Bengzon J, Kokaia Z, Ernfors P, Kokaia M, Leanza G, Nilsson O G, Persson H, Lindvall O
Department of Neurology, University Hospital, Lund, Sweden.
Neuroscience. 1993 Mar;53(2):433-46. doi: 10.1016/0306-4522(93)90207-v.
Levels of messenger RNA for nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and the tyrosine kinase receptors trkA, trkB and trkC have been studied using in situ hybridization in the rat brain 2 h and four weeks after kindling-induced seizures. Epileptiform activity evoked by hippocampal stimulation and exceeding 70 s lead to a concomitant and transient increase of brain- derived neurotrophic factor, nerve growth factor, trkB and trkC messenger RNA expression in dentate granule cells after both focal and generalized seizures. Brain-derived neurotrophic factor messenger RNA levels were also increased bilaterally in the CA1-CA3 regions, amygdala and the piriform, entorhinal, perirhinal, retrosplenial and temporal cortices after generalized seizures. The magnitude of the increases was similar throughout the development of kindling and in the fully kindled brain. No changes of trkA messenger RNA were observed. In amygdalar kindling, elevated brain-derived neurotrophic factor messenger RNA levels developed more rapidly in the amygdala-piriform cortex than after stimulation in the hippocampus but changes in the hippocampal formation were only seen in few animals. Intraventricular 6-hydroxydopamine or a bilateral fimbria-fornix lesion did not alter basal expression or seizure-evoked changes in messenger RNA levels for neurotrophins or trk receptors but increased the number of animals exhibiting elevated levels after the first stimulation, probably due to a prolongation of seizure activity. Both in sham-operated and fimbria-fornix-lesioned rats seizure activity caused a marked reduction of neurotrophin-3 messenger RNA levels in dentate granule cells. The results indicate that activation of the brain-derived neurotrophic factor gene, at least in dentate granule cells, is an "all-or-none" type of response and dependent on the duration but not the severity of seizures or the stage of kindling epileptogenesis. Changes in brain-derived neurotrophic factor, nerve growth factor, neurotrophin-3 and trkB and trkC were observed concomitantly in the dentate gyrus, which suggests that seizure activity sets in motion a cascade of genomic events possibly mediated via a common mechanism. Since altered messenger RNA levels outside hippocampus were detected only for brain-derived neurotrophic factor, neurotrophin and trk gene expression in these regions seems to be regulated differently.
利用原位杂交技术，研究了点燃诱导的癫痫发作后2小时和四周大鼠大脑中神经生长因子、脑源性神经营养因子、神经营养素-3以及酪氨酸激酶受体trkA、trkB和trkC的信使核糖核酸水平。海马刺激诱发的癫痫样活动持续超过70秒，在局灶性和全身性癫痫发作后，齿状颗粒细胞中脑源性神经营养因子、神经生长因子、trkB和trkC信使核糖核酸表达会伴随性短暂增加。全身性癫痫发作后，脑源性神经营养因子信使核糖核酸水平在CA1-CA3区域、杏仁核以及梨状、内嗅、嗅周、压后和颞叶皮质双侧也会升高。在点燃发展过程和完全点燃的大脑中，升高幅度相似。未观察到trkA信使核糖核酸的变化。在杏仁核点燃中，脑源性神经营养因子信使核糖核酸水平在杏仁核-梨状皮质比海马刺激后升高得更快，但海马结构的变化仅在少数动物中可见。脑室内注射6-羟基多巴胺或双侧穹窿海马伞损伤并未改变神经营养因子或trk受体信使核糖核酸水平的基础表达或癫痫发作诱发的变化，但增加了首次刺激后信使核糖核酸水平升高的动物数量，这可能是由于癫痫活动延长所致。在假手术和穹窿海马伞损伤的大鼠中，癫痫活动均导致齿状颗粒细胞中神经营养素-3信使核糖核酸水平显著降低。结果表明，脑源性神经营养因子基因的激活，至少在齿状颗粒细胞中，是一种“全或无”类型的反应，取决于癫痫发作的持续时间而非严重程度或点燃癫痫发生的阶段。在齿状回中同时观察到脑源性神经营养因子、神经生长因子、神经营养素-3以及trkB和trkC的变化，这表明癫痫活动启动了一系列可能通过共同机制介导的基因组事件。由于仅在海马体外检测到脑源性神经营养因子信使核糖核酸水平的改变，这些区域中神经营养素和trk基因的表达似乎受到不同的调节。
