The Relationship Between the Blood-Brain-Barrier and the Central Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors

Abstract

Diabetes and obesity are growing problems worldwide and are associated with a range of acute and chronic complications, including acute myocardial infarction (AMI) and stroke. Novel anti-diabetic medications designed to treat T2DM, such as glucagonlike peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is), exert beneficial effects on metabolism and the cardiovascular system. However, the underlying mechanisms are poorly understood. GLP-1RAs induce anorexic effects by inhibiting the central regulation of food intake to reduce body weight. Central/peripheral administration of GLP-1RAs inhibits food intake, accompanied by an increase in c-Fos expression in neurons within the paraventricular nucleus (PVN), amygdala, the nucleus of the solitary tract (NTS), area postrema (AP), lateral parabrachial nucleus (LPB) and arcuate nucleus (ARC), induced by the activation of GLP-1 receptors in the central nervous system (CNS). Therefore, GLP-1RAs need to pass through the blood-brain barrier to exert their pharmacological effects. In addition, studies revealed that SGLT-2is could reduce the risk of chronic heart failure in people with type 2 diabetes. SGLT-2 is extensively expressed throughout the CNS, and c-Fos expression was also observed within 2 hours of administration of SGLT-2is in mice. Recent clinical studies reported that SGLT-2is improved hypertension and atrial fibrillation by modulating the "overstimulated" renin-angiotensin-aldosterone system (RAAS) and suppressing the sympathetic nervous system (SNS) by directly/indirectly acting on the rostral ventrolateral medulla. Despite extensive research into the central mechanism of GLP-1RAs and SGLT-2is, the penetration of the blood-brain barrier (BBB) remains controversial. This review discusses the interaction between GLP-1RAs and SGLT-2is and the BBB to induce pharmacological effects via the CNS.

The Neuronal and Non-Neuronal Pathways of Sodium-Glucose Cotransporter-2 Inhibitor on Body Weight-Loss and Insulin Resistance

“… 5 According to the physical and chemical properties, SGLT-2i is lipid-soluble drugs with low molecular weight, indicating its ability to cross the blood–brain barrier. 6 This mechanism depends on the level of blood sugar and has nothing to do with the effect and availability of insulin. The increase in urine glucose caused by SGLT2I is accompanied by osmotic diuresis and a decrease in blood pressure.…”

Semaglutide as a Possible Calmodulin Binder: Ligand-Based Computational Analyses and Relevance to Its Associated Reward and Appetitive Behaviour Actions

“…In other words, one would argue if Sem can enter the cell and intracellularly exist in an active form to be able to affect CaM. Indeed, the remaining GLP-1 agonists (e.g., liraglutide and extendin-4 [29]) would be able to cross the blood-brain barrier (BBB) and to interact with GLP-r receptors in the central nervous system. Sem, a long-acting formulation derived from liraglutide's structure, presents with a longer aliphatic chain with respect to its precursor and this improves its hydrophobicity/liphophilicity levels.…”

The SGLT2 inhibitor Empagliflozin promotes post-stroke functional recovery in diabetic mice

“…However, recent literature suggests that direct effects of SGLT2i in the brain cannot be disregarded. It has been shown that SGLT2i may pass the blood-brain barrier (53)(54)(55), and several studies have demonstrated SGLT2 expression in various brain areas (29,56,57). Moreover, SGLT2 is also expressed in the human brain, and its expression is upregulated after traumatic brain injury (58).…”