Design of Dual-Targeting GABA_ARs and 5-HT_2AR molecules to combat Neuroinflammation in depressive disorders

Depression is a global mental health challenge closely related to neuroinflammation. Currently, there are no drugs that simultaneously target mood deficits and neuroinflammation. The aim of this study is to develop a novel dual-target therapeutic strategy that synergistically combats depression related neuroinflammation and dysregulation of emotional circuits by simultaneously enhancing GABAergic neurotransmission and regulating 5-HT_2A receptor. Thus, a series of molecules was designed to interact with the γ-aminobutyric acid type A receptors (GABA_ARs) and the 5-hydroxytryptamine 2 A receptor (5-HT_2AR). Among them, the results revealed that 4 f can inhibit neuroinflammation by activating GABA-A receptors on microglia, while simultaneously exerting antidepressant effects by antagonizing 5-HT_2AR. In vitro, 4 f reduced oxidative stress markers (NO, ROS) and suppressed pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) as well as inflammatory enzymes (iNOS and COX-2), thereby protecting hippocampal neurons from inflammation-mediated damage. In vivo, 4 f alleviated depression-like behaviors in both lipopolysaccharide (LPS) and Chronic Restraint Stress (CRS) challenged mice. Toxicological assessments indicated no obvious adverse effects at therapeutic doses. Taken together, 4 f may serve as a promising candidate for further development as a therapeutic agent for depression associated with neuroinflammation etiology.