No abstract

BackgroundCerebral 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.

Background: Perioperative cerebral hypoperfusion often occurs. However, the underlying mechanism and targeted interventions remain mostly to be determined. Anesthetic isoflurane induces neuronal injury via endoplasmic reticulum (ER) stress, whereas sub-anesthetic dose of propofol improves postoperative cognitive function. However, the effects of the combination of isoflurane plus propofol, which is a common combination of anesthesia for patient, on ER stress and the associated cognitive function remain unknown. Methods: We therefore set out to determine the effects of isoflurane plus propofol on the ER stress and cognitive function in the rats insulted by cerebral hypoperfusion. The rats received isoflurane alone (1.9%), propofol alone (40 mg·kg -1 ·h -1 ) or a combination of isoflurane and propofol (1% and 20 mg·kg -1 ·h -1 or 1.4% and 10 mg·kg -1 ·h -1 ). Behavior studies (Fear Conditioning test) and biochemical analyses (Nissl staining and western blotting for the harvested rat brain tissues) were employed in the studies. Results: We found that the combination of 1% isoflurane plus 20 mg·kg -1 ·h -1 propofol attenuated the cerebral hypoperfusion-induced cognitive impairment and the ER stress. Conclusions: These data suggest that ER stress contributes to the underlying mechanism of cognitive impairment and the combination of isoflurane and propofol was able to preserve cognitive function in the rats after cerebral hypoperfusion via prevention of ER stress. These findings have established a system to study the strategy in preventing and treating perioperative cerebral hypoperfusion, leading to promotion of the future larger scale studies.