8), chemokines (CCL2, CXCL8), and inflammatory mediators (COX-2, iNOS, PGE2). Simultaneously, DAMPs (damage-associated molecular patterns) such as ATP, HMGB1, HSPs, and cellular DNA/RNA activate a separate inflammatory cascade through the NLRP3 inflammasome. This process begins with potassium efflux, which triggers NLRP3 activation, followed by ASC recruitment and pro-caspase-1 processing. The end result is active caspase-1, which promotes the expression of inflammatory mediators, particularly GSDMD and HMGB1. PAMPs = pathogen-associated molecular patterns, LPS = lipopolysaccharide, RNA = ribonucleic Acid, DNA = deoxyribonucleic acid, TLR = toll-like receptor, TIRAP = TIR domain-containing adaptor protein, MyD88 = myeloid differentiation primary response 88, MAP3K = mitogen-activated protein kinase kinase kinase, MAP2K = mitogen-activated protein kinase kinase, MAPK = mitogen-activated protein kinase, TRIF = TIR domain-containing adapter-inducing interferon-β, TBL1 = transducin beta-like 1, IRF3 = interferon regulatory factor 3, NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells, TNF-α = tumor necrosis factor alpha, IL-1β = interleukin-1 beta, IL-6 = interleukin-6, IL-8 = interleukin-8, CCL2 = C-C motif chemokine ligand 2, CXCL8 = C-X-C motif chemokine ligand 8, COX-2 = cyclooxygenase-2, iNOS = inducible nitric oxide synthase, PGE2 = prostaglandin E2, DAMPs = damage-associated molecular patterns, ATP = adenosine triphosphate, HMGB1 = high mobility group box 1, HSPs = heat shock proteins, NLRP3 = NOD-like receptor protein 3, ASC = apoptosis-associated speck-like protein containing a CARD, GSDMD = gasdermin D, K+ = potassium. Created in BioRender. Kciuk, M. (2025) https://BioRender.com/zb9c38p (accessed on 27 March 2025).