Acetaldehyde dehydrogenase 2 activation attenuates sepsis-induced brain injury through NLRP3 inflammasome regulation

Meng Ling; Chunxia Huang; Tianfeng Hua; Hui Li; Wenyan Xiao; Zongqing Lu; Di Jia; Wuming Zhou; Linlin Zhang; Min Yang

doi:10.1016/j.brainresbull.2023.01.012

Acetaldehyde dehydrogenase 2 activation attenuates sepsis-induced brain injury through NLRP3 inflammasome regulation

Brain Res Bull. 2023 Mar:194:128-138. doi: 10.1016/j.brainresbull.2023.01.012. Epub 2023 Jan 29.

Authors

Meng Ling¹, Chunxia Huang², Tianfeng Hua³, Hui Li⁴, Wenyan Xiao⁵, Zongqing Lu⁶, Di Jia⁷, Wuming Zhou⁸, Linlin Zhang⁹, Min Yang¹⁰

Affiliations

¹ The 2nd Department of Intensive Care Unit, the Second Hospital of Anhui Medical University, Hefei, Anhui Province 230601, China; Department of Intensive Care Unit, West Branch of the First Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui Province 230031, China; The Laboratory of Cardiopulmonary Resuscitation and Critical Care Medicine, the Second Hospital of Anhui Medical University, Hefei, Anhui Province 230601, China. Electronic address: 2036020183@stu.ahmu.edu.com.
² Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, Anhui Province 230601, China; Department of Anesthesiology and Perioperative Medicine, the Second Hospital of Anhui Medical University, Hefei, Anhui Province 230601, China. Electronic address: huangchunxia@ahmu.edu.cn.
³ The 2nd Department of Intensive Care Unit, the Second Hospital of Anhui Medical University, Hefei, Anhui Province 230601, China; The Laboratory of Cardiopulmonary Resuscitation and Critical Care Medicine, the Second Hospital of Anhui Medical University, Hefei, Anhui Province 230601, China. Electronic address: 402637261@qq.com.
⁴ The 2nd Department of Intensive Care Unit, the Second Hospital of Anhui Medical University, Hefei, Anhui Province 230601, China; The Laboratory of Cardiopulmonary Resuscitation and Critical Care Medicine, the Second Hospital of Anhui Medical University, Hefei, Anhui Province 230601, China. Electronic address: 563245565@qq.com.
⁵ The 2nd Department of Intensive Care Unit, the Second Hospital of Anhui Medical University, Hefei, Anhui Province 230601, China; The Laboratory of Cardiopulmonary Resuscitation and Critical Care Medicine, the Second Hospital of Anhui Medical University, Hefei, Anhui Province 230601, China. Electronic address: 516956335@qq.com.
⁶ The 2nd Department of Intensive Care Unit, the Second Hospital of Anhui Medical University, Hefei, Anhui Province 230601, China; The Laboratory of Cardiopulmonary Resuscitation and Critical Care Medicine, the Second Hospital of Anhui Medical University, Hefei, Anhui Province 230601, China. Electronic address: 1945010967@stu.ahmu.edu.cn.
⁷ The 2nd Department of Intensive Care Unit, the Second Hospital of Anhui Medical University, Hefei, Anhui Province 230601, China; The Laboratory of Cardiopulmonary Resuscitation and Critical Care Medicine, the Second Hospital of Anhui Medical University, Hefei, Anhui Province 230601, China. Electronic address: 1335855152@qq.com.
⁸ The 2nd Department of Intensive Care Unit, the Second Hospital of Anhui Medical University, Hefei, Anhui Province 230601, China; The Laboratory of Cardiopulmonary Resuscitation and Critical Care Medicine, the Second Hospital of Anhui Medical University, Hefei, Anhui Province 230601, China. Electronic address: 1401220855@qq.com.
⁹ Department of Intensive Care Unit, West Branch of the First Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui Province 230031, China. Electronic address: zhanglinlinlqy@163.com.
¹⁰ The 2nd Department of Intensive Care Unit, the Second Hospital of Anhui Medical University, Hefei, Anhui Province 230601, China; The Laboratory of Cardiopulmonary Resuscitation and Critical Care Medicine, the Second Hospital of Anhui Medical University, Hefei, Anhui Province 230601, China. Electronic address: yangmin@ahmu.edu.cn.

PMID: 36720319
DOI: 10.1016/j.brainresbull.2023.01.012

Abstract

Objective: Acetaldehyde dehydrogenase 2 (ALDH2) plays an important part in neuroprotection; however, its effect on sepsis-induced brain injury is nuclear. Our aim is to investigate the potential effect and mechanism of ALDH2 in this condition.

Methods: We established an animal model using cecal ligation and perforation (CLP). Twenty-four rats were divided into sham group (n = 6), CLP group (n = 6), CLP + Alda-1 group (n = 6) and CLP + Cyanamide (CYA) group (n = 6). Vital signs were monitored, and arterial blood gas analysis, hippocampal histological staining and ALDH2 activity analysis were conducted. Western blot analysis and enzyme-linked immunosorbent assays were also carried out. Lipopolysaccharide (LPS)-treated HT22 cells were employed as an in vitro model of sepsis-induced brain injury, with and without pretreatment with Alda-1 or CYA, to further examine the potential mechanisms. Real-time quantitative polymerase chain reaction and western blot were used to determine the levels of pyrin domain-containing 3 (NLRP3) inflammasome.

Results: We found hippocampal cell injury in the CLP group (p < 0.05), with decreased ALDH2 activity (p < 0.05) and suspected overexpression of NLRP3/caspase-1 axis (p < 0.05). In the group pretreated with Alda-1, there were increased ALDH2 activity (p < 0.05), decreased hippocampal cell damage (p < 0.05), and reduced protein levels of NLRP3, apoptosis-associated speck like protein containing a caspase recruitment domain (ASC), cleaved caspase-1 and Gasdermin D (GSDMD) (p < 0.05). The levels of interleukin 18 (IL-18) and interleukin 1β (IL-1β) were also reduced (p < 0.05). In the group pretreated with CYA, ALDH2 activity was further declined, the cell injury grade increased, and the elevated levels of pyroptosis-related proteins aggravated (p < 0.05). LPS treatment decreased the cell viability and ALDH2 activity of the HT22 cells (p < 0.05), along with increased mRNA levels of the NLRP3 inflammasome, as well as IL-1β and IL-18 (p < 0.05). Western blot further revealed elevated levels of NLRP3, ASC, cleaved caspase-1 and GSDMD (p < 0.05). In the LPS+Alda-1 group, there were increased cell viability (p < 0.05), elevated ALDH2 activity (p < 0.05), and reduced levels of NLRP3 inflammasome and pyroptosis-related proteins (p < 0.05). In the CYA+LPS group, cell viability and ALDH2 activity were further declined (p < 0.05), while levels of NLRP3 /caspase-1 axis were increased (p < 0.05).

Conclusions: The activation of ALDH2 can attenuate sepsis-induced brain injury, hypothetically through regulation of the NLRP3/caspase-1 signaling pathway. Therefore, ALDH2 could potentially be considered as a new therapeutic target for the treatment of sepsis-induced brain injury.

Keywords: Acetaldehyde dehydrogenase 2 (ALDH2); Caspase-1; Pyrin domain-containing 3 (NLRP3); Pyroptosis; Sepsis-induced brain injury.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Injuries*
Caspase 1 / metabolism
Inflammasomes / metabolism
Interleukin-18 / metabolism
Interleukin-1beta / metabolism
Lipopolysaccharides / pharmacology
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Rats
Sepsis* / complications
Sepsis* / metabolism

Substances

Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
Interleukin-18
Lipopolysaccharides
aldehyde dehydrogenase (NAD(P)+)
Caspase 1
Interleukin-1beta
Nlrp3 protein, rat