Neuroprotective effect and mechanism of idebenone on hippocampal damage induced by epileptic seizure

doi:10.3969/j.issn.1672-6731.2022.07.008

Abstract

Abstract: Objective To investigate the protective effect of idebenone (IDBN) on hippocampal neuron injury in epileptic rats and its mechanism. Methods Forty-eight Wistar rats were randomly divided into normal control group, IDBN prevention group (prevention group), epilepsy group, IDBN 25, 50 and 100 mg groups. Behavioral changes of rats in different treatment groups before and after treatment with IDBN were observed. The activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and the content of malondialdehyde (MDA) in hippocampal were detected. The ultrastructural changes of hippocampal neurons and mitochondria were observed. Results The expression levels of SOD, GSH-Px and MDA in different treatment groups were significantly different (P=0.000, for all). The activity of SOD and GSH-Px was the highest and the content of MDA was the lowest in IDBN 100 mg group. The activity of SOD and GSH-Px in IDBN 100 mg group were higher than those in epilepsy group (P=0.000, 0.000), IDBN 25 mg group (P=0.000, 0.000) and 50 mg group (P=0.004, 0.005), while the content of MDA was lower than that in epilepsy group (P=0.000), IDBN 25 mg group (P=0.000) and 50 mg group (P=0.002). Compared with normal control group and prevention group, hippocampal neurons in epilepsy group showed different degrees of damage, which was relieved after treatment with IDBN and gradually decreased with the increase of dose. In epilepsy group, the mitochondrial structure of hippocampal neurons was damaged obviously, with deformation and swelling, and some mitochondria were vacuolated. After treatment with IDBN, the damage was relieved, and the 100 mg group had the least damage. Conclusions IDBN can protect hippocampal neuron structure and function by inhibiting oxidative stress injury in epileptic rats.

Key words: Benzoquinones, Epilepsy, Hippocampus, Apoptosis, Superoxide dismutase, Glutathione peroxidase, Malondialdehyde, Disease models, animal

摘要： 目的探讨艾地苯醌（IDBN）对癫痫大鼠海马神经元损伤的预防性保护作用及其作用机制。方法共48只Wistar大鼠随机分为正常对照组、IDBN预防组（预防组）、癫痫组和IDBN 25 mg组、50 mg组、100 mg组，观察不同处理组大鼠治疗前后行为学变化，检测海马组织超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH-Px）活性和丙二醛（MDA）含量，观察海马组织学形态及神经元线粒体超微结构。结果不同处理组大鼠海马组织SOD、GSH-Px和MDA表达水平差异具有统计学意义（均P=0.000）。IDBN不同剂量组以100 mg组SOD和GSH-Px活性最强、MDA含量最低：SOD和GSH-Px活性高于癫痫组（P=0.000，0.000）、IDBN 25 mg组（P=0.000，0.000）和50 mg组（P=0.004，0.005），MDA含量低于癫痫组（P=0.000）、IDBN 25 mg组（P=0.000）和50 mg组（P=0.002）。与正常对照组和预防组相比，癫痫组大鼠海马神经元出现不同程度损伤，经艾地苯醌处理后损伤减轻且随剂量的增加其程度逐渐减轻；癫痫组大鼠海马神经元线粒体结构破坏明显，可见变形、肿胀，部分线粒体呈空泡化；经艾地苯醌处理后损伤减轻，且随剂量的增加其程度逐渐减轻。结论艾地苯醌可通过抑制癫痫大鼠体内氧化应激损伤作用保护海马神经元结构及功能。

关键词: 苯醌类, 癫痫, 海马, 细胞凋亡, 超氧化物歧化酶, 谷胱甘肽过氧化酶, 丙二醛, 疾病模型,动物

QIAO Shan, SU Yong-xin, ZHANG Ran-ran, WU Yu-jiao, WANG Ke-mo, LIU Xue-wu. Neuroprotective effect and mechanism of idebenone on hippocampal damage induced by epileptic seizure[J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2022, 22(7): 592-600.

乔珊, 苏永鑫, 张冉冉, 吴玉娇, 王柯默, 刘学伍. 艾地苯醌对癫痫发作致海马损伤神经保护作用及其机制研究[J]. 中国现代神经疾病杂志, 2022, 22(7): 592-600.

/ / Recommend / Download Citations

URL: https://journal11.magtechjournal.com/cjcnn/EN/10.3969/j.issn.1672-6731.2022.07.008

https://journal11.magtechjournal.com/cjcnn/EN/Y2022/V22/I7/592

References

[1] Miyata H, Kuwashige H, Hori T, Kubota Y, Pieper T, Coras R, Blümcke I, Yoshida Y. Variable histopathology features of neuronal dyslamination in the cerebral neocortex adjacent to epilepsy-associated vascular malformations suggest complex pathogenesis of focal cortical dysplasia ILAE type Ⅲ c[J]. Brain Pathol, 2022.[Epub ahead of print]
[2] Shen KF, Yue J, Wu ZF, Wu KF, Zhu G, Yang XL, Wang ZK, Wang J, Liu SY, Yang H, Zhang CQ. Fibroblast growth factor 13 is involved in the pathogenesis of temporal lobe epilepsy[J]. Cereb Cortex, 2022.[Epub ahead of print]
[3] Parsons ALM, Bucknor EMV, Castroflorio E, Soares TR, Oliver PL, Rial D. The interconnected mechanisms of oxidative stress and neuroinflammation in epilepsy[J]. Antioxidants (Basel), 2022, 11:157.
[4] Ethemoglu O, Calık M, Koyuncu I, Ethemoglu KB, Göcmen A, Güzelcicek A, Cadırcı D. Interleukin-33 and oxidative stress in epilepsy patients[J]. Epilepsy Res, 2021, 176:106738.
[5] Kösem A, Yücel Ç, Titiz AP, Sezer S, Neşelioğlu S, Erel Ö, Turhan T. Evaluation of serum thiol-disulphide homeostasis parameters as oxidative stress markers in epilepsy patients[J]. Acta Neurol Belg, 2021, 121:1555-1559. and avoidance
[6] Finsterer J, Zarrouk-Mahjoub S. Ketogenic diet of mitochondrion-toxic AEDs may improve the outcome of mitochondrial epilepsy[J]. Clin Neurol Neurosurg, 2018, 173:202-203. Pearson-Smith JN, Huynh CQ, Fabisiak T, Liang
[7] Fulton RE, LP, Aivazidis S, High BA, Buscaglia G, Corrigan T, Valdez R, Shimizu T, Patel MN. Neuron-specific mitochondrial oxidative stress results in epilepsy, glucose dysregulation and a striking astrocyte response[J]. Neurobiol Dis, 2021, 158:105470.
[8] Lee HJ, Park JH, Hoe HS. Idebenone regulates Aβ and LPS-induced neurogliosis and cognitive function through inhibition of NLRP3 inflammasome/IL-1β axis activation[J]. Front Immunol, 2022, 13:749336.
[9] Akpinar E, Kutlu Z, Kose D, Aydin P, Tavaci T, Bayraktutan Z, Yuksel TN, Yildirim S, Eser G, Dincer B. Protective effects of idebenone against sepsis induced acute lung damage[J]. J Invest Surg, 2022, 35:560-568.
[10] Gueven N, Ravishankar P, Eri R, Rybalka E. Idebenone:when an antioxidant is not an antioxidant[J]. Redox Biol, 2021, 38:101812.
[11] Avcı B, Günaydın C, Güvenç T, Yavuz CK, Kuruca N, Bilge SS. Idebenone ameliorates rotenone-induced Parkinson's disease in rats through decreasing lipid peroxidation[J]. Neurochem Res, 2021, 46:513-522.
[12] Racine R, Okujava V, Chipashvili S. Modification of seizure activity by electrical stimulation. Ⅲ:Mechanisms[J]. Electroencephalogr Clin Neurophysiol, 1972, 32:295-299.
[13] Zhang R, Qiao S, Fang X, Wang K, Shi Y, Du Q, Yang T, Liu X. Efficacy and tolerability of perampanel as adjunctive therapy in Chinese patients with focal-onset seizures:an observational, prospective study[J]. Front Neurol, 2021, 12:731566.
[14] Li S, Zhang L, Wei N, Tai Z, Yu C, Xu Z. Research progress on the effect of epilepsy and antiseizure medications on PCOS through HPO axis[J]. Front Endocrinol (Lausanne), 2021, 12:787854.
[15] Ding D, Zhou D, Sander JW, Wang W, Li S, Hong Z. Epilepsy in China:major progress in the past two decades[J]. Lancet Neurol, 2021, 20:316-326.
[16] Elorza-Vidal X, Gaitán-Peñas H, Estévez R. Chloride channels in astrocytes:structure, roles in brain homeostasis and implications in disease[J]. Int J Mol Sci, 2019, 20:1034.
[17] Hanak TJ, Libbey JE, Doty DJ, Sim JT, DePaula-Silva AB, Fujinami RS. Positive modulation of mGluR5 attenuates seizures and reduces TNF-α⁺ macrophages and microglia in the brain in a murine model of virus-induced temporal lobe epilepsy[J]. Exp Neurol, 2019, 311:194-204.
[18] Deng X, Xie Y, Chen Y. Effect of neuroinflammation on ABC transporters:possible contribution to refractory epilepsy[J]. CNS Neurol Disord Drug Targets, 2018, 17:728-735.
[19] Tang Z, Wang Y, Wan Y, Xie Y, Li S, Tao D, Wang C, Wu YZ, Sui JD. Apurinic/apyrimidinic endonuclease 1/reduction-oxidation effector factor-1(APE1) regulates the expression of NLR family pyrin domain containing 3(NLRP3) inflammasome through modulating transcription factor NF-κB and promoting the secretion of inflammatory mediators in macrophages[J]. Ann Transl Med, 2021, 9:145.
[20] Xu C, Chen S, Zhao J, Luo X, Zhao S. A DNAzyme-mediated target-initiated rolling circle amplification strategy based on a microchip platform for the detection of apurinic/apyrimidinic endonuclease 1 at the single-cell level[J]. Chem Commun (Camb), 2021, 57:11017-11020.
[21] Jo Y, Kim Y, Park E, Lee Y, Kim J, Kang M, Lim J, Song I, Lim C, Jeon B. Changes in the plasma apurinic/apyrimidinic endonuclease 1/redox factor-1(APE1/Ref-1) level during cancer surgery:an observational study[J]. Medicina (Kaunas), 2021, 57:1280.
[22] Verma N, Maiti R, Mishra BR, Jha M, Jena M, Mishra A. Effect of add-on melatonin on seizure outcome, neuronal damage, oxidative stress, and quality of life in generalized epilepsy with generalized onset motor seizures in adults:a randomized controlled trial[J]. J Neurosci Res, 2021, 99:1618-1631.
[23] Goldenthal MJ, Kuruvilla T, Damle S, Salganicoff L, Sheth S, Shah N, Marks H, Khurana D, Valencia I, Legido A. Non-invasive evaluation of buccal respiratory chain enzyme dysfunction in mitochondrial disease:comparison with studies in muscle biopsy[J]. Mol Genet Metab, 2012, 105:457-462.
[24] Yang H, Yin F, Gan S, Pan Z, Xiao T, Kessi M, Yang Z, Zhang VW, Wu L. The study of genetic susceptibility and mitochondrial dysfunction in mesial temporal lobe epilepsy[J]. Mol Neurobiol, 2020, 57:3920-3930.
[25] Balan DJ, Rajavel T, Das M, Sathya S, Jeyakumar M, Devi KP. Thymol induces mitochondrial pathway-mediated apoptosis via ROS generation, macromolecular damage and SOD diminution in A549 cells[J]. Pharmacol Rep, 2021, 73:240-254.
[26] Sharma P, Kumar S. Metformin inhibits human breast cancer cell growth by promoting apoptosis via a ROS-independent pathway involving mitochondrial dysfunction:pivotal role of superoxide dismutase (SOD)[J]. Cell Oncol (Dordr), 2018, 41:637-650.
[27] Chang Q, Cai H, Wei L, Lan R. Chitosan oligosaccharides alleviate acute heat stress-induced oxidative damage by activating ERK1/2-mediated HO-1 and GSH-Px gene expression in breast muscle of broilers[J]. Poult Sci, 2022, 101:101515.
[28] Alyethodi RR, Sirohi AS, Karthik S, Tyagi S, Perumal P, Singh U, Sharma A, Kundu A. Role of seminal MDA, ROS, and antioxidants in cryopreservation and their kinetics under the influence of ejaculatory abstinence in bovine semen[J]. Cryobiology, 2021, 98:187-193.
[29] Mishra P, Mittal AK, Rajput SK, Sinha JK. Cognition and memory impairment attenuation via reduction of oxidative stress in acute and chronic mice models of epilepsy using antiepileptogenic Nux vomica[J]. J Ethnopharmacol, 2021, 267:113509.
[30] Wu ZS, Huang WL, Gong SJ. Effect of adenovirus-mediated overexpression of PTEN on brain oxidative damage and neuroinflammation in a rat kindling model of epilepsy[J]. Chin Med J (Engl), 2019, 132:2628-2635.
[31] Misra UK, Kalita J, Tripathi A, Kumar M. Oxidative and endoplasmic reticulum stress in tuberculous meningitis related seizures[J]. Epilepsy Res, 2019, 156:106160.
[32] Liang LP, Patel M. Mitochondrial oxidative stress and increased seizure susceptibility in Sod2(-/+) mice[J]. Free Radic Biol Med, 2004, 36:542-554. HJ, Wie
[33] Shin EJ, Ko KH, Kim WK, Chae JS, Yen TP, Kim MB, Kim HC. Role of glutathione peroxidase in the ontogeny of hippocampal oxidative stress and kainate seizure sensitivity in the genetically epilepsy-prone rats[J]. Neurochem Int, 2008, 52:1134-1147.
[34] Wang M, Zhang X, Jia W, Zhang C, Boczek T, Harding M, Liu Y, Li M, Zhang S, Lei S, Zhang D, Guo F. Circulating glutathione peroxidase and superoxide dismutase levels in patients with epilepsy:a meta-analysis[J]. Seizure, 2021, 91:278-286.
[35] Sun H, Li J, Maimaiti B, Liu J, Li Z, Cheng Y, Zhao W, Mijiti S, Jiang T, Meng Q, Wang J, Jin Q, Meng H. Circulating malondialdehyde level in patients with epilepsy:a meta-analysis[J]. Seizure, 2022, 99:113-119.
[36] Iwuozo EU, Obiako OR, Ejiofor JI, Kehinde JA, Abubakar SA. Effect of epilepsy and antiepileptic drugs therapy on erythrocyte malondialdehyde and some antioxidants in persons with epilepsy[J]. West Afr J Med, 2019, 36:211-216.

Please choose a citation manager

Content to export