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MANF Alleviates Sevoflurane-Induced Cognitive Impairment in Neonatal Mice by Modulating Microglial Activation and
Jie Gao1,2, Huiping Zhang1,3,4, Leiying Zhou1,2
1Department of Anesthesiology, the First Affiliated Hospital of Anhui Medical University, NO.218 Jixi Road, Hefei, 230000, China.
Abstract:
The precise mechanism underlying sevoflurane-induced neurotoxicity and cognitive impairment remains largely unknown. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neuroprotective factor that has shown promise in various neurological disorders. However, its impact on sevoflurane-induced alterations has not been investigated. Thus, the objective of this study was to examine the effect of MANF in mitigating sevoflurane-induced neurotoxicity in young mice. Anesthesia with 3% sevoflurane 2 h daily was administered to young mice on postnatal day (P) 3, 6 and 9. We also constructed mono-macrophage-specific MANF knockout (MKO) mice in the mechanistic studies. Finally, the recombinant human MANF (rhMANF, 20 μg) protein was intraperitoneally administrated to neonatal mice before the sevoflurane anesthesia and the cognitive function, levels of pro-inflammatory cytokine and synapse-associated protein PSD95, the status of neural apoptosis, microglia activation and oxidative stress in hippocampus of the mice were investigated. The sevoflurane anesthesia increased the expression of endogenous MANF in the hippocampus, especially in microglia. MKO upregulated the expression of tumor necrosis factor-α (TNF-α), accelerated the neural apoptosis and the activation of microglia in hippocampus in young mice. MANF reversed the sevoflurane-induced cognitive impairment and inhibited the upregulation of TNF-α, the neural apoptosis and the reduction of the postsynaptic density protein-95 (PSD95) induced by sevoflurane anesthesia. Also, pretreatment with MANF alleviated the sevoflurane-induced activation of microglia and oxidative stress. Our current results demonstrated that MANF ameliorated neurotoxicity induced by the sevoflurane anesthesia in young mice, and such protective effect was associated with inhibition of microglia activation and neuroinflammation.
Insights
Mesencephalic astrocyte-derived neurotrophic factor (MANF) protects young mice from sevoflurane-induced neurotoxicity. MANF treatment reversed cognitive impairment and reduced neuroinflammation by inhibiting microglia activation.
Area of Science:
- Neuroscience
- Anesthesiology
- Molecular Biology
Background:
- Sevoflurane anesthesia can cause neurotoxicity and cognitive impairment, particularly in young individuals.
- The precise mechanisms underlying these effects are not fully understood.
- Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a known neuroprotective agent with potential therapeutic applications.
Purpose of the Study:
- To investigate the neuroprotective effects of MANF against sevoflurane-induced neurotoxicity in young mice.
- To elucidate the role of MANF in mitigating sevoflurane-induced cognitive deficits and hippocampal damage.
Main Methods:
- Young mice were exposed to sevoflurane anesthesia on specific postnatal days.
- Mono-macrophage-specific MANF knockout (MKO) mice were generated to study MANF's role.
- Recombinant human MANF (rhMANF) was administered to mice before sevoflurane exposure.
- Cognitive function, pro-inflammatory cytokines (TNF-α), PSD95, neural apoptosis, microglia activation, and oxidative stress were assessed in the hippocampus.
Main Results:
- Sevoflurane anesthesia increased endogenous MANF expression in the hippocampus, particularly in microglia.
- MANF administration reversed sevoflurane-induced cognitive impairment.
- MANF inhibited sevoflurane-induced TNF-α upregulation, neural apoptosis, and PSD95 reduction.
- MANF pretreatment alleviated sevoflurane-induced microglia activation and oxidative stress.
Conclusions:
- MANF demonstrates significant neuroprotective effects against sevoflurane-induced neurotoxicity in young mice.
- The protective mechanisms involve the inhibition of microglia activation and neuroinflammation.
- MANF holds promise as a therapeutic agent to mitigate anesthetic-induced brain injury.
