Dichloroacetate attenuates brain injury through inhibiting neuroinflammation and mitochondrial fission in a rat model of sepsis-associated encephalopathy.

Autor: Wang P; Department of Emergency Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Institute of Cardiopulmonary Cerebral Resuscitation, Sun Yat-sen University, Guangzhou 510120, China., Liang L; Department of Emergency Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Institute of Cardiopulmonary Cerebral Resuscitation, Sun Yat-sen University, Guangzhou 510120, China., Ge Q; Department of Emergency Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Institute of Cardiopulmonary Cerebral Resuscitation, Sun Yat-sen University, Guangzhou 510120, China., Liu S; Department of Emergency Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China., Yang Z; Department of Emergency Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Institute of Cardiopulmonary Cerebral Resuscitation, Sun Yat-sen University, Guangzhou 510120, China. Electronic address: yangzhengfei@vip.163.com., Jiang L; Department of Emergency Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Institute of Cardiopulmonary Cerebral Resuscitation, Sun Yat-sen University, Guangzhou 510120, China. Electronic address: jiangly@mail.sysu.edu.cn.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2024 Oct 25; Vol. 140, pp. 112840. Date of Electronic Publication: 2024 Aug 06.
DOI: 10.1016/j.intimp.2024.112840
Abstrakt: Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis, characterized by neuroinflammation, mitochondrial dysfunction, and oxidative stress, leading to cognitive decline and high mortality. The effectiveness of dichloroacetate (DCA) in modulating mitochondrial function provides a novel therapeutic strategy for SAE. In this study, we evaluated the neuroprotective effects of DCA in a rat model of SAE induced by cecal ligation and puncture (CLP). Rats treated with DCA exhibited significant improvements in neurological function and survival, as evidenced by less neuron loss from histopathologic analysis, restored neurologic deficit scores, improved Y-maze alternation percentages, and enhanced recognition index performance. Biochemical analyses showed that DCA administration at 25 mg/kg and 100 mg/kg reduced astrocyte and microglial activation, indicating reduced neuroinflammation. Furthermore, DCA simultaneously reduced the production of circulating and cerebral inflammatory cytokines (including TNF-α, IL-1β, and IL-10), concomitant with mitigating oxidative stress through down-regulating expression of 8-Hydroxy-2'-deoxyguanosine (8-OHdG) and reactive oxygen species (ROS) in the brain. Mechanistically, DCA modulated mitochondrial dynamics by suppressing Drp1 and pDrp1 expression, which are indicators of mitochondrial fission. This was corroborated by transmission electron microscopy, quantification of mitochondrial area, and Western blot analyses. Furthermore, DCA treatment improved ATP levels, mitochondrial complex I activity, and NAD + /NADH ratio, indicating a significant attenuation of brain mitochondrial dysfunction. In conclusion, our findings suggest that DCA confers neuroprotection in SAE by curtailing neuroinflammation and mitochondrial fission, outlining a promising therapeutic strategy for treating SAE in critically ill patients.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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