Journal of Evolutionary Biochemistry and Physiology ( IF 0.6 ) Pub Date : 2021-05-06 , DOI: 10.1134/s0022093021020125 A. A. Kulikov , E. V. Nasluzova , N. A. Dorofeeva , M. V. Glazova , E. A. Lavrova , E. V. Chernigovskaya
Abstract
One of the main challenges of modern neurobiology is finding approaches to prevent structural abnormalities in the brain, specifically, in the hippocampus affected by epileptic activity. It is well known that epilepsy leads to an increase in proliferation in the hippocampal neurogenic niche, the subgranular layer of the dentate gyrus. In the recent years, there is a prevalent idea that newborn neural cells contribute to epileptogenesis to a larger extent than prevent neurodegenerative disorders associated with increased cell death. We hypothesized that a proapoptotic protein p53 can be one of the possible therapeutic targets in treating epilepsy and its neurodegenerative consequences. In the present work, we used the Krushinsky–Molodkina (KM) inbred rats, which are genetically prone to audiogenic seizures (AGS). Audiogenic kindling, a commonly accepted model of epileptogenesis, induces epileptiform activity in the limbic system and cerebral cortex. In KM rats, it has been shown that 4 AGS lead to an increase in proliferation, aberrant migration of newborn cells to the hilus, and accelerated neural differentiation of these cells. We revealed abnormalities neither in apoptosis nor in autophagy levels at the initial stages of temporal lobe (limbic) epilepsy. Treatment with pifithrin-α, a chemical p53 inhibitor, did not change apoptosis and autophagy levels but caused an increase in proliferation and migration of newborn cells to the granule cell layer of the dentate gyrus and to the hilus. However, a week after the last seizure, p53 inactivation entailed a decrease in the number of differentiating cells, as compared to the vehicle control group, despite a significant increase in the number of newborn cells. These data indicate a decrease in the neural differentiation rate of newborn cells, thus allowing pifitrin-α to be considered as a potential therapeutic agent to alleviate neurodegenerative disorders in epilepsy.
中文翻译:
Pifithrin-α在Krushinsky-Molodkina大鼠品系的成因点燃初期抑制齿状回齿状亚区新生细胞的神经分化
摘要
现代神经生物学的主要挑战之一是找到预防脑部结构异常的方法,特别是预防受到癫痫活动影响的海马结构异常的方法。众所周知,癫痫会导致海马神经源性小生境(齿状回的亚颗粒层)增殖增加。近年来,有一个普遍的想法是,新生神经细胞比预防与细胞死亡增加相关的神经退行性疾病更大程度地促进了癫痫的发生。我们假设凋亡蛋白p53可能是治疗癫痫及其神经退行性后果的可能治疗靶标之一。在当前的工作中,我们使用了Krushinsky-Molodkina(KM)自交系大鼠,它们在基因上容易发生音源性癫痫发作(AGS)。音源点燃,癫痫发生的一种普遍接受的模型,在边缘系统和大脑皮层中诱导癫痫样活动。在KM大鼠中,已显示4 AGS导致增殖增加,新生细胞异常转移到hilus并加速这些细胞的神经分化。我们揭示了颞叶(边缘)癫痫发作初期细胞凋亡和自噬水平均未见异常。使用p53的化学抑制剂pifithrin-α的治疗不会改变细胞凋亡和自噬水平,但会导致新生细胞向齿状回的颗粒细胞层和hilus的增殖和迁移增加。但是,在最后一次癫痫发作后的一周,与媒介物对照组相比,p53失活导致分化细胞数量减少,尽管新生细胞数量显着增加。这些数据表明新生细胞的神经分化速率降低,因此使匹菲特林-α被认为是缓解癫痫性神经退行性疾病的潜在治疗剂。