Sendrowski Krzysztof, Sobaniec Wojciech, Sobaniec Piotr, Sobaniec-Lotowska Maria E
Department of Pediatric Neurology and Rehabilitation, Medical University of Bialystok, Waszyngtona St. 17, Bialystok, Poland.
Folia Histochem Cytobiol. 2013;51(1):31-7. doi: 10.5603/FHC.2013.005.
Valproate (VPA) is a widely used antiepileptic drug. A serious neurological-outcome defined as valproate encephalopathy (VE) may rarely occur during VPA therapy. Structural abnormalities within neurons are postulated as one of the reasons for VE. The aim of this study was to assess the ultrastructure of neurons in the hippocampal cortex during the course of chronic application of VPA to rats. VPA was chronically administered to rats, intragastrically, once daily at a dose of 200 mg/kg b.w. for 1, 3, 6, 9 and 12 months. The samples of hippocampal cortex, after routine laboratory preparation, were examined by electron microscopy. The drug induced pronounced ultrastructural changes in the population of pyramidal neurons within the hippocampal cortex after 9 and 12 months of VPA administration. The most expressed abnormalities were observed within the mitochondria and manifested by fragmentation of crests and almost complete disappearance of intramitochondrial granules. Mitochondria of numerous neurons resembled large vacuolar structures. Widening, shortening and irregular distribution of rough endoplasmic reticulum was also found. A characteristic feature of damaged neurocytes in the last two phases of the experiment was the disintegration of nuclear chromatin and the presence of numerous lipofuscin deposits within hyaloplasm. These cells assumed the look of "dark neurons" and presented the ultrastructural features of apoptosis and necrosis. Our results indicate that long-term VPA administration to rats leads to aponecrosis of hippocampal neurons.
丙戊酸盐（VPA）是一种广泛使用的抗癫痫药物。在VPA治疗期间，可能很少会出现一种被定义为丙戊酸盐脑病（VE）的严重神经学后果。神经元内的结构异常被认为是VE的原因之一。本研究的目的是评估在对大鼠长期应用VPA的过程中，海马皮质中神经元的超微结构。以200mg/kg体重的剂量，每天一次通过胃内给药的方式对大鼠长期给予VPA，持续1、3、6、9和12个月。在经过常规实验室制备后，通过电子显微镜检查海马皮质样本。在给予VPA 9个月和12个月后，该药物在海马皮质锥体细胞群体中引起了明显的超微结构变化。最明显的异常出现在线粒体中，表现为嵴的断裂和线粒体内颗粒几乎完全消失。许多神经元的线粒体类似大的空泡结构。还发现粗面内质网增宽、缩短和分布不规则。在实验的最后两个阶段，受损神经细胞的一个特征是核染色质解体以及透明质质内存在大量脂褐素沉积。这些细胞呈现出“暗神经元”的外观，并表现出凋亡和坏死的超微结构特征。我们的结果表明，对大鼠长期给予VPA会导致海马神经元的凋亡性坏死。
