Melatonin Exerts Neuroprotective Effects in Escherichia coli/Lipopolysaccharide Induced Neuronal Injury via Regulating TFRC-Related Ferroptosis

Abstract

Neonatal bacterial meningitis (NBM) is a severe neonatal infectious disease associated with a high incidence of neurological sequelae. Lipopolysaccharide (LPS) and inflammatory cytokines aggravate cerebral injury, whereas the mechanism of ferroptosis in the pathogenesis of NBM remains unclear. Melatonin (MT), an endogenous neurohormone, provides anti-ferroptotic neuroprotection in models of cerebral injury; however, its mechanism of action against NBM-related injury through ferroptosis has not been clarified. This study investigated the protective effects mediated by MT in vivo and in vitro. Rat models of LPS-induced inflammatory brain injury were established through intracerebroventricular (i.c.v.) injection, and Escherichia coli (E. coli)-infected cell models were developed to investigate the neuroprotective effects of MT against TFRC-related ferroptosis. CCK-8 assays, Western blotting, transmission electron microscopy (TEM), iron detection, and immunofluorescence, BODIPY staining were used to assess cell viability, inflammatory factors, mitochondrial ultrastructure, iron accumulation, and GPX4 expression. E. coli infection induced typical ferroptotic mitochondrial damage. MT alleviated neuroinflammation and reduced the expression of ferroptosis-related proteins both in vitro and in vivo. MT treatment increased mitochondrial GPX4 expression. The ferroptosis agonist RSL3 reversed the neuroprotective effects of MT. MT inhibited TFRC-related ferroptosis and alleviated neuronal damage. MT protects against E. coli/Lipopolysaccharide induced neuronal injury by regulating TFRC-related ferroptosis, indicating that MT may be a promising therapeutic agent for NBM.