Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del IPN (Cinvestav), Unidad Sede Sur, Ciudad de Mexico, Mexico.
Laboratorio de Neurofarmacología Molecular y Nanotecnología, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City, Mexico.
J Neurochem. 2022 Jan;160(2):256-270. doi: 10.1111/jnc.15527. Epub 2021 Oct 31.
Huntington´s disease (HD) is a pathological condition that can be studied in mice by the administration of quinolinic acid (QUIN), an agonist of the N-methyl-d-aspartate receptor (NMDAR) that induces NMDAR-mediated cytotoxicity and neuroinflammation. Mast cells (MCs) participate in numerous inflammatory processes through the release of important amounts of histamine (HA). In this study, we aimed to characterize the participation of MCs and HA in the establishment of neural and oxidative damage in the QUIN-induced model of HD. C57BL6/J mice (WT), MC-deficient c-Kit (Wsh) mice and Wsh mice reconstituted by intracerebroventricular (i.c.v.) injection of 5 × 10 bone marrow-derived mast cells (BMMCs), or i.c.v. administered with HA (5 µg) were used. All groups of animals were intrastriatally injected with 1 µL QUIN (30 nmol/µL) and 3 days later, apomorphine-induced circling behavior, striatal GABA levels and the number of Fluoro-Jade positive cells, as indicators of neuronal damage, were determined. Also, lipid peroxidation (LP) and reactive oxygen species production (ROS), as markers of oxidative damage, were analyzed. Wsh mice showed less QUIN-induced neuronal and oxidative damage than WT and Wsh-MC reconstituted animals. Histamine administration restored the QUIN-induced neuronal and oxidative damage in the non-reconstituted Wsh mice to levels equivalent or superior to those observed in WT mice. Our results demonstrate that MCs and HA participate in the neuronal and oxidative damages observed in mice subjected to the QUIN -induced model of Huntington's disease.
亨廷顿病（HD）是一种可以通过给予喹啉酸（QUIN）来在小鼠中研究的病理状况，QUIN 是 N-甲基-D-天冬氨酸受体（NMDAR）的激动剂，可诱导 NMDAR 介导的细胞毒性和神经炎症。肥大细胞（MCs）通过释放大量组胺（HA）参与许多炎症过程。在这项研究中，我们旨在表征 MCs 和 HA 在 QUIN 诱导的 HD 模型中建立神经和氧化损伤中的作用。使用 C57BL6/J 小鼠（WT）、MC 缺陷 c-Kit（Wsh）小鼠和通过脑室内（i.c.v.）注射 5×10 个骨髓来源的肥大细胞（BMMCs）或 i.c.v. 给予 HA（5µg）重建的 Wsh 小鼠。所有动物组均接受纹状体注射 1µL QUIN（30nmol/µL），3 天后，通过阿扑吗啡诱导的旋转行为、纹状体 GABA 水平和氟-Jade 阳性细胞数量（作为神经元损伤的指标）来确定。还分析了脂质过氧化（LP）和活性氧（ROS）的产生（作为氧化损伤的标志物）。与 WT 和 Wsh-MC 重建动物相比，Wsh 小鼠的 QUIN 诱导的神经元和氧化损伤较少。给予组胺可将非重建的 Wsh 小鼠的 QUIN 诱导的神经元和氧化损伤恢复到与 WT 小鼠相当或更高的水平。我们的结果表明，MCs 和 HA 参与了接受 QUIN 诱导的亨廷顿病模型的小鼠中观察到的神经元和氧化损伤。
