Chemotactic and mitogenic stimuli of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy.
Chemotactic and mitogenic stimuli of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy.
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DOI：
10.1016/j.pathophys.2012.02.003
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发表时间：
2013-02-01
期刊：
影响因子：
--
通讯作者：
Weinand, Martin
中科院分区：
文献类型：
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作者：
Fiala, Milan;Avagyan, Hripsime;Weinand, Martin
为了确定药物难治性颞叶癫痫（TLE）患者神经元凋亡的上游信号，我们通过免疫组织化学和共聚焦显微镜对13例TLE患者和5例对照患者的脑组织进行了评估，涉及趋化因子和细胞周期蛋白的表达。趋化因子RANTES（CCR 5）和其他CC趋化因子及凋亡标志物（caspase-3、-8、-9）在TLE患者的颞叶外侧皮质和海马神经元中表达，而在对照组的神经元中不表达。趋化因子RANTES通常存在于细胞质和细胞外位置。然而，在TLE神经元，RANTES显示在一个不寻常的位置，神经元核。此外，细胞周期调控转录因子E2 F1被发现在一个异常的位置在神经元细胞质。促炎酶环氧合酶-2和细胞因子白细胞介素-1 β在颞叶癫痫和脑外伤患者的神经元中均有表达。血管显示纤维蛋白渗漏、血管周围巨噬细胞和内皮细胞上的IL-6表达。总之，E2 F1的细胞质效应和RANTES的核效应可能在TLE神经元的神经元凋亡中具有新的作用，并表明需要开发新的针对这些分子的凋亡信号的医学和/或外科神经保护策略。RANTES和E2 F1信号都位于caspase激活的上游，因此RANTES和/或E2 F1阻断剂可能对药物难治性颞叶癫痫患者具有神经保护作用。这些结果对开发新的内科和外科治疗方法具有重要意义，这些治疗方法的基础是抑制药物难治性颞叶癫痫患者神经元凋亡的趋化性和促有丝分裂刺激。
To identify the upstream signals of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy (TLE), we evaluated by immunohistochemistry and confocal microscopy brain tissues of 13 TLE patients and 5 control patients regarding expression of chemokines and cell-cycle proteins. The chemokine RANTES (CCR5) and other CC-chemokines and apoptotic markers (caspase-3, -8, -9) were expressed in lateral temporal cortical and hippocampal neurons of TLE patients, but not in neurons of control cases. The chemokine RANTES is usually found in cytoplasmic and extracellular locations. However, in TLE neurons, RANTES was displayed in an unusual location, the neuronal nuclei. In addition, the cell-cycle regulatory transcription factor E2F1 was found in an abnormal location in neuronal cytoplasm. The pro-inflammatory enzyme cyclooxygenase-2 and cytokine interleukin-1beta were expressed both in neurons of patients suffering from temporal lobe epilepsy and from cerebral trauma. The vessels showed fibrin leakage, perivascular macrophages and expression of IL-6 on endothelial cells. In conclusion, the cytoplasmic effects of E2F1 and nuclear effects of RANTES might have novel roles in neuronal apoptosis of TLE neurons and indicate a need to develop new medical and/or surgical neuroprotective strategies against apoptotic signaling by these molecules. Both RANTES and E2F1 signaling are upstream from caspase activation, thus the antagonists of RANTES and/or E2F1 blockade might be neuroprotective for patients with medically intractable temporal lobe epilepsy. The results have implications for the development of new medical and surgical therapies based on inhibition of chemotactic and mitogenic stimuli of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy.