目的: 探索海马脑区脑源性神经营养因子(BDNF)及其信号通路在低氧预适应处理小鼠癫痫模型中的表达变化和作用。方法: 将ICR雄性小鼠随机分为三组,即正常组(Control)、癫痫组(Epilepsy)、低氧预适应治疗癫痫组(HPC1+E),对小鼠注射戊四氮构建急性癫痫样行为模型。观察小鼠的癫痫行为,并检测小鼠海马中的相关生化指标;检测小鼠BDNF以及原肌球蛋白受体激酶B(TrkB)蛋白的表达变化。结果: 与Control组相比,Epilepsy组的五级发作率和发作等级明显升高(P＜0.05),HPC1+E组的五级发作率和发作等级明显降低;Epilepsy组BDNF和P-TrkB的蛋白表达明显降低(P＜0.05),HPC1+E组BDNF和P-TrkB的蛋白表达有明显上升。结论: 低氧预适应处理后可以明显缓解癫痫样行为,而这可能是通过上调BDNF表达、激活其下游信号通路而发挥作用。
Objective: To explore the expression and role of brain-derived neurotrophic factor (BDNF) and its signaling pathway in hippocampal brain region of hypoxic preconditioning-treated mouse epilepsy model. Methods: ICR male mice were randomly divided into three groups: normal group (Control), epilepsy group (Epilepsy), hypoxic preconditioning treatment epilepsy group (HPC1+E). The mice were injected with pentylenetetrazol to construct an acute epilepsy-like behavior model. The epileptic behavior of mice was observed, the related biochemical indexes in the hippocampus of mice were detected, and the expression of BDNF and tropomyosin receptor kinase B (TrkB) protein in mice was detected. Results: Compared with the Control group, the five-level seizure rate and seizure level of the Epilepsy group were significantly increased (P＜0.05), and the five-level seizure rate and seizure level of the HPC1+E group were significantly decreased. The protein expression of BDNF and P-TrkB in the Epilepsy group was significantly decreased (P＜0.05), and the protein expression of BDNF and P-TrkB in the HPC1+E group was significantly increased. Conclusion: Hypoxic preconditioning treatment can significantly alleviate epilepsy-like behavior, which may play a role by up-regulating BDNF expression and activating its downstream signaling pathway.
[1] Neri S, Mastroianni G, Gardella E, et al. Epilepsy in neurodegenerative diseases[J].Epileptic Disord, 2022, 24(2): 249-273.
[2] Pong AW, Xu KJ, Kliein P. Recent advances in pharmacotherapy for epilepsy[J].Curr Opin Neurol, 2023, 36(2): 77-85.
[3] Volkmer E, Kallukalam BC, Maertz J, et al.Hypoxic Preconditioning of Human Mesenchymal Stem Cells Overcomes Hypoxia-Induced Inhibition of Osteogenic Differentiation[J].Tissue Eng Part A, 2010, 16(1): 153-164.
[4] Yang Y, Chen J, Li L, et al. Effect of different mild hypoxia manipulations on kainic acid-induced seizures in the hippocampus of rats[J].Neurochem Res, 2013, 38(1): 123-132.
[5] Wang CS, Kavalali ET, Monteggia LM. BDNF signaling in context: From synaptic regulation to psychiatric disorders[J].Cell, 2022, 185(1): 62-76.
[6] Wang Y, Linag J, Xu B, et al. TrkB/BDNF signaling pathway and its small molecular agonists in CNS injury[J].Life Sci, 2024, 336(1): 122-282.
[7] Paradiso B, Zucchini S, Su T, et al. Localized overexpression of FGF-2 and BDNF in hippocampus reduces mossy fiber sprouting and spontaneous seizures up to 4 weeks after pilocarpine-induced status epilepticus[J].Epilepsia, 2011, 52(3): 572-578.
[8] Zhu X, Shen K, Bai Y, et al. NADPH oxidase activation is required for pentylenetetrazole kindling-induced hippocampal autophagy[J].Free Radic Biol Med, 2016, 94: 230-242.
[9] 吴天龙. L-23对戊四氮诱导的急慢性癫痫模型小鼠的保护作用及机制研究[D].长春:吉林大学,2022.
[10] Thijs RD, Surges R, O'brien TJ, et al. Epilepsy in adults[J].Lancet, 2019, 393(10172): 689-701.
[11] Deng RM, Li HY, Li X, et al. Neuroprotective effect of helium after neonatal hypoxic ischemia: a narrative review[J].Med Gas Res, 2021, 11(3): 121-123.
[12] Isildar B, Ozkan S, Koyuturk M. Preconditioning of Human Umbilical Cord Mesenchymal Stem Cells with a Histone Deacetylase Inhibitor: Valproic Acid[J].Balkan Med J, 2024, 41(5): 369-376.
[13] Alruwai R, Al-kuraishy HM, Al-gareeb AI, et al. The Possible Role of Brain-derived Neurotrophic Factor in Epilepsy[J].Neurochem Res, 2024, 49(3): 533-547.
[14] Mcgongal A, Becker C, Fat J, et al. BDNF as potential biomarker of epilepsy severity and psychiatric comorbidity: pitfalls in the clinical population[J].Epilepsy Res, 2023, 195(1): 107-200.
[15] Nowroozi A, Salehi MA, Mohammadi S. Brain-derived neurotrophic factor in patients with epilepsy: A systematic review and meta-analysis[J].Epilepsy Res, 2021, 178(1): 106-794.
[16] Falcicchia C, Paolone G, Emwrich DF, et al. Seizure-Suppressant and Neuroprotective Effects of Encapsulated BDNF-Producing Cells in a Rat Model of Temporal Lobe Epilepsy[J].Mol Ther Methods Clin Dev, 2018, 9(1): 211-214.
