Tat-NR2B9c is designed to prevent nitric oxide (NO) production by preventing postsynaptic density protein 95 (PSD-95) binding to N-methyl-D-aspartate (NMDA) receptors and neuronal nitric oxide synthase. Tat-NR2B9c dissociates NMDA glutamate receptors from downstream excitotoxic signaling pathways without affecting normal glutamate receptor function. Neuroprotective effects of Tat-NR2B9c have been demonstrated in a diverse range of stroke models in several species including rodents, primates, and humans. Moreover, Tat-NR2B9c peptide has shown clinical efficacy as a neuroprotective agent in acute stroke.[1][2]
In vitro study indicated that Tat-NR2B9c have no measurable effect on the rate or magnitude of NMDA-induced calcium influx. However, Tat-NR2B9c prevented NMDA-induced DNA breaks, and the neuronal death could be significantly reduced by Tat-NR2B9c. Tat-NR2B9c also prevented NMDA-induced superoxide p47phox formation by blocking phosphorylation, and neuroprotective effect of Tat-NR2B9c may be partly or wholly attributable to its suppression of NOX2 activation. In addition, Tat-NR2B9c, which targets the PDZ domain of PSD-95, disrupts the functional coupling between NR2B and NOX2.[2]
In vivo experiments demonstrated that Tat-NR2B9c would be effective in treating or preventing perinatal and neonatal hypoxic-ischemic brain injury, as well as its related brain disorders. Results indicated that Tat-NR2B9c reduced brain damage caused by hypoxic-ischemic injury when administered either before or after ischemia and improved post-HI neurobehavioral outcomes when delivered before or after ischemia. Moreover, Tat-NR2B9c might exert neuroprotective effects through the promotion of pro-survival signaling and inhibition of pro-apoptotic signaling.[1]
References:
[1]. Xu B, et al. Neuroprotective Effects of a PSD-95 Inhibitor in Neonatal Hypoxic-Ischemic Brain Injury. Mol Neurobiol. 2016 Nov;53(9):5962-5970.
[2]. Chen Y, et al. Tat-NR2B9c prevents excitotoxic neuronal superoxide production. J Cereb Blood Flow Metab. 2015 May;35(5):739-42.
Tat-NR2B9c 旨在通过阻止突触后密度蛋白 95 (PSD-95) 与 N-甲基-D-天冬氨酸 (NMDA) 受体和神经元一氧化氮结合来阻止一氧化氮 (NO) 的产生氧化物合成酶。 Tat-NR2B9c 将 NMDA 谷氨酸受体与下游兴奋性毒性信号通路解离，而不影响正常的谷氨酸受体功能。 Tat-NR2B9c 的神经保护作用已在多个物种（包括啮齿动物、灵长类动物和人类）的各种中风模型中得到证实。此外，Tat-NR2B9c 肽作为急性中风的神经保护剂已显示出临床疗效。[1][2]
体外研究表明，Tat-NR2B9c 对 NMDA 诱导的钙内流的速率或幅度没有可测量的影响。然而，Tat-NR2B9c 阻止了 NMDA 诱导的 DNA 断裂，并且 Tat-NR2B9c 可以显着减少神经元死亡。 Tat-NR2B9c 还通过阻断磷酸化阻止 NMDA 诱导的超氧化物 p47phox 形成，Tat-NR2B9c 的神经保护作用可能部分或全部归因于其抑制 NOX2 激活。此外，靶向 PSD-95 的 PDZ 结构域的 Tat-NR2B9c 破坏了 NR2B 和 NOX2 之间的功能耦合。[2]
体内实验表明，Tat-NR2B9c 可有效治疗或预防围产期和新生儿缺氧缺血性脑损伤及其相关脑部疾病。结果表明，Tat-NR2B9c 在缺血前或缺血后给药可减少缺氧缺血性损伤引起的脑损伤，在缺血前或缺血后给药可改善 HI 后的神经行为结果。此外，Tat-NR2B9c 可能通过促进促生存信号传导和抑制促凋亡信号传导发挥神经保护作用。[1]