Sub‐dose anesthetics combined with chloride regulators protect the brain against chronic ischemia–hypoxia injury

Author:

Yang Chenyi12345ORCID,Wang Ye3ORCID,Li Yun3,Wang Xinyi23456,Hua Wei23456,Yang Zhuo1,Wang Haiyun12345ORCID

Affiliation:

1. Nankai University Tianjin China

2. Nankai University Affinity the Third Central Hospital Tianjin China

3. The Third Central Clinical College of Tianjin Medical University Tianjin China

4. Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases Tianjin China

5. Artificial Cell Engineering Technology Research Center Tianjin China

6. Tianjin Institute of Hepatobiliary Disease Tianjin China

Abstract

AbstractBackgroundCerebral ischemia–hypoxia leads to excitotoxicity‐mediated neuronal damage and cognitive dysfunction, especially in the elderly. Excessive intracellular [Cl]i accumulation weakens γ‐aminobutyric acid (GABA) compensatory effects. Sub‐anesthetic dose of propofol protected the brain against ischemia–hypoxia, which was abolished by blocking Cl efflux transporter K+/Cl cotransporter 2 (KCC2). We aimed to determine whether low‐dose anesthetic combined with [Cl]i regulators could restore the compensatory GABAergic system and improve cognitive function.MethodsChronic cerebral hypoxia (CCH) model was established by bilateral carotid artery ligation in aged rats. Sub‐dose of anesthetics (propofol and sevoflurane) with or without KCC2 agonist N‐ethylmaleimide (NEM) or Na+/K+/Cl cotransporter 1 (NKCC1) antagonist bumetanide (BTN) was administered systemically 30 days post‐surgery. Primary rat hippocampal neuronal cultures were subjected to hypoxic injury with or without drug treatment. Memory function, hippocampal neuronal survival, GABAergic system functioning, and brain‐derived neurotrophic factor (BDNF) expressions were evaluated.ResultsSub‐anesthetic dose of combined propofol (1.2 μg mL−1) and sevoflurane [0.7 MAC (minimum alveolar concentration)] did not aggravate the hypoxic brain injury in rats or cell damage in neuronal cultures. Adding either BTN or NEM protected against hypoxic injury, associated with improved cognitive function in vivo, less intracellular accumulation of [Cl]i, reduced cell death, restored GABAergic compensation, and increased BDNF expression both in vivo and in vitro.ConclusionSub‐anesthetic dose of propofol and sevoflurane is a recommended anesthesia regimen in at‐risk patients. Restoration of [Cl]i homeostasis and GABAergic could further reduce the brain damage caused by ischemia–hypoxia.

Funder

National Natural Science Foundation of China

Natural Science Foundation of Tianjin City

Publisher

Wiley

Subject

Pharmacology (medical),Physiology (medical),Psychiatry and Mental health,Pharmacology

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