β2 肾上腺素能介导的创伤性脑损伤后血谷氨酸水平降低和神经功能改善。
β2 adrenergic-mediated reduction of blood glutamate levels and improved neurological outcome after traumatic brain injury in rats.
机构信息
Division of Anesthesiology, Soroka Medical Center and Ben Gurion University of the Negev, Beer-Sheva, Israel.
出版信息
J Neurosurg Anesthesiol. 2012 Jan;24(1):30-8. doi: 10.1097/ANA.0b013e318232deaa.
BACKGROUND
Isoflurane-anesthetized rats subjected to traumatic brain injury (TBI) show a transient reduction in blood L-glutamate levels. Having previously observed that isoproterenol produces a sustained decrease in blood glutamate levels in naive rats, we investigated the possible effects of nonselective and selective β1 and β2 adrenergic agonists and antagonists both on blood glutamate levels and on the neurological outcomes of rats subjected to TBI.
METHODS
Rats received either 10 mL/kg of isotonic saline 1 hour after TBI, 50 µg/kg of isoproterenol pretreatment 30 minutes before TBI, 10 mg/kg of propranolol pretreatment 60 minutes before TBI, 10 mg/kg of metoprolol pretreatment 60 minutes before TBI, or 10 mg/kg of butaxamine pretreatment 40 minutes before TBI and 10 minutes before pretreatment with 50 µg/kg isoproterenol or 10 mg/kg of propranolol 60 minutes after TBI. A neurological severity score (NSS) was measured at 1, 24, and 48 hours after TBI. Blood glutamate, blood glucose, mean arterial blood pressure, and heart rate were measured at the time of drug injection, at the time of TBI, 60 minutes after TBI, and 90 minutes after TBI.
RESULTS
Blood glutamate levels decreased spontaneously by 60 minutes after TBI in the control group (P<0.05), reverting to baseline levels by 90 minutes after TBI. A pretreatment with either 10 mg/kg of metoprolol 60 minutes before TBI or with 50 µg/kg of isoproterenol 30 minutes before TBI also reduced blood glutamate levels (P<0.05) both at 90 minutes after TBI and improved the NSS measured 24 and 48 hours after TBI in comparison with the control saline-treated group. However, a 10-mg/kg butoxamine pretreatment 40 minutes before TBI and 10 minutes before pretreatment with 50 µg/kg of isoproterenol or 10 mg/kg of propranolol 60 minutes before TBI neither affected blood glutamate levels across time after TBI nor caused any significant change in the NSS measured 24 and 48 hours after TBI in comparison with the control saline-treated group. A strong correlation (r(2)=0.73) was demonstrated between the percent decrease in blood glutamate levels at 90 minutes after TBI and the percent improvement of NSS measured 24 hours after TBI.
CONCLUSIONS
The results suggest that the transient blood glutamate reduction seen after TBI is the result of a stress response and of the activation of the sympathetic nervous system through the β2 adrenergic receptors, causing an increase of the brain-to-blood efflux of glutamate observed with excess brain glutamate levels after a brain insult. This strongly correlates with the neurological improvement observed 24 hours after TBI.
背景
在经历创伤性脑损伤（TBI）后，异氟烷麻醉的大鼠血液中的 L-谷氨酸水平会短暂降低。我们之前观察到，异丙肾上腺素会使未受伤的大鼠血液中的谷氨酸水平持续降低，因此我们研究了非选择性和选择性β1和β2肾上腺素能激动剂和拮抗剂对 TBI 大鼠的血液谷氨酸水平和神经功能结局的可能影响。
方法
TBI 后 1 小时，大鼠接受 10 mL/kg 的等渗盐水，TBI 前 30 分钟，大鼠接受 50 µg/kg 的异丙肾上腺素预处理，TBI 前 60 分钟，大鼠接受 10 mg/kg 的普萘洛尔预处理，TBI 前 60 分钟，大鼠接受 10 mg/kg 的美托洛尔预处理，TBI 前 40 分钟，大鼠接受 10 mg/kg 的布他沙明预处理，并在 TBI 前 10 分钟和 TBI 后 60 分钟，用 50 µg/kg 的异丙肾上腺素或 10 mg/kg 的普萘洛尔预处理。TBI 后 1、24 和 48 小时测量神经功能严重程度评分（NSS）。在药物注射时、TBI 时、TBI 后 60 分钟和 TBI 后 90 分钟测量血液谷氨酸、血糖、平均动脉压和心率。
结果
与对照组相比，TBI 后 60 分钟血液谷氨酸水平自发下降（P<0.05），并在 90 分钟后恢复至基线水平。TBI 前 60 分钟给予 10 mg/kg 美托洛尔或 TBI 前 30 分钟给予 50 µg/kg 异丙肾上腺素预处理也降低了血液谷氨酸水平（P<0.05），并改善了 TBI 后 24 和 48 小时的 NSS，与对照组生理盐水治疗组相比。然而，TBI 前 40 分钟给予 10 mg/kg 布他沙明预处理，TBI 前 10 分钟给予 50 µg/kg 异丙肾上腺素或 TBI 前 60 分钟给予 10 mg/kg 普萘洛尔预处理，均未影响 TBI 后不同时间的血液谷氨酸水平，也未导致 TBI 后 24 和 48 小时的 NSS与对照组生理盐水治疗组相比发生任何显著变化。在 TBI 后 90 分钟血液谷氨酸水平下降百分比与 TBI 后 24 小时 NSS 改善百分比之间显示出很强的相关性（r(2)=0.73）。
结论
结果表明，TBI 后短暂的血液谷氨酸降低是应激反应的结果，也是通过β2 肾上腺素能受体激活交感神经系统的结果，导致脑损伤后谷氨酸水平升高时脑内到血液的谷氨酸外排增加。这与 TBI 后 24 小时观察到的神经功能改善有很强的相关性。
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