Département de Biologie Cellulaire et de Morphologie, University of Lausanne, Lausanne, Switzerland.
J Neurochem. 2011 Dec;119(6):1243-52. doi: 10.1111/j.1471-4159.2011.07535.x. Epub 2011 Nov 9.
Excitotoxicity and cerebral ischemia induce strong endocytosis in neurons, and we here investigate its functional role in neuroprotection by a functional transactivator of transcription (TAT)-peptide, the c-Jun N-terminal kinase (JNK) inhibitor D-JNKI1, against NMDA-excitotoxicity in vitro and neonatal ischemic stroke in P12 Sprague-Dawley rats. In both situations, the neuroprotective efficacy of D-JNKI1 was confirmed, but excessively high doses were counterproductive. Importantly, the induced endocytosis was necessary for neuroprotection, which required that the TAT-peptide be administered at a time when induced endocytosis was occurring. Uptake by other routes failed to protect, and even promoted cell death at high doses. Blocking the induced endocytosis of D-JNKI1 with heparin or with an excess of D-TAT-peptide eliminated the neuroprotection. We conclude that excitotoxicity-induced endocytosis is a basic property of stressed neurons that can target neuroprotective TAT-peptides into the neurons that need protection. Furthermore, it is the main mediator of neuroprotection by D-JNKI1. This may explain promising reports of strong neuroprotection by TAT-peptides without apparent side effects, and warns that the timing of peptide administration is crucial.
兴奋性毒性和脑缺血会在神经元中诱导强烈的内吞作用，我们在这里研究了一种功能性转录激活因子（TAT）肽——c-Jun N 末端激酶（JNK）抑制剂 D-JNKI1，在体外 NMDA 兴奋性毒性和 P12 斯普拉格-道利大鼠新生脑缺血中的功能作用及其在神经保护中的作用。在这两种情况下，D-JNKI1 的神经保护效果都得到了证实，但过高的剂量适得其反。重要的是，诱导的内吞作用对于神经保护是必要的，这要求 TAT 肽在诱导内吞作用发生时给药。通过其他途径摄取不能起到保护作用，甚至在高剂量时会促进细胞死亡。用肝素或过量的 D-TAT 肽阻断 D-JNKI1 的诱导内吞作用会消除神经保护作用。我们得出结论，兴奋性毒性诱导的内吞作用是应激神经元的基本特性，它可以将神经保护 TAT 肽靶向需要保护的神经元。此外，它是 D-JNKI1 神经保护作用的主要介导者。这可能解释了 TAT 肽具有强大的神经保护作用而没有明显副作用的有希望的报告，并警告说肽给药的时间是至关重要的。
