Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI, 02912, USA.
Neurotrauma and Brain Barriers Research Laboratory, Department of Emergency Medicine, Alpert Medical School of Brown University, Providence, RI, 02903, USA.
Sci Rep. 2017 Sep 8;7(1):10995. doi: 10.1038/s41598-017-11316-8.
Brain-derived neurotrophic factor (BDNF), a key player in regulating synaptic strength and learning, is dysregulated following traumatic brain injury (TBI), suggesting that stimulation of BDNF signaling pathways may facilitate functional recovery. This study investigates whether CN2097, a peptidomimetic ligand which targets the synaptic scaffold protein, postsynaptic density protein 95, to enhance downstream signaling of tropomyosin-related kinase B, a receptor for BDNF, can improve neurological function after TBI. Moderate to severe TBI elicits neuroinflammation and c-Jun-N-terminal kinase (JNK) activation, which is associated with memory deficits. Here we demonstrate that CN2097 significantly reduces the post-traumatic synthesis of proinflammatory mediators and inhibits the post-traumatic activation of JNK in a rodent model of TBI. The recordings of field excitatory post-synaptic potentials in the hippocampal CA1 subfield demonstrate that TBI inhibits the expression of long-term potentiation (LTP) evoked by high-frequency stimulation of Schaffer collaterals, and that CN2097 attenuates this LTP impairment. Lastly, we demonstrate that CN2097 significantly improves the complex auditory processing deficits, which are impaired after injury. The multifunctionality of CN2097 strongly suggests that CN2097 could be highly efficacious in targeting complex secondary injury processes resulting from neurotrauma.
脑源性神经营养因子（BDNF）是调节突触强度和学习的关键因子，在创伤性脑损伤（TBI）后发生失调，这表明刺激 BDNF 信号通路可能有助于功能恢复。本研究探讨了 CN2097（一种针对突触支架蛋白后突触密度蛋白 95 的肽模拟配体）是否可以改善 TBI 后的神经功能。中重度 TBI 会引发神经炎症和 c-Jun-N-末端激酶（JNK）的激活，这与记忆缺陷有关。在这里，我们证明 CN2097 可显著减少创伤后促炎介质的合成，并抑制 TBI 啮齿动物模型中 JNK 的创伤后激活。在海马 CA1 亚区的场兴奋性突触后电位记录中，我们发现 TBI 抑制了高频刺激 Schaffer 侧支引起的长时程增强（LTP）的表达，而 CN2097 可减轻这种 LTP 损伤。最后，我们证明 CN2097 可显著改善复杂听觉处理缺陷，这些缺陷在损伤后会受到影响。CN2097 的多功能性强烈表明，CN2097 可能在针对神经创伤引起的复杂继发性损伤过程方面非常有效。
