Neuroprotective and brain edema-reducing efficacy of the novel cannabinoid receptor agonist BAY 38-7271
Neuroprotective and brain edema-reducing efficacy of the novel cannabinoid receptor agonist BAY 38-7271
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DOI：
10.1016/s0006-8993(03)03376-6
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发表时间：
2003-10-31
期刊：
影响因子：
2.9
通讯作者：
Horváth, E
中科院分区：
文献类型：
--
作者：
Mauler, F;Hinz, V;Horváth, E
BAY 38-7271 是一种新型高亲和力大麻素受体激动剂，在大鼠脑损伤（急性硬膜下血肿，SDH）模型中具有强大的神经保护功效。在本研究中，我们在原位和体外研究了 [S-35]GTPgammaS 结合的 CB1 受体信号转导，以评估 SDH 后受体功能的变化。此外，我们继续研究 BAY 38-7271 在大鼠 SDH 和短暂性大脑中动脉闭塞 (tMCA-O) 模型中的神经保护特性以及对 SDH 诱导的脑水肿的功效。 [S-35]GTPgammaS 结合显示，与未受伤的半球或对照相比，受伤半球脑膜上的 CB1 受体功能略有减弱。在大鼠 SDH 模型中，SDH 后立即给药 1 小时（0.1 杯/公斤时梗死体积减少 65%）或短时间（15 分钟）输注（10 杯/公斤时梗塞体积减少 53%）时，BAY 38-7271 显示出强大的神经保护功效。当损伤后延迟 5 It 进行 4 小时输注时，观察到显着的神经保护作用（1.0 mua/kg/h 时为 49%）。当 BAY 38-7271 作为 5 小时延迟 15 分钟短时输注给药时也观察到了这一点（3 杯/公斤时为 64%）。此外，BAY 38-7271 的神经保护潜力在大鼠 tMCA-O 模型中得到了证实。对大脑皮层（1 ng/kg/h 时为 91%）和纹状体（10 ng/kg/h 时为 53%）显示出显着的神经保护功效。 SDH 后 24 小时测定时，BAY 38-7271 还降低了颅内压（250 ng/kg/h 时降低 28%）和脑含水量（250 ng/kg/h 时降低 20%）。根据这些数据得出的结论是，BAY 38-7271 的神经保护功效是由大麻素受体触发的多种机制介导的。 (C) 2003 Elsevier B.V. 保留所有权利。
BAY 38-7271 is a new high-affinity cannabinoid receptor agonist with strong neuroprotective efficacy in a rat model of traumatic brain injury (acute subdural hematoma, SDH). In the present study we investigated CB1 receptor signal transduction by [S-35]GTPgammaS binding in situ and in vitro to assess changes in receptor functionality after SDH. Further, we continued to investigate the neuroprotective properties of BAY 38-7271 in the rat SDH and transient middle cerebral artery occlusion (tMCA-O) model as well as the efficacy with respect to SDH-induced brain edema. [S-35]GTPgammaS binding revealed minor attenuation of CB1 receptor functionality on brain membranes from injured hemispheres when compared to non-injured hemispheres or controls. In the rat SDH model, BAY 38-7271 displayed strong neuroprotective efficacy when administered immediately after SDH either as a 1 h (65% infarct volume reduction at 0.1 mug/kg) or short-duration (15 min) infusion (53% at 10 mug/kg). When administered as a 4 h infusion with a 5 It delay after injury, significant neuroprotection was observed (49% at 1.0 mua/kg/h). This was also observed when BAY 38-7271 was administered as a 5 h delayed 15 min short-duration infusion (64% at 3 mug/kg). In addition, the neuroprotective potential of BAY 38-7271 was demonstrated in the rat tMCA-O model. displaying pronounced neuroprotective efficacy in the cerebral cortex (91% at 1 ng/kg/h) and striatum (53% at 10 ng/kg/h). BAY 38-7271 also reduced intracranial pressure (28% at 250 ng/kg/h) and brain water content (20% at 250 ng/kg/h) when determined 24 h post-SDH. Based on these data it is concluded that the neuroprotective efficacy of BAY 38-7271 is mediated by multiple mechanisms triggered by cannabinoid receptors. (C) 2003 Elsevier B.V. All rights reserved.