丙泊酚对慢性间歇性低氧小鼠认知功能的影响及其机制

Effect of propofol on cognitive function in mice with chronic intermittent hypoxia and its mechanism

目的探讨丙泊酚对慢性间歇性低氧小鼠认知功能的影响及其机制。方法雄性12周C57BL/6小鼠随机分为对照组、模型组、丙泊酚低剂量组(2 mg/kg,临床用量)、丙泊酚中剂量组(10 mg/kg,5倍临床用量)及丙泊酚高剂量组(20 mg/kg,10倍临床用量),每组12只。空气舱氧气含量在21%与6%之间交替维持90 s构建慢性间歇性低氧小鼠模型(共14 d,每天8 h)。造模完成后,丙泊酚组小鼠腹腔注射对应剂量丙泊酚,对照组和模型组注射与丙泊酚组等体积脂肪乳。采用Morris水迷宫测试小鼠逃避潜伏期及穿越平台次数。行为学测试后每组取6只小鼠新鲜海马组织检测腺苷A_(2A)受体(adenosine A_(2A) receptor,A_(2A) R)、谷氨酸转运体-1(glutamate transporter-1,GLT-1)、谷氨酸-天冬氨酸转运体(glutamate-aspartate transporter,GLAST)、肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)、白细胞介素1β(interleukin-1β,IL-1β)及谷氨酸水平。另取6只小鼠海马组织行免疫荧光染色检测小胶质细胞激活标志物离子钙结合衔接分子1(ionized calcium binding adapter molecule 1,Iba1)水平。结果与对照组相比,模型组小鼠逃避潜伏期明显增加(P<0.01),穿越平台次数明显减少(P<0.01),海马A_(2A) R、TNF-α、IL-1β、Iba1及谷氨酸含量明显增加(P<0.001),GLT-1明显降低(P<0.01)。与模型组相比,丙泊酚中剂量组和高剂量组小鼠逃避潜伏期明显缩短(P<0.05),穿越平台次数明显增加(P<0.01),海马A_(2A) R、TNF-α、IL-1β、Iba1及谷氨酸含量明显减少(P<0.05),GLT-1明显增加(P<0.05)。结论丙泊酚(10,20 mg/kg)明显改善慢性间歇性低氧小鼠认知功能,可能与其抑制海马炎症反应及谷氨酸含量密切相关。

Objective To investigate the effect of propofol on cognitive function in mice with chronic intermittent hypoxia(CIH)and its mechanism.Methods Male 12-week-old C57BL/6 mice were randomly divided into five groups:control group,model group,low-dose propofol group(2 mg/kg,clinical dosage),medium-dose propofol group(10 mg/kg,5 times the clinical dosage)and high-dose propofol group(20 mg/kg,10 times the clinical dosage),with 12 mice in each group.The CIH mouse model was constructed by alternating the oxygen content of the air chamber between 21%and 6%for 90 s(14 d,8 h per day).After the modeling,the mice in propofol groups were injected intraperitoneally with the corresponding dosages of propofol,and the mice in control group and model group were injected with the same volume of fat milk as that in propofol group.Morris water maze was used to test the escape latency and the number of crossing platform.After behavioral test,six mice in each group were used to detect the levels of adenosine A_(2A) receptor(A_(2A)R),glutamate transporter-1(GLT-1),glutamate-aspartate transporter(GLAST),tumor necrosis factorα(TNF-α),interleukin-1β(IL-1β)and glutamate in hippocampus.The level of ionized calcium binding adapter molecule 1(Iba1),a marker of hippocampal microglia activation,was measured in six mice by immunofluorescence staining.Results Compared with control group,the escape latency was significantly increased in model group(P<0.01),the number of platform crossing was significantly decreased(P<0.01),the hippocampal A_(2A)R,TNF-α,IL-1β,Iba1 and glutamate contents were significantly increased(P<0.001),and GLT-1 was significantly decreased(P<0.01).Compared with model group,the escape latency significantly shortened in medium-dose group and high-dose group(P<0.05),the number of platform crossing was significantly increased(P<0.01),hippocampal A_(2A)R,TNF-α,IL-1β,Iba1 and glutamate contents were significantly decreased(P<0.05),and GLT-1 was significantly increased(P<0.05).Conclusion Propofol(10,20 mg/kg)can significantly improve the cognitive function of CIH by inhibiting hippocampal inflammatory response and glutamate concentration.