Neuroprotective Effects of Metformin Through the Modulation of Neuroinflammation and Oxidative Stress

Abstract

Epidemiological studies have shown that individuals with type 2 diabetes have an increased risk of developing neurodegenerative diseases. These diseases and type 2 diabetes share several risk factors. Meanwhile, the antidiabetic drug metformin offers promising neuroprotective effects by reducing oxidative stress and neuroinflammation, two significant factors in neurodegenerative diseases. This review examines the mechanisms by which metformin mitigates neuronal damage. Metformin reduces neuroinflammation by inhibiting microglial activation and suppressing proinflammatory cytokines. It also triggers the nuclear factor erythroid-2-related factor-2 (Nrf2) pathway to combat oxidative stress, an essential regulator of antioxidant defenses. These outcomes support the possible neuroprotective roles of metformin in type 2 diabetes-related cognitive decline and conditions like Alzheimer's disease. Metformin's therapeutic potential is further supported by its capacity to strengthen the blood-brain barrier's (BBB's) integrity and increase autophagic flux. Metformin also offers several neuroprotective effects by targeting multiple pathological pathways. Moreover, metformin is being studied for its potential benefits beyond glycemic control, particularly in the areas of cognition, Alzheimer's disease, aging, and stroke management. Evidence from both clinical and preclinical studies indicates a complex and multifaceted impact, with benefits varying among populations and depending on underlying disease conditions, making it an appealing candidate for managing several neurodegenerative diseases.

Keywords: metformin; neurodegeneration; neuroinflammation; oxidative stress; type 2 diabetes.

Figure 1

The effect of metformin. This diagram illustrates metformin’s well-established effects on several organs in T2DM. Metformin reduces glucose absorption in the intestines. In the liver, metformin activates AMPK, resulting in suppression of hepatic gluconeogenesis and reduced endogenous glucose production. In skeletal muscle, metformin enhances glucose uptake. β-Cell function in the pancreas is improved and preserved. These coordinated actions result in reduced glucose levels in the blood, reducing hyperglycemia [17].

Figure 4

Causes of neurodegeneration. Neuroinflammation, oxidative stress, and chronically activated microglia are well-known causes of neurodegeneration.

Figure 2

Pathophysiology of type 2 diabetes. Risk factors, like obesity and genetics, trigger a multitude of mechanisms, including adipokine dysregulation, ER stress, and mitochondrial dysfunction. Adipokines (TNF-α) can disrupt insulin signaling and trigger the Ser/Thr phosphorylation of insulin receptor substrates (IRSs). This, along with ER stress, inhibits IRS and insulin receptor (IR) interaction. These mechanisms result in increased insulin resistance, causing reduced glycogen synthesis and glucose metabolism. Dysfunctional pancreatic β-cells exhibit impaired insulin secretion and reduced proinsulin-to-insulin conversion. Reduced insulin secretion gives rise to gluconeogenesis. This deficiency in insulin production and a lack of insulin sensitivity exacerbate the imbalance between glucose and insulin, resulting in hyperglycemia, which is a major indicator of T2DM.

Figure 3

The effects of type 2 diabetes. This diagram illustrates the molecular mechanisms linking type 2 diabetes (T2DM) to neuronal microtubule damage and synaptic dysfunction. T2DM induces oxidative stress, advanced glycation end-products (AGEs), inflammation, and autophagic dysfunction. These pathways increase reactive oxygen species (ROSs), cytokines (TNFα and IFNγ), and Aβ oligomers while impairing protein clearance. The resulting stressors destabilize tau-bound microtubules, leading to the progressive breakdown of microtubules and synaptic impairment, which contribute to neurodegenerative processes.

Figure 5

Metformin’s neuroprotective effects through microglial modulation. Metformin increases AMPK activation, lowers NF-κB activation, and reduces microglial activation. Decreasing microglial activation can reduce NF-κB activation and increase AMPK activation.