Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Mitigates Neuroinflammation and Cognitive Impairment by Modulating Glial Activation in Sepsis-Associated Encephalopathy

Sepsis-associated encephalopathy (SAE) is a severe neurological complication of sepsis, characterized by cognitive impairment and increased mortality. Owing to the established neuroprotective and immunomodulatory effects of Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) in a plethora of neurological disorders, our study aimed to investigate the role of MANF in SAE and evaluate its potential as a therapeutic target. Employing a cecal ligation and puncture (CLP) mouse model of sepsis, we analyzed MANF expression in the hippocampus and cortex, and evaluated the influence of intranasally administered recombinant human MANF (rhMANF) on symptoms of SAE. Our results disclosed a substantial increase in MANF protein levels within the hippocampus and cortex of septic mice, primarily found in neurons. Post-CLP surgical administration of rhMANF led to numerous favorable outcomes. Specifically, rhMANF therapy mitigated sepsis-induced behavioral deviations and cognitive impairments, as gauged by SHIRPA scores and Morris water maze tests, and enhanced survival rates in septic mice. These enhancements were concomitant with alterations in neuroinflammation and synaptic integrity. The rhMANF treatment attenuated activation of microglia and astrocytes in the hippocampus and cortex, as evidenced by diminished Iba-1 and GFAP positive cells. It also curtailed the generation of pro-inflammatory cytokines TNF-α and IL-6, and obstructed the p38 MAPK inflammatory pathway. Moreover, rhMANF sustained the expression of synaptic proteins PSD95 and SYN, and conserved neuronal integrity, as demonstrated by Nissl staining. In conclusion, our study underscores the potential of MANF as an innovative therapeutic target for SAE, emphasizing its anti-inflammatory and neuroprotective capabilities.