PDF(Pubmed)
Abstract：
Cerebral 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.
Chronic 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.
Sub-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.
Sub-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.
Chronic 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.
Sub-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.
Sub-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.
摘要：
背景：脑缺血缺氧导致兴奋性毒性介导的神经元损伤和认知功能障碍，尤其是老年人。细胞内[Cl-]i的过度积累削弱了γ-氨基丁酸（GABA）的补偿作用。亚麻醉剂量的丙泊酚保护大脑免受缺血缺氧，通过阻断Cl-efflux转运蛋白K+/Cl-共转运蛋白2(KCC2)来废除。我们旨在确定低剂量麻醉药联合[Cl-]i调节剂是否可以恢复代偿性GABA能系统并改善认知功能。
方法：采用双侧颈动脉结扎法建立老年大鼠慢性脑缺氧(CCH)模型。手术后30天全身给药含有或不含KCC2激动剂N-乙基马来酰亚胺（NEM）或Na/K/Cl-共转运蛋白1（NKCC1）拮抗剂布美他尼（BTN）的亚剂量麻醉药（异丙酚和七氟烷）。在有或没有药物治疗的情况下，对原代大鼠海马神经元培养物进行缺氧损伤。记忆功能,海马神经元存活，GABA能系统功能，评估脑源性神经营养因子（BDNF）的表达。
结果：亚麻醉剂量的异丙酚（1.2μgmL-1）和七氟烷[0.7MAC（最低肺泡浓度）]并没有加重大鼠缺氧性脑损伤或神经元培养中的细胞损伤。添加BTN或NEM可防止缺氧损伤，与体内认知功能改善有关，细胞内[Cl-]i积累较少，减少细胞死亡，恢复GABA能补偿，体内和体外BDNF表达增加。
结论：亚麻醉剂量的丙泊酚和七氟烷是高危患者推荐的麻醉方案。[Cl-]i稳态和GABA能的恢复可以进一步减轻缺血缺氧引起的脑损伤。
方法：采用双侧颈动脉结扎法建立老年大鼠慢性脑缺氧(CCH)模型。手术后30天全身给药含有或不含KCC2激动剂N-乙基马来酰亚胺（NEM）或Na/K/Cl-共转运蛋白1（NKCC1）拮抗剂布美他尼（BTN）的亚剂量麻醉药（异丙酚和七氟烷）。在有或没有药物治疗的情况下，对原代大鼠海马神经元培养物进行缺氧损伤。记忆功能,海马神经元存活，GABA能系统功能，评估脑源性神经营养因子（BDNF）的表达。
结果：亚麻醉剂量的异丙酚（1.2μgmL-1）和七氟烷[0.7MAC（最低肺泡浓度）]并没有加重大鼠缺氧性脑损伤或神经元培养中的细胞损伤。添加BTN或NEM可防止缺氧损伤，与体内认知功能改善有关，细胞内[Cl-]i积累较少，减少细胞死亡，恢复GABA能补偿，体内和体外BDNF表达增加。
结论：亚麻醉剂量的丙泊酚和七氟烷是高危患者推荐的麻醉方案。[Cl-]i稳态和GABA能的恢复可以进一步减轻缺血缺氧引起的脑损伤。
