Abnormal Rat Cortical Development Induced by Ventricular Injection of rHMGB1 Mimics the Pathophysiology of Human Cortical Dysplasia.
Abnormal Rat Cortical Development Induced by Ventricular Injection of rHMGB1 Mimics the Pathophysiology of Human Cortical Dysplasia.
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脑室注射rHMGB1诱导大鼠皮质发育异常，模拟人类皮质发育不良的病理生理学
DOI：
10.3389/fcell.2021.634405
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发表时间：
2021
影响因子：
5.5
通讯作者：
Liu S
中科院分区：
文献类型：
--
作者：
Yang X;Zhang X;Ma Y;Wang Z;Huang K;Liu G;Shen K;Zhu G;Wang T;Lv S;Zhang C;Yang H;Liu S
皮质发育不良（CD）是耐药性癫痫的常见原因。越来越多的研究表明先天免疫与 CD 合并癫痫有关。然而，目前尚不清楚先天免疫因素是否会诱发癫痫性 CD。在这里，我们将重组人高迁移率族蛋白1（rHMGB1）注射到胚胎大鼠心室中，以确定rHMGB1是否可以诱导具有与人类CD相似的病理生理特征的致癫痫性CD。与对照组和0.1 μg rHMGB1处理组大鼠相比，0.2 μg rHMGB1处理组大鼠皮质组织严重破坏，并出现小脑回和异位；此外，在皮质病变和异位中观察到迷失方向和变形的神经元。 0.2 μg rHMGB1 治疗的大鼠的白质和灰白交界处出现皮质下异位。此外，皮层病变的 V-VI 层神经元数量减少，I 层和 V 层星形胶质细胞数量增加。 HMGB1拮抗剂右美托咪定减轻了rHMGB1引起的变化。此外，我们发现给予rHMGB1后TLR4和NF-κB增加。此外，与对照组相比，0.2 μg rHMGB1 治疗组大鼠的兴奋性受体、N-甲基-D-天冬氨酸受体 1 (NR1)、2A (NR2A) 和 2B (NR2B) 免疫反应性增加，兴奋性氨基酸转运蛋白 1 (EAAT1) 和 2 (EAAT2) 免疫反应性降低。而两组之间的谷氨酸脱羧酶65/67（GAD65/67）免疫反应性没有差异。这些结果表明皮质病变的兴奋显着增加。此外，脑电图（EEG）显示，0.2μg rHMGB1治疗的大鼠癫痫发作潜伏期较短，癫痫持续状态发生率较高。治疗组大鼠的脑电图频率和振幅均高于对照组。有趣的是，在 5 个月大后，在 0.2 μg rHMGB1 治疗的大鼠中检测到自发电图癫痫放电，并且大约 8 Hz 的尖波放电是整个大脑皮层中最显着增加的同步传播波。总而言之，这些发现表明，怀孕期间暴露 rHMGB1 可能有助于致癫痫性 CD 的发展，其模仿了人类 CD 的一些病理生理学特征。
Cortical dysplasia (CD) is a common cause of drug-resistant epilepsy. Increasing studies have implicated innate immunity in CD with epilepsy. However, it is unclear whether innate immune factors induce epileptogenic CD. Here, we injected recombinant human high mobility group box 1 (rHMGB1) into embryonic rat ventricles to determine whether rHMGB1 can induce epileptogenic CD with pathophysiological characteristics similar to those of human CD. Compared with controls and 0.1 μg rHMGB1-treated rats, the cortical organization was severely disrupted in the 0.2 μg rHMGB1-treated rats, and microgyria and heterotopia also emerged; additionally, disoriented and deformed neurons were observed in the cortical lesions and heterotopias. Subcortical heterotopia appeared in the white matter and the gray–white junction of the 0.2 μg rHMGB1-treated rats. Moreover, there was decreased number of neurons in layer V–VI and an increased number of astrocytes in layer I and V of the cortical lesions. And the HMGB1 antagonist dexmedetomidine alleviated the changes induced by rHMGB1. Further, we found that TLR4 and NF-κB were increased after rHMGB1 administration. In addition, the excitatory receptors, N-methyl-D-aspartate receptor 1 (NR1), 2A (NR2A), and 2B (NR2B) immunoreactivity were increased, and immunoreactivity of excitatory amino acid transporter 1 (EAAT1) and 2 (EAAT2) were reduced in 0.2 μg rHMGB1-treated rats compared with controls. While there were no differences in the glutamic acid decarboxylase 65/67 (GAD65/67) immunoreactivity between the two groups. These results indicate that the excitation of cortical lesions was significantly increased. Furthermore, electroencephalogram (EEG) showed a shorter latency of seizure onset and a higher incidence of status epilepticus in the 0.2 μg rHMGB1-treated rats; the frequency and amplitude of EEG were higher in the treated rats than controls. Intriguingly, spontaneous electrographic seizure discharges were detected in the 0.2 μg rHMGB1-treated rats after 5 months of age, and spike-wave discharges of approximately 8 Hz were the most significantly increased synchronous propagated waves throughout the general brain cortex. Taken together, these findings indicate that rHMGB1 exposure during pregnancy could contribute to the development of epileptogenic CD, which mimicked some pathophysiological characteristics of human CD.
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影响因子：
6.1
作者：
Cepeda, Carlos;Levinson, Simon;Wu, Joyce Y.
通讯作者：
Wu, Joyce Y.
DOI：
10.1177/0300060518781382
发表时间：
2018-07
期刊：
The Journal of international medical research
影响因子：
--
作者：
Cheng J;Zhu P;Qin H;Li X;Yu H;Yu H;Peng X
通讯作者：
Peng X
影响因子：
12.7
作者：
Finardi, Adele;Colciaghi, Francesca;Battaglia, Giorgio Stefano
通讯作者：
Battaglia, Giorgio Stefano
影响因子：
9.8
作者：
Lim, Jae Seok;Gopalappa, Ramu;Lee, Jeong Ho
通讯作者：
Lee, Jeong Ho
影响因子：
5.3
作者：
Meneghini, Vasco;Bortolotto, Valeria;Grilli, Mariagrazia
通讯作者：
Grilli, Mariagrazia