Neuroprotective Effect of SGLT2 Inhibitors

Abstract

Patients with diabetes are at higher risk of cardiovascular diseases and cognitive impairment. SGLT2 inhibitors (Empagliflozin, Canagliflozin, Dapagliflozin, Ertugliflozin, Sotagliflozin) are newer hypoglycemic agents with many pleiotropic effects. In this review, we discuss their neuroprotective potential. SGLT2 inhibitors (SGLT2i) are lipid-soluble and reach the brain/serum ratio from 0.3 to 0.5. SGLT receptors are present in the central nervous system (CNS). Flozins are not fully SGLT2-selective and have an affinity for the SGLT1 receptor, which is associated with protection against ischemia/reperfusion brain damage. SGLT2i show an anti-inflammatory and anti-atherosclerotic effect, including reduction of proinflammatory cytokines, M2 macrophage polarization, JAK2/STAT1 and NLRP3 inflammasome inhibition, as well as cIMT regression. They also mitigate oxidative stress. SGLT2i improve endothelial function, prevent remodeling and exert a protective effect on the neurovascular unit, blood-brain barrier, pericytes, astrocytes, microglia, and oligodendrocytes. Flozins are also able to inhibit AChE, which contributes to cognitive improvement. Empagliflozin significantly increases the level of cerebral BDNF, which modulates neurotransmission and ensures growth, survival, and plasticity of neurons. Moreover, they may be able to restore the circadian rhythm of mTOR activation, which is quite a novel finding in the field of research on metabolic diseases and cognitive impairment. SGLT2i have a great potential to protect against atherosclerosis and cognitive impairment in patients with type 2 diabetes mellitus.

Keywords: SGLT2i; atheroprotection; cognitive impairment; inflammation; mTOR; neuroprotection; oxidative stress; sodium-glucose cotransporter 2 inhibitors; type 2 diabetes mellitus.

Figure 1

Distribution of SGLT1 and SGLT2 receptors in the Central Nervous System: 1. Pyramidal cells of brain cortex; 2. Purkinje cerebellum cells; 3. Hippocampus pyramidal and granular cells; 4. Hypothalamus; 5. Microvessels; 6. Amygdala; 7. Periaqueductal grey; 8. Dorsomedial medulla—nucleus of the solitary tract (NTS).

Figure 2

Influence of SGLT2 inhibitors on inflammation, atherosclerosis, and neuroinflammation. IL-1RA—Interleukin 1 Receptor Agonist, cIMT—carotid intima-media thickness, STAT1—Signal transducer and activator of transcription 1, VCAM—Vascular Cell Adhesion Molecule; ICAM-Intracellular Adhesion Molecule.

Figure 3

Influence of SGLT2 inhibitors on unrestrained activation of mTOR (mechanistic/mammalian target of rapamycin). AMPK-AMP-activated protein kinase, SIRT-Sirtuin.

Figure 4

SGLT1 inhibition and ischemic brain damage. 1. Brain damage; 2. In the area of brain damage, there is an increase in the expression of SGLT1; 3. Sodium influx through SGLT1 receptors is associated with increased ischemia/reperfusion damage, lesion size, edema, inflammation, neuronal cell death, and decline in cognitive functions; 4. SGLT receptor blockage/knockdown was associated with improvement in damages caused by ischemia and ischemia/reperfusion damage.