Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Physiology and Pharmacology, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
Student Research Committee, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
Life Sci. 2020 Sep 1;256:117450. doi: 10.1016/j.lfs.2020.117450. Epub 2020 Feb 20.
Late treatment with tissue plasminogen activator (tPA) leads to reperfusion injury and poor outcome in ischemic stroke. We have recently shown the beneficial effects of local brain hypothermia after late thrombolysis. Herein, we investigated whether transient whole-body hypothermia was neuroprotective and could prevent the side effects of late tPA therapy at 5.5 h after embolic stroke. After induction of stroke, male rats were randomly assigned into four groups: Control, Hypothermia, tPA and Hypothermia+tPA. Hypothermia started at 5 h after embolic stroke and continued for 1 h. Thirty min after hypothermia, tPA was administrated. Infarct volume, brain edema, blood-brain barrier (BBB) and matrix metalloproteinase-9 (MMP-9) were assessed 48 h and neurological functions were assessed 24 and 48 hour post-stroke. Compared with the control or tPA groups, whole-body hypothermia decreased infarct volume (P < 0.01), BBB disruption (P < 0.05) and MMP-9 level (P < 0.05). However, compared with hypothermia alone a combination of hypothermia and tPA was more effective in reducing infarct volume. While hypothermia alone did not show any effect, its combination with tPA reduced brain edema (P < 0.05). Hypothermia alone or when combined with tPA decreased MMP-9 compared with control or tPA groups (P < 0.01). Although delayed tPA therapy exacerbated BBB integrity, general cooling hampered its leakage after late thrombolysis (P < 0.05). Moreover, only combination therapy significantly improved sensorimotor function as well as forelimb muscle strength at 24 or 48 h after stroke (P < 0.01). Transient whole-body hypothermia in combination with delayed thrombolysis therapy shows more neuroprotection and extends therapeutic time window of tPA up to 5.5 h.
晚期使用组织型纤溶酶原激活物（tPA）治疗会导致缺血性中风再灌注损伤和预后不良。我们最近已经证明了晚期溶栓后局部脑低温的有益作用。在此，我们研究了短暂的全身低温是否具有神经保护作用，并可以防止在栓塞性中风后 5.5 小时进行 tPA 治疗的副作用。诱导中风后，雄性大鼠被随机分为四组：对照组、低温组、tPA 组和低温+tPA 组。低温从栓塞性中风后 5 小时开始，并持续 1 小时。低温 30 分钟后给予 tPA。在中风后 48 小时评估梗塞体积、脑水肿、血脑屏障（BBB）和基质金属蛋白酶-9（MMP-9），并在中风后 24 小时和 48 小时评估神经功能。与对照组或 tPA 组相比，全身低温降低了梗塞体积（P < 0.01）、BBB 破坏（P < 0.05）和 MMP-9 水平（P < 0.05）。然而，与单独低温相比，低温联合 tPA 更有效地降低梗塞体积。虽然单独低温没有效果，但它与 tPA 联合使用可减少脑水肿（P < 0.05）。单独低温或与 tPA 联合使用可降低 MMP-9，与对照组或 tPA 组相比（P < 0.01）。虽然延迟 tPA 治疗加重了 BBB 完整性，但全身冷却阻碍了其在晚期溶栓后的渗漏（P < 0.05）。此外，只有联合治疗在中风后 24 小时或 48 小时才能显著改善感觉运动功能和前肢肌肉力量（P < 0.01）。短暂的全身低温联合延迟溶栓治疗显示出更强的神经保护作用，并将 tPA 的治疗时间窗延长至 5.5 小时。
