Promising use of metformin in treating neurological disorders: biomarker-guided therapies

Abstract

Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases (Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), cerebrovascular conditions (stroke), and neurodevelopmental disorders (autism spectrum disorder). Although they affect millions of individuals around the world, only a limited number of effective treatment options are available today. Since most neurological disorders express mitochondria-related metabolic perturbations, metformin, a biguanide type II antidiabetic drug, has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism. However, controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders. Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging, lifestyle, genetics, and environment, it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders. These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment, ultimately developing targeted therapy. In this review, we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.

Keywords: Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; metformin; mitochondrial perturbation; multiple sclerosis; neural degenerative diseases; stroke; targeted therapy.

Figure 1

Schematic of metformin’s neuroprotective effects. Metformin reduces protein aggregation through (1) AMPK-PP2A pathway to inhibit p-Ser129 α-synuclein in PD, (2) AMPK-mediated inhibition of p35 cleavage to p25, (3) through activation of the AMPK-PP2A-S6K-BACE1 pathway in AD, and (4) by disrupting the mitotic disruption-induced protein phosphatase 2A complex to activate PP2A via AMPK to reduce tau-phosphorylation in AD. Metformin can also increase neuronal survival via increased neuroprotective genes (Bcl-2 and CREB), mitochondria-associated genes (PGC1α, nuclear respiratory factor 1, and transcription factor A mitochondrial) expression, and reduced NF-κB gene expression that is AMPK dependent. Metformin treatment can reduce neuronal cell death by activating the AMPK-mTOR pathway to restore impaired autophagy, lower ROS production, mitochondrial fission, and increase mitochondrial membrane depolarization. Created with BioRender.com. AMPK: AMP-activated protein kinase; BACE1: beta-secretase 1; Bcl-2: B-cell lymphoma 2; BDNF: brain-derived neurotrophic factor; cdk5: cyclin-dependent kinase 5; CREB: cAMP response element-binding protein; mHtt: mutant huntingtin; mTOR: mammalian target of rapamycin; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; Nrf1: nuclear respiratory factor 1; PGC1α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PP2A: protein phosphatase 2A; p-Ser129: phosphorylated at Ser129; ROS: reactive oxygen species; TFAM: transcription factor A, mitochondrial.

Figure 2

Schematic of metformin’s neural regenerative effects. Metformin can stimulate the proliferation of NSCs by increased expression of TAp73. Metformin also promotes neurogenesis via the activation of the AMPK-aPKC-CBP pathway, which inhibits the transcription of Mgll, leading to enhanced differentiation. Metformin enhances OPC proliferation through early-stage autophagy inhibition, while it promotes OPC differentiation into mature oligodendrocytes through the AMPK-aPKC-CBP pathway to enhance the genesis of newborn oligodendrocytes. Created with BioRender.com. AMPK: AMP-activated protein kinase; aPKC: atypical protein kinase C; CBP: CREB-binding protein; Mgll: monoacylglycerol lipase; Tap73: tumor protein p73.

Figure 3

Schematic of metformin’s effects on angiogenesis and anti-inflammation in the central nervous system. Metformin treatment reduces inflammatory molecules by (1) lowering mononuclear cells entering the central nervous system through CAMs; (2) increasing production of Th1 and Th17 to reduce proinflammatory cytokines (interferon-γ, TNF-α, IL-6, IL-17, and inducible nitric oxide synthase) release; (3) inhibiting transcription of Mgll via the AMPK-aPKC-CBP pathway to reduce the conversion of 2-AG to inflammatory ARA; and (4) activating AMPK-P65 NF-κB pathway to suppress the transcription of proinflammatory cytokines (IL-1β and TNF-α). Metformin treatment also reduces glial activation through the AMPK-mTOR-S6K pathway. Finally, metformin can also restore autophagy via the AMPK-mTOR pathway. Created with BioRender.com. 2-AG: 2-Arachidonoylglycerol; AMPK: AMP-activated protein kinase; aPKC: atypical protein kinase C; ARA: arachidonic acid; CAM: cell adhesion molecule; CBP: CREB-binding protein; FFA: free fatty acid; IL-1β: interleukin-1 beta; Mgll: monoacylglycerol lipase; mTOR: mammalian target of rapamycin; p65-NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells subunit p65; Th1: T helper 1; Th17: T helper 17; TNF-α: tumor necrosis factor-alpha.

Figure 4

Personalized medicine: biomarkers-guided metformin-responsive treatment in neurological diseases. Proposed biomarker screening methodology to stratify subpopulations of AD, stoke, and MS patients for metformin-responsive treatment. Subpopulations of interest would be individuals with elevated Mgll, reduced AMPK activity, and reduced mitochondrial respiration for AD, stroke, and MS patients, respectively. Created with BioRender.com. AD: Alzheimer’s disease; AMPK: AMP-activated protein kinase; Mgll: monoacylglycerol lipase; MS: multiple sclerosis.