产前对烟酰胺腺嘌呤二核苷酸磷酸氧化酶的调节可逆转丙戊酸自闭症谱系障碍大鼠模型中紊乱的γ-氨基丁酸转换，并挽救行为缺陷。

Prenatal modulation of NADPH-oxidase reverses the deranged GABA switch and rescues behavioral deficits in valproate ASD rat model.

作者信息

Yasseen Basma A, Abdelkhalek Hadeer, Gohar Sara, Hatem Yasmin, El-Sayed Hajar, Elkhodiry Aya A, Galal Aya, Samir Aya, Al-Shehaby Nouran, Elbenhawi Malak W, Hamdy Rehab, Prince Christine S, Kamel Azza G, Badawy Mohamed A, Soliman Ghada F, ElMorsy Soha Aly, Gamal El-Din Tamer M, El-Demerdash Ebtehal, Ali Sameh S, Abdel-Rahman Engy A

机构信息

Tumor Biology Research Program, Research Department, Children's Cancer Hospital Egypt, Cairo, Egypt.

Cancer Research UK Scotland Institute, Glasgow, United Kingdom.

出版信息

Front Pharmacol. 2025 May 30;16:1571008. doi: 10.3389/fphar.2025.1571008. eCollection 2025.

DOI:10.3389/fphar.2025.1571008

PMID:40520207

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12162577/

Abstract

INDRODUCTION

Impaired depolarizing-to-hyperpolarizing (D/H) switch of gamma-aminobutyric acid (GABA) is reported during brain development in rodent valproate-model of autism spectrum disorder (VPA-ASD). We hypothesize that this impairment triggers NADPH oxidases (NOXs)-induced reactive oxygen species (ROS) overproduction.

METHODS

Here, we followed the impact of prenatal exposure to VPA on the synaptic protein expression of potassium chloride cotransporter 2 (KCC2), sodium potassium chloride cotransporter 1 (NKCC1) and, in brains of male and female Wistar rats during infantile (P15), juvenile (P30) and adult (P60) stages. We also assessed alterations in synaptic NOX isoforms 2 and 4 (NOX2 and NOX4) activities and expressions in developing rat brains.

RESULTS

Our findings revealed a significant reduction in KCC2 expression and a concomitant increase in NOX activity and NOX4 expression in synaptosomes of VPA-exposed rats, particularly at P15 and P30. Prenatal exposure to shikonin, (10 mg/kg/day, intraperitoneal (i.p.) into pregnant dam, daily from G12.5 until birth), ameliorated these effects by reducing synaptic protein expression of NOX4, generally quenched synaptic NOX activity and enhanced synaptic protein expression of KCC2. Indeed, shikonin reversed VPA-induced sociability deficits in ASD rats.

DISCUSSION

These results suggest that targeting the NOX-ROS pathway may be a potential therapeutic strategy for ASD.

摘要

引言

在啮齿动物自闭症谱系障碍丙戊酸盐模型（VPA-ASD）的大脑发育过程中，γ-氨基丁酸（GABA）从去极化到超极化（D/H）转换受损。我们假设这种损伤会触发NADPH氧化酶（NOXs）诱导的活性氧（ROS）过量产生。

方法

在此，我们追踪了产前暴露于丙戊酸对雄性和雌性Wistar大鼠在婴儿期（P15）、幼年期（P30）和成年期（P60）大脑中氯化钾共转运体2（KCC2）、氯化钠共转运体1（NKCC1）突触蛋白表达的影响。我们还评估了发育中大鼠大脑中突触NOX亚型2和4（NOX2和NOX4）活性和表达的变化。

结果

我们的研究结果显示，暴露于丙戊酸的大鼠突触体中KCC2表达显著降低，同时NOX活性和NOX4表达增加，尤其是在P15和P30时。产前给予紫草素（10mg/kg/天，腹腔注射至怀孕母鼠，从G12.5开始每天一次直至出生），通过降低NOX4的突触蛋白表达、普遍抑制突触NOX活性并增强KCC2的突触蛋白表达，改善了这些影响。事实上，紫草素逆转了ASD大鼠中VPA诱导的社交缺陷。