Traumatic brain injury (TBI) remains the leading cause of injury-related death and disability. Brain edema, one of the most major complications of TBI, contributes to elevated intracranial pressure, and poor prognosis following TBI. Nerve growth factor (NGF) appears to be a viable strategy to treat brain edema and TBI. Unfortunately, due to its poor blood-brain barrier (BBB) permeability, the clinical application of NGF has been greatly limited. We previously demonstrated that intranasal NGF could bypass the BBB and distribute throughout the brain. Here we further studied whether intranasal NGF could attenuate TBI-induced brain edema and its putative mechanisms. TBI was produced by a modified weight-drop model. We found that intranasal administration of NGF (5μg/d) attenuated the brain edema, as assayed by hemisphere water content, at 12h, 24h and 72h after TBI induction. This attenuation was associated with a prominent decrease of the content of aquaporin-4, which plays a pivotal role in the formation of brain edema. By the use of RT-PCR and ELISA, we showed that intranasal NGF markedly inhibited the transcription and expression of pro-inflammatory cytokines including IL-1β and TNF-α. An electrophoretic mobility shift assay (EMSA) displayed a significant activation of nuclear factor-κB following TBI, which was, however, much lowered in the NGF-treated rats. Furthermore, upon intranasal NGF supplementation, mitochondria-mediated apoptosis following TBI was minimized, as indicated by upregulation of Bcl-2 and downregulation of caspase-3. Collectively, our findings suggested that intranasal NGF may be a promising strategy to treat brain edema and TBI.

译文

创伤性脑损伤 (TBI) 仍然是与伤害相关的死亡和残疾的主要原因。脑水肿是TBI的主要并发症之一,可导致颅内压升高和TBI后预后不良。神经生长因子 (NGF) 似乎是治疗脑水肿和TBI的可行策略。不幸的是,由于其血脑屏障 (BBB) 渗透性差,NGF的临床应用受到了极大的限制。我们先前证明鼻内NGF可以绕过BBB并分布在整个大脑中。在这里,我们进一步研究了鼻内NGF是否可以减轻TBI诱导的脑水肿及其推测的机制。TBI是通过改进的重量下降模型产生的。我们发现,经TBI诱导后12小时,24小时和72小时,鼻内施用NGF (5 μ g/d) 可减轻脑水肿,如半球含水量所测定。这种衰减与aquaporin-4含量的显着降低有关,这在脑水肿的形成中起着关键作用。通过rt-pcr和ELISA,我们发现鼻内NGF显着抑制促炎细胞因子 (包括IL-1β 和TNF-α) 的转录和表达。电泳迁移率变化测定 (EMSA) 显示TBI后核因子-κ b的显着激活,但是,在NGF处理的大鼠中,这一激活大大降低。此外,在鼻内补充NGF时,TBI后线粒体介导的凋亡被最小化,如Bcl-2上调和caspase-3下调所表明的。总的来说,我们的发现表明鼻内NGF可能是治疗脑水肿和TBI的有希望的策略。

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