GABA receptor agonists(Massachusetts General Hospital Clinical Research Program)

Etomidate and its structural analogs—metomidate, propoxate, and isopropoxate—have emerged as prevalent substances of abuse in China due to their high addictive potential. This study developed and validated a sensitive, reliable, and high‐throughput method using HPLC–MS/MS for simultaneous quantification of four imidazoline‐derived new psychoactive substances and the metabolite etomidate acid and then applied it for the molecular pharmacokinetics of five analytes in murine blood. Method validation demonstrated excellent linearity (r2 ≥ 0.999) across calibration curves, with LLOQ ranging from 0.2 to 1 ng/mL and LOD ranging from 0.1 to 0.5 ng/mL. Intraday/interday precision reached 0.123%–11.2%, and accuracy was in the range of −9.68% to 9.86%, which met bioanalytical criteria. Recovery rates (89.3%–103%) and matrix effects (87.1%–105%) were within acceptable ranges. Male KM mice with a body weight of 25 ± 2 g were selected for pharmacokinetic evaluation. Pharmacokinetic analysis revealed significant dose‐dependent relationships for maximum plasma concentration (Cmax), area under the concentration–time curve (AUC0–∞), and detection window (Twindow). Metabolic rates followed a descending order: propoxate > isopropoxate > etomidate > metomidate, likely attributed to their lipophilicity gradient. This study systematically elucidates the dose‐metabolism kinetics and structure–activity relationships of etomidate analogs, addressing the knowledge gap in toxicokinetic data for propoxate and isopropoxate.

The activation of glycogen synthase kinase 3β (GSK‐3β) and the deterioration of spatial memory represent prominent pathological and clinical manifestations of Alzheimer's disease (AD). Nevertheless, the precise intrinsic mechanisms linking these pathological features remain poorly elucidated. In this study, we identified significant upregulation of GSK‐3β activity in inhibitory interneurons within the hippocampal dentate gyrus (DG) of 3×Tg‐AD mice. Subsequent investigations demonstrated that targeted overexpression of GSK‐3β in these interneurons triggered aberrant activation of neural stem cells (NSCs), culminating in apoptotic cell death and consequent deficits in adult hippocampal neurogenesis (AHN). Utilizing in vivo fiber‐optic recording techniques, we further established that GSK‐3β overexpression in DG inhibitory interneurons elicited hyperactivation of excitatory neurons, thereby disrupting the excitation–inhibition (E/I) balance within the DG circuitry. Notably, these pathological alterations were ameliorated through chemogenetic suppression of excitatory neuronal activity. Mechanistically, we determined that impaired GABAergic transmission, characterized by reduced GABA release in the DG region, underlies these observed effects. Pharmacological intervention with GABA receptor agonists effectively rescued AHN impairment and attenuated spatial cognitive deficits. Collectively, these findings demonstrate that GSK‐3β overexpression in GABAergic interneurons compromises AHN and promotes NSC apoptosis via disruption of GABAergic signaling, while pharmacological potentiation of GABAergic transmission exerts neuroprotective effects. This study elucidates a previously unrecognized mechanism contributing to AHN impairment in AD and identifies a promising therapeutic target for pro‐neurogenic strategies.