The expression of EPO-R, JAK2 and STAT-5 in the human brain with refractory epilepsy_Journal of Epilepsy

Authors：

WANG Guangwen ¹ , WANG Zan ² ,  LIN Weihong ² , 张文娟 ³

1. Department of Neurology, General Hospital of TISCO, 030003, China;
2. Department of Neurology, The First Hospital of Jilin University, 130021, China;
3. Department of Neurology, Shanxi Provincial People’s Hospital,Taiyuan 030012, China;

Corresponding author：

LIN Weihong, Email: linweihong321@126.com

Keywords：

Intractable epilepsy; Apotosis; EPO-R; JAK2; STAT-5

DOI：

10.7507/2096-0247.20180077

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Objective The purpose of this study was to explore the expressions of EPO-R, JAK2 and STAT-5 in the human brain with refractory epilepsy and the role in neural apotosis. Methods Collecting the brain tissue of 24 patients with intractable epilepsy (as experimental group) who were hospitalized and underwent surgery in the Epilepsy Center of the First Hospital Jilin University between March 2010 to July 2011 and 6 cases of accidental or unnatural death immediately following autopsy (as control group) as required by law during the same term. Immunohistochemical was performed to observe the expression of EPO-R, JAK2 and STAT-5 in brain tissue and statistical analysis was performed. Results ① EPO-R, JAK2 and STAT-5 were expressed in both experimental and control groups. In experimental group, the positive-cell number were 41.05±2.40, 50.21±2.50 and 60.18±2.84 under light microscope (400×). While in control group, the positive-cell number were 23.00±0.49, 27.00±0.88 and 25.93±0.33. There were significant differences between the 2 groups (P<0.001). ② There were the pathologic and ultrastructural changes in the human brain with refractory epilepsy. Under the optical microscope, we can observe that the distribution of neurons was uneven and immature neurons were visible. We can see that the nuclei were vacuolar, less cytoplasm, dark staining, hyalomitome acidophilic body, and the neurons became triangular due to degeneration. The proliferation and hyperemia appeared in small vascular and glial cells. Under the transmission electron microscope we observed degeneration and necrosis of the nerve cells, nuclear karyopyknosis, nucleolis dyssymmetry and karyolemma breakage and even dissolution. The mitochondria and astrocytes were swelling. We also saw that part of the mitochondrial cristae was abnormal. Conclusion ① We found neuronal apotosis in the human brain with refractory epilepsy. ② The expression of EPO-R, JAK2 and STAT-5 in intractable epilepsy was significantly increased in neurons and glial cells compared with the control group. The high expression of EPO-R, JAK2 and STAT-5 is unrelated with course and frequency of epileptic seizures. ③ The pathway of EPO-R/JAK2/STAT-5 may be involved in the pathophysiological processes of neural protective effect of endogenous EPO against brain injury induced by epileptic seizures.

Citation： WANG Guangwen, WANG Zan, LIN Weihong. The expression of EPO-R, JAK2 and STAT-5 in the human brain with refractory epilepsy. Journal of Epilepsy, 2018, 4(6): 480-485. doi: 10.7507/2096-0247.20180077 Copy

1.	张淑琴, 林卫红, 赵丽曼. 实验性癫痫不同脑区细胞凋亡的观察及意义. 中风与神经疾病杂志, 2002, 19(4): 205-207.
2.	Henshall DC, Murphy BM. Modulators of neuronal cell death in epilepsy. Curr Opini Pharmacol, 2008, 8(1): 75-81.
3.	Uzüm G, Sarper Diler A, Bahcekapili N, et al. Erythropoietin prevents the increase in blood-brain barrier permeability during pentylentetrazol induced seizures. Life Sci, 2006, 78(22): 2571-2576.
4.	Yang J, Huang Y, Yu X, et al. Erythropoietin preconditioning suppresses neuronal death following status epilepticus in rats. Acta Neurobiol. Exp(Wars), 2007, 67(2): 141-148.
5.	Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia, 1989, 30(4): 389-399.
6.	Yatsiv I, Grigoriadis N, Simeonidou C, et al. Erythropoietin is neuroprotective, improves functional recovery, and reduces neuronal apoptosis and inflammation in a rodent model of experimental closed head injury. FASEB J, 2005, 19(12): 1701-1703.
7.	Ma SL, Chen JW, Chen C, et al. Erythropoietin Rescues Memory Impairment in a Rat Model of Chronic Cerebral Hypoperfusion via the EPO-R/JAK2/STAT5/PI3K/Akt/GSK-3β Pathway. Mol Neurobiol, 2018, 55(4): 3290-3299.
8.	Wei SW, Luo CX, Yu SP, et al. Erythropoietin ameliorates early brain injury after subarachnoid haemorrhage by modulating microglia polarization via the EPOR/JAK2-STAT3 pathway. Exp Cell Res, 2017, 361(2): 342-352.
9.	Yang J, Xu JT, Huang YG, et al. Erythropoietin pre-treatment prevents cognitive impairments following status epilepticus in rats. Brain Res, 2009, 1282: 57-66.
10.	裘银虹, 朱国行, 丁晶, 等. 促红细胞生成素对毛果芸香碱诱导的小鼠癫痫发作脑保护的研究. 现代实用医学, 2011, 23(5): 496-497, 565.
11.	Zhao J, Li G, Zhang Y, et al. The potential role of JAK2/STAT3 pathway on the anti-apoptotic effect of recombinant humanerythropoietin (rhEPO) after experimental traumatic brain injury of rats. Cytokine, 2011, 56(2): 343-350.
12.	史志勤, 王维平, 于江华, 等. 重组人红细胞生成素经 PI3K/Akt 途径对大鼠癫痫持续状态诱导的神经元凋亡的保护作用. 中国组织化学与细胞化学杂志, 2009, 18(1): 94-102.
13.	Ghezzi P, Brines M. Erythropoietin as an antiapoptotic, tissue-protective cytokine. Cell Death Differ, 2004, 11(Suppl 1): 37-44.
14.	Xu Z, Xue T, Zhang Z, et al. Role of signal transducer and activator of transcription-3 in up-regulation of GFAP after epilepsy. Neurochem Res, 2011, 36(12): 2208-2215.
15.	Socolovsky M, Fallon AE, Wang S, et al. Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/-mice. a direct role for Stat5 in Bcl-X(L) induction. Cell, 1999, 98(2): 181-191.
16.	Henshall DC, Simon RP. Epilepsy and apoptosis pathways. Journal of Cerebral Blood Flow & Metabolism, 2005, 25(2): 1557-1572.

1. 张淑琴, 林卫红, 赵丽曼. 实验性癫痫不同脑区细胞凋亡的观察及意义. 中风与神经疾病杂志, 2002, 19(4): 205-207.
2. Henshall DC, Murphy BM. Modulators of neuronal cell death in epilepsy. Curr Opini Pharmacol, 2008, 8(1): 75-81.
3. Uzüm G, Sarper Diler A, Bahcekapili N, et al. Erythropoietin prevents the increase in blood-brain barrier permeability during pentylentetrazol induced seizures. Life Sci, 2006, 78(22): 2571-2576.
4. Yang J, Huang Y, Yu X, et al. Erythropoietin preconditioning suppresses neuronal death following status epilepticus in rats. Acta Neurobiol. Exp(Wars), 2007, 67(2): 141-148.
5. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia, 1989, 30(4): 389-399.
6. Yatsiv I, Grigoriadis N, Simeonidou C, et al. Erythropoietin is neuroprotective, improves functional recovery, and reduces neuronal apoptosis and inflammation in a rodent model of experimental closed head injury. FASEB J, 2005, 19(12): 1701-1703.
7. Ma SL, Chen JW, Chen C, et al. Erythropoietin Rescues Memory Impairment in a Rat Model of Chronic Cerebral Hypoperfusion via the EPO-R/JAK2/STAT5/PI3K/Akt/GSK-3β Pathway. Mol Neurobiol, 2018, 55(4): 3290-3299.
8. Wei SW, Luo CX, Yu SP, et al. Erythropoietin ameliorates early brain injury after subarachnoid haemorrhage by modulating microglia polarization via the EPOR/JAK2-STAT3 pathway. Exp Cell Res, 2017, 361(2): 342-352.
9. Yang J, Xu JT, Huang YG, et al. Erythropoietin pre-treatment prevents cognitive impairments following status epilepticus in rats. Brain Res, 2009, 1282: 57-66.
10. 裘银虹, 朱国行, 丁晶, 等. 促红细胞生成素对毛果芸香碱诱导的小鼠癫痫发作脑保护的研究. 现代实用医学, 2011, 23(5): 496-497, 565.
11. Zhao J, Li G, Zhang Y, et al. The potential role of JAK2/STAT3 pathway on the anti-apoptotic effect of recombinant humanerythropoietin (rhEPO) after experimental traumatic brain injury of rats. Cytokine, 2011, 56(2): 343-350.
12. 史志勤, 王维平, 于江华, 等. 重组人红细胞生成素经 PI3K/Akt 途径对大鼠癫痫持续状态诱导的神经元凋亡的保护作用. 中国组织化学与细胞化学杂志, 2009, 18(1): 94-102.
13. Ghezzi P, Brines M. Erythropoietin as an antiapoptotic, tissue-protective cytokine. Cell Death Differ, 2004, 11(Suppl 1): 37-44.
14. Xu Z, Xue T, Zhang Z, et al. Role of signal transducer and activator of transcription-3 in up-regulation of GFAP after epilepsy. Neurochem Res, 2011, 36(12): 2208-2215.
15. Socolovsky M, Fallon AE, Wang S, et al. Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/-mice. a direct role for Stat5 in Bcl-X(L) induction. Cell, 1999, 98(2): 181-191.
16. Henshall DC, Simon RP. Epilepsy and apoptosis pathways. Journal of Cerebral Blood Flow & Metabolism, 2005, 25(2): 1557-1572.

Journal of Epilepsy

The expression of EPO-R, JAK2 and STAT-5 in the human brain with refractory epilepsy

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