SGLT2 inhibitors: a novel therapy for cognitive impairment via multifaceted effects on the nervous system

Abstract

The rising prevalence of diabetes mellitus has casted a spotlight on one of its significant sequelae: cognitive impairment. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed for diabetes management, are increasingly studied for their cognitive benefits. These benefits may include reduction of oxidative stress and neuroinflammation, decrease of amyloid burdens, enhancement of neuronal plasticity, and improved cerebral glucose utilization. The multifaceted effects and the relatively favorable side-effect profile of SGLT2 inhibitors render them a promising therapeutic candidate for cognitive disorders. Nonetheless, the application of SGLT2 inhibitors for cognitive impairment is not without its limitations, necessitating more comprehensive research to fully determine their therapeutic potential for cognitive treatment. In this review, we discuss the role of SGLT2 in neural function, elucidate the diabetes-cognition nexus, and synthesize current knowledge on the cognitive effects of SGLT2 inhibitors based on animal studies and clinical evidence. Research gaps are proposed to spur further investigation.

Keywords: Cognitive impairment; Diabetes; Neuron; SGLT2 inhibitor; Sodium-glucose cotransporter-2.

Fig. 1

Physiological roles of SGLT2 in the brain. SGLT2 is mainly expressed in pericytes and brain parenchyma. SGLT2 expressed in pericytes facilitates glucose transport to support their nourishment and metabolic functions, with the additional role of distributing glucose to adjacent astrocytes. SGLT2 inhibitors enhance insulin sensitivity in the brains of obese rats by mitigating inflammation, apoptosis, and oxidative stress, markedly improving hippocampal synaptic plasticity

Fig. 2

Diabetes mellitus affects the nervous system. Diabetes can affect the nervous system through three mechanisms. First, it reduces the levels of extracellular superoxide dismutase (SOD) and glutathione (GSH), which in turn promotes inflammation and oxidative stress in peripheral nerves. Second, it promotes the production of reactive oxygen species (ROS), leading to the activation of nuclear factor κ-light chain enhancer (NF-κB), activation protein-1 (AP-1), and the signal transducer and activator of transcription (STAT) pathways, resulting in increased inflammatory cytokines and then increased BBB breakdown. Third, it increases the level of dynamin-related protein 1 (Drp1) in mitochondria within neurons and stimulates the overproduction of ROS, resulting in impaired mitochondrial morphology and function, which in turn leads to neuron apoptosis

Fig. 3

Diabetes mellitus is associated with cognitive decline. Diabetes can affect cognitive decline through the following mechanisms. First, it induces neuroinflammation by activating the NF-κB pathway, enhancing proinflammatory cytokine production, and stimulating oxidative stress and inflammasome activation. Second, it accelerates vascular aging through inflammatory responses that elevate cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), resulting in neuronal loss and apoptosis. Third, it leads to neuronal glucotoxicity, which leads to an abnormal intracellular accumulation of methylglyoxal. Methylglyoxal promotes the formation of advanced glycosylation end-products (AGEs) and activates the receptor for advanced glycosylation end products (RAGE), leading to activation of ROS and thus neuronal death. Fourth, it promotes oxidative stress and facilitates the production of NF-kB and NADPH oxidase 2 (NOX2), which lead to neuronal damage and neuroinflammation. Fifth, treatment of diabetes may trigger hypoglycemia. Hypoglycemia promotes neuronal death by inducing activation of poly(ADP-ribose) polymerase 1 (PARP-1) and mitochondrial dysfunction. Sixth, insulin resistance ultimately reduces brain insulin levels and leads to neuronal insulin receptor desensitization, resulting in reduced clearance of Aβ peptides and increased hyperphosphorylation of tau protein. Last, triglyceride (TG) and cholesterol levels are increased under the condition of diabetes, which facilitate Aβ overproduction and deposition

Fig. 4

Mechanisms underlying the regulation of neuronal survival by SGLT2 inhibitors. (1) SGLT2 inhibitors suppress NLRP3 inflammasome activation in macrophages by elevating serum β-hydroxybutyrate (BHB) and reducing serum insulin, which in turn inhibit the NLRP3/IL-1/TNF-α/miR-501-3p/ZO-1 axis. Furthermore, SGLT2 inhibitors inhibit the ROS-dependent neuronal apoptosis, downregulate the PI3K/Akt/GSK-3β signaling pathway, and inhibit the NF-κB pathway and TNF-α activation. These pathways inhibit the neuroinflammation. (2) SGLT2 inhibitors target SGLT2 on the proximal renal tubules, reduce glucose reabsorption and promote urinary glucose excretion, which lead to the shift of brain metabolism from utilizing carbohydrates to fatty acid oxidation, and thus optimizes cerebral glucose metabolism. (3) SGLT2 inhibitors increase levels of neurotrophic factors like brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), contributing to synaptic plasticity together. (4) SGLT2 inhibitors activate adenosine monophosphate-activated protein kinase (AMPK) via liver kinase B1, and AMPK modulates the expression of α and β secretases, thereby reducing Aβ generation from amyloid precursor protein (APP). (5) SGLT2 inhibitors promote macrophage polarization to the M2 phenotype, and M2 macrophages promote nerve regeneration. Meanwhile, SGLT2 inhibitors significantly increase tissue BDNF and NGF levels. BDNF can promote mRNA expression that provokes intrinsic regeneration capacity of neurons and NGF can bind to pro-myosin receptor kinase A (TrkA) to activate a cascade of molecular pathways to induce neural regeneration