Clinical Pharmacology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
Clinical Pharmacology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
Eur J Pharmacol. 2023 Sep 15;955:175916. doi: 10.1016/j.ejphar.2023.175916. Epub 2023 Jul 15.
Several reports indicate a plausible role of calcium (Ca) permeable AMPA glutamate receptors (with RNA hypo-editing at the GluA2 Q/R site) and the subsequent excitotoxicity-mediated neuronal death in the pathogenesis of a wide array of neurological disorders including autism spectrum disorder (ASD). This study was designed to examine the effects of chronic risperidone treatment on the expression of adenosine deaminase acting on RNA 2 (Adar2), the status of AMPA glutamate receptor GluA2 editing, and its effects on oxidative/nitrosative stress and excitotoxicity-mediated neuronal death in the prenatal valproic acid (VPA) rat model of ASD. Prenatal VPA exposure was associated with autistic-like behaviors accompanied by an increase in the apoptotic marker "caspase-3" and a decrease in the antiapoptotic marker "BCL2" alongside a reduction in the Adar2 relative gene expression and an increase in GluA2 Q:R ratio in the hippocampus and the prefrontal cortex. Risperidone, at doses of 1 and 3 mg, improved the VPA-induced behavioral deficits and enhanced the Adar2 relative gene expression and the subsequent GluA2 subunit editing. This was reflected on the cellular level where risperidone impeded VPA-induced oxidative/nitrosative stress and neurodegenerative changes. In conclusion, the present study confirms a possible role for Adar2 downregulation and the subsequent hypo-editing of the GluA2 subunit in the pathophysiology of the prenatal VPA rat model of autism and highlights the favorable effect of risperidone on reversing the RNA editing machinery deficits, giving insights into a new possible mechanism of risperidone in autism.
有几项报告表明，钙 (Ca) 通透性 AMPA 谷氨酸受体（在 GluA2 Q/R 位点 RNA 低编辑）及其随后的兴奋性毒性介导的神经元死亡在广泛的神经疾病发病机制中起重要作用，包括自闭症谱系障碍 (ASD)。本研究旨在研究慢性利培酮治疗对腺苷脱氨酶作用于 RNA 2 (Adar2) 的表达、AMPA 谷氨酸受体 GluA2 编辑的状态及其对氧化/硝化应激和兴奋性毒性介导的神经元死亡的影响在产前丙戊酸 (VPA) 大鼠 ASD 模型中的作用。产前 VPA 暴露与类似自闭症的行为有关，同时凋亡标志物“半胱天冬酶-3”增加，抗凋亡标志物“BCL2”减少，海马体和前额叶皮质中的 Adar2 相对基因表达减少，GluA2 Q:R 比值增加。利培酮的剂量为 1 和 3mg，可改善 VPA 引起的行为缺陷，增强 Adar2 相对基因表达和随后的 GluA2 亚基编辑。这反映在细胞水平上，利培酮抑制了 VPA 诱导的氧化/硝化应激和神经退行性变化。总之，本研究证实了 Adar2 下调和随后 GluA2 亚基低编辑在产前 VPA 大鼠自闭症模型发病机制中的可能作用，并强调了利培酮对逆转 RNA 编辑机制缺陷的有利影响，为利培酮在自闭症中的新可能机制提供了深入了解。
