Current Drug Targets - Volume 26, Issue 14, 2025

Amylin is a thirty-seven amino acid peptide hormone that is secreted from the pancreas with insulin. The peptide hormone amylin activates its receptors in the brain to regulate blood glucose and food appetite. Interestingly, the amylin receptor is the heterodimer of the calcitonin receptor (which is the receptor for the peptide hormone calcitonin) and an accessory protein called receptor activity-modifying protein. Amylin receptor activation has emerged as a promising drug target for the treatment of diabetes and obesity. Recent pharmaceutical efforts with amylin receptor activators have focused on developing drugs for the treatment of obesity. Multiple amylin analogs have been tested in pre-clinical settings, and some are currently being tested in clinical trials. For this review, recent research publications and available information regarding drug development targeting amylin receptors were collected. This review summarizes the amylin receptor activators currently being tested in clinical trials for the treatment of obesity. In addition, recent research achievements were demonstrated, such as the introduction of mutations that enhanced receptor affinity/potency and the development of a method for measuring selective amylin receptor activation. Potential issues along with peptide drug development were described, including lipidation to achieve a long-acting property. The combination of an amylin analog and other anti-obesity peptide drugs has demonstrated higher clinical efficacy in reducing body weight than monotherapy. The combination therapy is likely to be the first drug therapy where an amylin analog is used for obesity treatment. In addition, amylin receptor activators may have an adverse effect profile more favorable than that of GLP-1 receptor activators, which could be a potential benefit of amylin receptor activators.

Sepsis is a lethal clinical condition representing severe inflammation and immune suppression to pathogen or infection, leading to tissue damage or organ dysfunction. Hyper-inflammation and immune suppression cause a fatal, escalated Blood-Brain Barrier permeability, being a secondary response towards infection resulting in sepsis-associated brain dysfunction. These changes in the BBB lead to the brain’s susceptibility to increased morbidity and mortality. An important mechanism of sepsis-associated brain dysfunction includes excessive activation of microglial cells, altered brain endothelial barrier function, and BBB dysfunction. Lipopoly- saccharide, a bacterial cell wall component (endotoxin), by forming a complex through membrane-bound CD receptors on macrophages, monocytes, and neutrophils, begins synthesizing anti-inflammatory agents for defense of the host, including nitric oxide, cytokines, chemokines, interleukins, and the complement system. Unrestrained endotoxemia and pro-inflammatory cytokines result in microglial as well as brain endothelial cell stimulation, downregulation of tight junctions, along with intense recruitment of leucocytes. Subsequent neuroinflammation, together with BBB dysfunction, aggravates brain pathology as well as worsens sepsis-associated brain dysfunction. The clinical demonstration includes mild (confusion and delirium) along with severe (cognitive impairment, coma, as well as sequel death). Different clinical neurophysiological evaluation parameters can be used for the quantification and important issues of the disorder, including SOFA, imaging methods, and the use of biomarkers associated with brain dysfunction. The present review addresses the mechanism, clinical examination, the long-term cognitive effects, and current treatment modalities for sepsis-associated brain dysfunction.

Depression is a debilitating psychiatric disorder characterized by loss of interest, anhedonia, and social isolation, which is projected to become the leading cause of disability worldwide by 2030. Despite the greater economic and social burden imposed by depression, the precise pathophysiology underlying the development of depression remains elusive. Betaine (N, N, N-trimethylglycine), an amino acid derivative, is widely distributed in various animals and plants and has been shown to have numerous beneficial effects, including antioxidant activities, anti-inflammatory functions, regulation of energy metabolism, and reduction of endoplasmic reticulum stress. It has been used to treat Alcohol-Associated Liver Disease (AALD), type 2 diabetes, cancer, obesity, and Alzheimer's Disease (AD). Interestingly, accumulating evidence has shown that betaine exerts a significant role in alleviating depressive-like behavior in patients and animals resulting from chronic stress. Although the antidepressant effects of betaine have not been compared with traditional antidepressants with insufficient verification, based on the neurobiological mechanisms of depression, it may be a potential alternative medicine for the treatment of depression. This is the first review aiming to provide a comprehensive overview of the remarkable effects of betaine in the pathophysiology of depression. These pieces of evidence are of great importance for deepening our understanding of the antidepressant mechanism of betaine, so as to develop betaine supplements for the supplementary treatment of depression.