Mhyre T R, Applegate C D
Strong Epilepsy Center, Department of Neurology, University of Rochester Medical Center, Box 673, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Neuroscience. 2003;121(4):1031-45. doi: 10.1016/s0306-4522(03)00475-5.
Brain-derived neurotrophic factor (BDNF) appears to be both regulated by and a regulator of epileptogenesis. In the flurothyl (HFE) model of kindling mice exposed to successive flurothyl trials over 8 days express a rapid, long-lasting reduction in generalized seizure threshold and a more slowly evolving change in seizure phenotype in response to subsequent flurothyl exposure. The BDNF genotype of particular mouse strains appears to influence the epileptogenic progression in this model. Thus, we hypothesized that BDNF signaling pathways are altered by flurothyl-induced seizures. Following HFE kindling, fully kindled (eight seizures) adult male C57BI/6J mice had significantly elevated whole brain BDNF levels through at least 28 days after their final seizure. Mice that received only four HFE seizures (not kindled) had elevated BDNF levels, but only at 1 day post-seizure (DPSz), while BDNF levels were not significantly altered in mice receiving just one HFE seizure at any time point studied. Regional expression patterns of BDNF in the hippocampus, hypothalamus, and frontal cortex were also elevated by one DPSz and returned to control values by 14 DPSz in mice that received four HFE seizures. No changes were seen in the cerebellum, striatum, or piriform cortex. In contrast, fully kindled mice had significantly elevated BDNF levels within the hippocampus, hypothalamus, neocortex, and striatum that remained elevated through at least 14 DPSz, while levels were unchanged in the cerebellum and piriform cortex. Regional results were confirmed using anti-BDNF immunohistochemistry (IHC). Despite changes in BDNF levels following HFE kindling, we were unable to demonstrate alterations either in full-length tyrosine kinase receptor B (TrkB) expression (Western blot and IHC) or in truncated TrkB (IHC) expression levels. Together, these data suggest a model of a positive feedback loop involving seizure activity and seizure number and persistently modified BDNF signaling pathways that influences seizure phenotypes within the HFE kindling paradigm. Thus, long-term elevations in BDNF may be responsible in part for epileptogenic processes and the development of human refractory epilepsies.
脑源性神经营养因子（BDNF）似乎既受癫痫发生的调节，又是癫痫发生的调节因子。在氟烷（HFE）点燃模型中，连续8天接受氟烷试验的小鼠表现出全身性癫痫阈值迅速、持久降低，以及对随后氟烷暴露的癫痫发作表型变化更为缓慢。特定小鼠品系的BDNF基因型似乎会影响该模型中的癫痫发生进程。因此，我们假设BDNF信号通路会因氟烷诱导的癫痫发作而改变。在HFE点燃后，完全点燃（八次癫痫发作）的成年雄性C57BI/6J小鼠在最后一次癫痫发作后至少28天内，全脑BDNF水平显著升高。仅接受四次HFE癫痫发作（未点燃） 的小鼠BDNF水平升高，但仅在癫痫发作后1天（DPSz），而在任何研究时间点，仅接受一次HFE癫痫发作的小鼠BDNF水平均无显著变化。接受四次HFE癫痫发作的小鼠，海马体、下丘脑和额叶皮质中BDNF的区域表达模式在癫痫发作后1天也升高，并在癫痫发作后14天恢复到对照值。在小脑、纹状体或梨状皮质中未观察到变化。相比之下，完全点燃的小鼠海马体、下丘脑、新皮质和纹状体中的BDNF水平显著升高，至少在癫痫发作后14天内一直升高，而小脑和梨状皮质中的水平未发生变化。使用抗BDNF免疫组织化学（IHC）证实了区域结果。尽管HFE点燃后BDNF水平发生了变化，但我们无法证明全长酪氨酸激酶受体B（TrkB）表达（蛋白质印迹法和IHC）或截短型TrkB（IHC）表达水平有改变。总之，这些数据表明了一个正反馈回路模型，该模型涉及癫痫发作活动和癫痫发作次数以及持续改变的BDNF信号通路，这些通路会影响HFE点燃范式中的癫痫发作表型。因此，BDNF的长期升高可能部分导致癫痫发生过程和人类难治性癫痫的发展。
