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Brain, Behavior, and Immunity

Brain, Behavior, and Immunity

IF: 8.8
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Vitamin D can mitigate Sepsis-associated neurodegeneration by inhibiting exogenous Histone-Induced pyroptosis and Ferroptosis: Implications for brain protection and cognitive Preservation

Published:19 November 2024 DOI: 10.1016/j.bbi.2024.11.019 PMID: 39566666
Yibing Sun, Zhuonan Pu, Ruquan Han

Abstract

Background

Sepsis-induced neurodegeneration and cognitive dysfunction remain critical challenges worldwide. Vitamin D was reported to reduce neuronal injury and neurotoxicity and its deficiency was associated with neurocognitive disorders. This study investigates the mechanisms by which vitamin D exerts neuroprotective potential against damage-associated molecular patterns (DAMPs), specifically extracellular histones, in sepsis-related brain dysfunction.

Methods

The cultured mouse hippocampal neuronal HT22 cells were exposed to 20?μg/ml exogenous histone for 24?h to induce pyroptosis and ferroptosis in the presence or absence of the active form of vitamin D, calcitriol (1?nM). A cecal ligation and puncture mouse sepsis model was used to evaluate histone release and pyroptosis/ferroptosis biomarkers in the brain together with neurobehavioral performance with or without calcitriol treatment (1?μg/kg, i.p. injection) at 24?h or 1?week after sepsis onset.

Results

In vitro, histone exposure triggered both pyroptosis and ferroptosis in neuronal cells, which was significantly suppressed by calcitriol treatment with the reduced expression of caspase-1 by 38?%, GSDMD by 30?%, ACSL4 by 33?%, and the increased expression of GPX4 by 35?% (n?=?6, P?<?0.05). Similarly, in vivo, calcitriol treatment inhibited both neuronal pyroptosis and ferroptosis by reducing expression of pyroptosis marker, GSDMD/NeuN (11.6?±?1.2?% vs. 19.4?±?1.1?%) and increasing expression of ferroptosis marker, GPX4/NeuN (21.4?±?1.7?% vs. 13.5?±?1.1?%), in the brain of septic mice (n?=?6, P?<?0.01). In addition, calcitriol increased survival rate (72?% vs. 41?%) and ameliorated cognitive dysfunction of septic mice (n?=?8–13, P < 0.05).

Conclusions

This study demonstrates that vitamin D exerts a neuroprotective effect against sepsis by attenuating histone-induced pyroptosis and ferroptosis. These findings highlight the potential therapeutic role of vitamin D supplementation in mitigating brain dysfunction associated with sepsis which needs for further investigation.

Substances (1)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Calcitriol 32222-06-3 C27H44O3 629 suppliers $64.00-$6980.00

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