Intranasal dantrolene nanoparticles inhibit lipopolysaccharide-induced depression and anxiety behavior in mice

Abstract

This study investigates the therapeutic effectiveness of intranasal dantrolene nanoparticle pretreatment to inhibit lipopolysaccharide (LPS)-induced pathological inflammation, synapse destruction, and depressive and anxiety behavior in mice. B6SJLF1/J adult mice were pretreated with intranasal dantrolene nanoparticles (dantrolene: 5 mg/kg), daily, Monday to Friday, 5 days per week, for 4 weeks. Afterwards, mice were treated with a single intraperitoneal injection of LPS (5 mg/kg). Behavioral tests for depression and anxiety were performed 24 h after the one-time LPS injection. Biomarkers for pyroptosis-related inflammation cytokine levels (IL-1β and IL-18) in the blood and brain were measured using enzyme-linked immunosorbent assay (ELISA) and immunoblotting, respectively. Changes in primary protein (NLRP3: NLR family pyrin domain containing 3, Caspase-1, N-GSDMD: N-terminal protein gasdermin D) and synapse protein-related (PSD-95 and synaptin-1) activation of inflammatory pyroptosis in mouse brains were measured using immunoblotting. Results indicated that intranasal dantrolene nanoparticle treatment robustly inhibited LPS-induced increases in depressive and anxiety behavior, LPS-induced pathological elevation of IL-1β and IL-18 levels in the blood and brain, and LPS-induced activation of pyroptosis. Furthermore, intranasal dantrolene nanoparticles significantly inhibited decreased PSD-95 and synaptin-1 levels. Intranasal dantrolene nanoparticles have demonstrated neuroprotective effects against inflammation-mediated depression and anxiety behaviors and should be studied further as a future effective drug treatment of major depressive or anxiety disorders.