Gu Xiaohuan, Wei Zheng Zachory, Espinera Alyssa, Lee Jin Hwan, Ji Xiaoya, Wei Ling, Dix Thomas A, Yu Shan Ping
Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, GA 30033, USA.
Exp Neurol. 2015 May;267:135-142. doi: 10.1016/j.expneurol.2015.02.029. Epub 2015 Feb 26.
Neonatal brain trauma is linked to higher risks of mortality and neurological disability. The use of mild to moderate hypothermia has shown promising potential against brain injuries induced by stroke and traumatic brain injury (TBI) in various experimental models and in clinical trials. Conventional methods of physical cooling, however, are difficult to use in acute treatments and in induction of regulated hypothermia. In addition, general anesthesia is usually required to mitigate the negative effects of shivering during physical cooling. Our recent investigations demonstrate the potential therapeutic benefits of pharmacologically induced hypothermia (PIH) using the neurotensin receptor (NTR) agonist HPI201 (formerly known as ABS201) in stroke and TBI models of adult rodents. The present investigation explored the brain protective effects of HPI201 in a P14 rat pediatric model of TBI induced by controlled cortical impact. When administered via intraperitoneal (i.p.) injection, HPI201 induced dose-dependent reduction of body and brain temperature. A 6-h hypothermic treatment, providing an overall 2-3°C reduction of brain and body temperature, showed significant effect of attenuating the contusion volume versus TBI controls. Attenuation occurs whether hypothermia is initiated 15min or 2h after TBI. No shivering response was seen in HPI201-treated animals. HPI201 treatment also reduced TUNEL-positive and TUNEL/NeuN-colabeled cells in the contusion area and peri-injury regions. TBI-induced blood-brain barrier damage was attenuated by HPI201 treatment, evaluated using the Evans Blue assay. HPI201 significantly decreased MMP-9 levels and caspase-3 activation, both of which are pro-apototic, while it increased anti-apoptotic Bcl-2 gene expression in the peri-contusion region. In addition, HPI201 prevented the up-regulation of pro-inflammatory tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6. In sensorimotor activity assessments, rats in the HPI201 treated group exhibited improved functional recovery after TBI versus controls. These data support that PIH therapy using our NTR agonist is effective in reducing neuronal and BBB damage, attenuating inflammatory response and detrimental cellular signaling, and promoting functional recovery after TBI in the developing brain, supporting its potential for further evaluation towards clinical development.
新生儿脑损伤与更高的死亡率和神经功能残疾风险相关。在各种实验模型和临床试验中，使用轻度至中度低温疗法已显示出对中风和创伤性脑损伤（TBI）所致脑损伤具有潜在的治疗前景。然而，传统的物理降温方法难以用于急性治疗和诱导可控性低温。此外，通常需要全身麻醉来减轻物理降温过程中寒战的负面影响。我们最近的研究表明，使用神经降压素受体（NTR）激动剂HPI201（原称ABS201）进行药物诱导低温（PIH）在成年啮齿动物的中风和TBI模型中具有潜在的治疗益处。本研究探讨了HPI201在P14大鼠可控皮质撞击诱导的小儿TBI模型中的脑保护作用。通过腹腔内（i.p.）注射给药时，HPI201可诱导体温和脑温呈剂量依赖性降低。6小时的低温治疗使脑温和体温总体降低2-3°C，与TBI对照组相比，显示出显著减轻挫伤体积的效果。无论在TBI后15分钟还是2小时开始低温治疗，均出现减轻效果。在接受HPI201治疗的动物中未观察到寒战反应。HPI201治疗还减少了挫伤区域和损伤周边区域的TUNEL阳性细胞以及TUNEL/NeuN双标记细胞。使用伊文思蓝试验评估发现，HPI201治疗减轻了TBI诱导的血脑屏障损伤。HPI201显著降低了促凋亡的基质金属蛋白酶-9（MMP-9）水平和半胱天冬酶-3激活，同时增加了挫伤周边区域抗凋亡的Bcl-2基因表达。此外，HPI201可防止促炎细胞因子肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6的上调。在感觉运动活动评估中，与对照组相比，接受HPI201治疗的大鼠在TBI后功能恢复情况有所改善。这些数据支持使用我们的NTR激动剂进行PIH治疗可有效减少神经元和血脑屏障损伤，减轻炎症反应和有害的细胞信号传导，并促进发育中大脑TBI后的功能恢复，支持其进一步评估用于临床开发的潜力。
