Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 min after reperfusion
Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 min after reperfusion
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DOI：
10.1152/ajpregu.00329.2013
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发表时间：
2014-01-01
影响因子：
2.8
通讯作者：
Marrelli, Sean P.
中科院分区：
文献类型：
--
作者：
Cao, Zhijuan;Balasubramanian, Adithya;Marrelli, Sean P.
传统的治疗性低温方法对脑缺血再灌注（I/R）的神经保护作用有希望，但存在局限性。我们通过瞬时受体电位香草酸1（TRPV 1）通道激动来检测药物低温（PH）治疗局灶性脑I/R的有效性和特异性。在清醒的C57 BL/6 WT和TRPV 1敲除（KO）小鼠中皮下输注TRPV 1激动剂二氢辣椒素（DHC）后测量核心温度（T核心）。在DHC治疗前后测量心率（HR）、平均动脉压（MAP）和脑灌注。采用大脑中动脉远端闭塞法制备局灶性脑缺血再灌注模型（1h缺血+ 24 h再灌注）。在再灌注开始后90分钟通过DHC输注（渗透泵）开始低温（>8小时）。在24 h时测量神经功能（行为测试）和梗死体积（TTC染色）。DHC（1.25 mg/kg）在未处理和I/R小鼠模型中产生T核心（33 ℃）的稳定下降，但在TRPV 1 KO小鼠中没有。DHC（1.25 mg/kg）对HR和脑灌注没有可测量的影响，但引起MAP轻微短暂下降（< 6 mmHg）。在中风小鼠中，DHC输注产生低温，使梗死体积减少87%，并改善神经功能评分。DHC的低温和神经保护作用在TRPV 1 KO小鼠或维持正常体温的热支持小鼠中不存在。通过TRPV 1激动剂的PH似乎是一种耐受性良好且有效的促进清醒小鼠轻度低温的方法。此外，TRPV 1激动剂在I/R小鼠中产生有效的低温，并且在再灌注开始后90分钟开始时显著改善结果。
Traditional methods of therapeutic hypothermia show promise for neuroprotection against cerebral ischemia-reperfusion (I/R), however, with limitations. We examined effectiveness and specificity of pharmacological hypothermia (PH) by transient receptor potential vanilloid 1 (TRPV1) channel agonism in the treatment of focal cerebral I/R. Core temperature (T-core) was measured after subcutaneous infusion of TRPV1 agonist dihydrocapsaicin (DHC) in conscious C57BL/6 WT and TRPV1 knockout (KO) mice. Acute measurements of heart rate (HR), mean arterial pressure (MAP), and cerebral perfusion were measured before and after DHC treatment. Focal cerebral I/R (1 h ischemia + 24 h reperfusion) was induced by distal middle cerebral artery occlusion. Hypothermia (>8 h) was initiated 90 min after start of reperfusion by DHC infusion (osmotic pump). Neurofunction (behavioral testing) and infarct volume (TTC staining) were measured at 24 h. DHC (1.25 mg/kg) produced a stable drop in T-core (33 degrees C) in naive and I/R mouse models but not in TRPV1 KO mice. DHC (1.25 mg/kg) had no measurable effect on HR and cerebral perfusion but produced a slight transient drop in MAP (< 6 mmHg). In stroke mice, DHC infusion produced hypothermia, decreased infarct volume by 87%, and improved neurofunctional score. The hypothermic and neuroprotective effects of DHC were absent in TRPV1 KO mice or mice maintained normothermic with heat support. PH via TRPV1 agonist appears to be a well-tolerated and effective method for promoting mild hypothermia in the conscious mouse. Furthermore, TRPV1 agonism produces effective hypothermia in I/R mice and significantly improves outcome when initiated 90 min after start of reperfusion.