癫痫杂志

癫痫杂志

非典型海马硬化中自噬流异常阻滞的初步研究

查看全文

目的自噬流增强或减弱均参与耐药性颞叶癫痫(Temporal lobe epilepsy,TLE)的病理生理过程,海马硬化(Hippocampal sclerosis,HS)是耐药性TLE主要的病理类型。但不同亚型HS不仅预后有差异,其病因、病理生理也存在差异。而自噬流异常阻滞是否参与其中,目前尚罕见报道,研究拟初步比较典型及非典型HS患者自噬流情况,探讨非典型HS患者可能的发生及耐药机制。 方法收集2015年3月-2015年12月于华西医院就诊的耐药性TLE患者17例,手术切除海马及颞叶癫痫灶。根据2013年国际抗癫痫联盟HS病理分型标准分组,分为10例典型HS组(HS1型),7例非典型HS组(HS2型6例+HS3型1例),并对手术切除组织采用免疫组织化学及免疫印迹检测LC3B、Beclin-1及P62表达分布及表达量。 结果与既往报道一致,LC3B、Beclin-1及P62主要表达于神经元细胞浆。以β-actin为内参,非典型HS组较典型HS组,自噬流下游产物LC3B、Beclin-1有明显升高(P<0.01),非典型HS组出现了自噬底物的堆积和自噬流不畅,而自噬流底物P62在组间无差异;同时发现3-磷酸甘油醛脱氢酶(GAPDH)在两组间有极显著差异(P=0.003)。 结论非典型HS中存在自噬流异常阻滞现象,并且GAPDH可能参与到其机制中,这为未来治疗手术效果不佳的非典型HS提供了新的靶点和思路。

ObjectiveThe abnormal autophagy fluxis involved in the pathophysiological process of drug-resistance temporal lobe epilepsy (TLE).Hippocampal sclerosis (HS) is the main pathological type of drug-resistance TLE.Different subtypes of HS have various prognosis, etiology and pathophysiology.However, whether theabnormal block ofautophagy flux involved in this process has not been reported.This study proposed a preliminary comparison of autophagy fluxin typical and atypical HS to investigate the potential pathogenesis and drug-resistance mechanism of atypical HS. MethodsSurgical excision of hippocampal and temporal lobe epilepsy foci were performed in 17 patients with drug-resistance TLE.Patients were grouped according to the HS classification issued by International League Against Epilepsy in 2013.The distribution and expression of LC3B, beclin-1 and P62 were detected by immunohistochemistry and Western blot in each group. ResultsLC3B, beclin-1 and P62 are mainly expressed in neuronal cytoplasm, which is consistent with previous reports.Taking β-actin as internal reference, we found that LC3B and Beclin-1, the downstream products of autophagy flux, have increased significantly (P < 0.01) in the atypical HS group compared to typical HS group.However, the autophagy flux substrate P62 has no difference between the groups.This result suggested that compared with the typical HS group, atypical HS group had autophagy substrate accumulation and autophagy flux abnormal block.Besides, we found that glyceraldehycle-3-phosphate dehydrogenase(GAPDH) was significantly different between the two groups (P=0.003). ConclusionThere is abnormal phenomenon of autophagy flux in atypical HS, and GAPDH elevation may be involved in its mechanism, which might provide new targets and ideas for future treatment of atypical HS.

关键词: 非典型海马硬化; 自噬; 颞叶癫痫

Key words: Atypical hippocampal sclerosis; Autophagy; Temporal lobe epilepsy

引用本文: 熊维希, 吴梦倩, 张乐, 迟潇洒, 李劲梅, 周东. 非典型海马硬化中自噬流异常阻滞的初步研究. 癫痫杂志, 2017, 3(5): 380-384. doi: 10.7507/2096-0247.20170058 复制

登录后 ,请手动点击刷新查看全文内容。 没有账号,
登录后 ,请手动点击刷新查看图表内容。 没有账号,
1. Semah F, Picot MC, Adam C, et al. Is the underlying cause of epilepsy a major prognostic factor for recurrence.Neurology, 1998, 51(5): 1256-1262.
2. Thom M.Review: Hippocampal sclerosis in epilepsy: a neuropathology review.Neuropathol Appl Neurobiol, 2014, 40(5): 520-543.
3. Blumcke I, Thom M, Aronica E, et al. International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: a Task Force report from the ILAE Commission on Diagnostic Methods.Epilepsia, 2013, 54(7): 1315-1329.
4. Blumcke I, Pauli E, Clusmann H, et al. A new clinico-pathological classification system for mesial temporal sclerosis.Actaneuropathol, 2007, 113(3): 235-244.
5. Yang Z, Klionsky DJ.Eaten alive: a history of macroautophagy.Nat Cell Biol, 2010, 12(9): 814-822.
6. Wu M, Liu X, Chi X, et al. Mitophagy in Refractory Temporal Lobe Epilepsy Patients with Hippocampal Sclerosis.Cell Mol Neurobiol, published online, 12 April 2017.
7. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies.Epilepsia, 2010, 51(5): 1069-1077.
8. Klionsky DJ, Abdalla FC, Abeliovich H, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy, 2012, 8(4): 445-544.
9. Martinez-Vicente M.Neuronal Mitophagy in Neurodegenerative Diseases.Front Mol Neurosci, 2017, 10: 64.
10. Giorgi FS, Biagioni F, Lenzi P, et al. The role of autophagy in epileptogenesis and in epilepsy-induced neuronal alterations. J Neural Transm (Vienna), 2015, 122(6): 849-862.
11. Shacka JJ, Lu J, Xie ZL, et al. Kainic acid induces early and transient autophagic stress in mouse hippocampus.Neuroscilett, 2007, 414(1): 57-60.
12. Cao L, Xu J, Lin Y, et al. Autophagy is upregulated in rats with status epilepticus and partly inhibited by Vitamin E.Biochem Biophys Res Commun, 2009, 379(4): 949-953.
13. Chang C, Su H, Zhang D, et al. AMPK-dependent phosphorylation of GAPDH triggers sirt1 activation and is necessary for autophagy upon glucose starvation.Mol Cell, 2015, 60(6): 930-940.