Ferrer I, Blanco R, Carmona M, Puig B, Domínguez I, Viñals F
Departament de Biologia Cel.lular i Anatomia Patològica, Hospital Princeps d'Espanya, Universitat de Barcelona, Campus de Bellvitge, Hospitalet de Llobregat, Spain.
Acta Neuropathol. 2002 Apr;103(4):391-407. doi: 10.1007/s00401-001-0481-9. Epub 2002 Jan 31.
Excitotoxicity is considered a major cell death inductor in neurodegeneration. Yet the mechanisms involved in cell death and cell survival following excitotoxic insults are poorly understood. Expression of active, phosphorylation-dependent mitogen-activated extracellular signal-regulated kinases (MAPK/ERKs), stress-activated c-Jun N-terminal kinases (SAPK/JNKs) and p38 kinases, as well as their putative active, phosphorylation-dependent specific transcriptional factor substrates CREB, Elk-1, ATF-2, c-Myc and c-Jun, has been examined following systemic administration of kainic acid (KA) at convulsant doses to rats. Increased phosphorylated MAPK (MAPK(P)) immunoreactivity has been found at 3 and 6 h in the vulnerable regions entorhinal cortex and CA3, in which neurons are committed to die, as well as in sensitive regions dentate gyrus and gyrus cinguli, in which neurons will survive. JNK(P) has been observed in the entorhinal cortex and dentate gyrus, and p38(P) immunoreactivity occurs in the entorhinal cortex. Strong c-Myc(P) expression parallels MAPK(P) immunoreactivity in the entorhinal cortex, CA3, dentate gyrus and gyrus cinguli, showing that enhanced c-Myc(P) expression does not preclude cell death or cell survival. Selective decrease of CREB(P) immunoreactivity in entorhinal cortex and CA3 indicates CREB(P) reduction associated with cell death. Strong c-Jun(P) immunoreactivity has been found in the entorhinal cortex, CA3 and dentate gyrus, thus suggesting that regulation of two opposing cellular programs (cell death or cell survival) of c-Jun(P) depends on c-Jun interactions with other factors. Interestingly, ATF-2(P), and to a lesser extent Elk-1(P), is selectively increased in the dentate gyrus. These results suggest ATF-2(P) involvement in cell survival of dentate gyrus granule cells. The present results demonstrate activation of specific MAPK pathways in association with either cell death or cell survival triggered by KA. Furthermore, increased Ras activation, as seen with p21 Ras activation assay, indicates a crucial role for Ras in activating MAP kinases following excitotoxic insult.
兴奋性毒性被认为是神经退行性变中主要的细胞死亡诱导因素。然而，兴奋性毒性损伤后细胞死亡和细胞存活所涉及的机制仍知之甚少。在给大鼠注射惊厥剂量的 kainic acid（KA）后，检测了活性、磷酸化依赖性丝裂原活化细胞外信号调节激酶（MAPK/ERKs）、应激激活的 c-Jun N 末端激酶（SAPK/JNKs）和 p38 激酶的表达，以及它们假定的活性、磷酸化依赖性特异性转录因子底物 CREB、Elk-1、ATF-2、c-Myc 和 c-Jun 的表达。在海马内嗅皮质和 CA3 这些易损区域（其中的神经元注定会死亡）以及齿状回和扣带回这些敏感区域（其中的神经元会存活），在 3 小时和 6 小时时发现磷酸化 MAPK（MAPK(P)）免疫反应性增加。在海马内嗅皮质和齿状回中观察到 JNK(P)，p38(P)免疫反应性出现在海马内嗅皮质中。在海马内嗅皮质、CA3、齿状回和扣带回中，强烈的 c-Myc(P)表达与 MAPK(P)免疫反应性平行，表明增强的 c-Myc(P)表达并不排除细胞死亡或细胞存活。海马内嗅皮质和 CA3 中 CREB(P)免疫反应性的选择性降低表明 CREB(P)减少与细胞死亡相关。在海马内嗅皮质、CA3 和齿状回中发现强烈的 c-Jun(P)免疫反应性，因此表明 c-Jun(P)对两个相反细胞程序（细胞死亡或细胞存活）的调节取决于 c-Jun 与其他因子的相互作用。有趣的是，ATF-2(P)以及程度较轻的 Elk-1(P)在齿状回中选择性增加。这些结果表明 ATF-2(P)参与齿状回颗粒细胞的细胞存活。目前的结果表明，特定的 MAPK 途径的激活与 KA 触发的细胞死亡或细胞存活相关。此外，如 p21 Ras 激活试验所示，Ras 激活增加表明 Ras 在兴奋性毒性损伤后激活 MAP 激酶中起关键作用。
