A mitochondrial-derived peptide MOTS-c contributes to the protective effect against brain injury associated with LPS-induced sepsis by strengthening the blood-brain barrier's ultrastructure

Background: Sepsis-associated encephalopathy (SAE) is a serious complication of sepsis, increasing short-term and long-term mortality. It involves neuroinflammation, neuronal damage, and blood-brain barrier (BBB) disruption. MOTS-c, a mitochondrion-derived peptide, exerts neuroprotective effects by modulating inflammatory responses and cellular functions. This study explored the protective effects of MOTS-c against brain injury in mice with LPS-induced sepsis.

Methods: A mouse model of sepsis was established via intraperitoneal injection of LPS. The mice were divided into four groups: Control, Control + MOTS-c, LPS, and LPS + MOTS-c groups. The mice in the latter two groups received MOTS-c (20 mg/kg) four hours before model establishment. Survival rates and the murine sepsis score (MSS) were recorded. H&E staining, ELISA, Evans blue staining, brain water content detremination, immunofluorescence staining, western blotting, and qPCR were performed to assess brain tissue damage, inflammation, BBB permeability, and BBB-related protein expression.

Results: MOTS-c treatment increased the survival rate, decreased the MSS score, alleviated brain tissue damage, downregulated the expression of inflammatory factors, reversed the increase in BBB permeability, upregulated the expression of BBB-related proteins and CD31/PDGFRβ, decreased the expression of GFAP/Iba-1/MMP-9, and increased the expression of Neurotrophic Factors in septic mice.

Conclusion: MOTS-c effectively reduced mortality rates and the MSS, attenuated neuroinflammatory responses, mitigated increase in BBB permeability, promoted neurotrophic factor production, and protecting against brain injury in mice with LPS-induced sepsis.

MOTS-c; Sepsis-associated encephalopathy; blood-brain barrier; inflammation; neurotrophic factors; ultrastructure.