Prenatal modulation of NADPH-oxidase reverses the deranged GABA switch and rescues behavioral deficits in valproate ASD rat model
IndroductionImpaired 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...
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Frontiers Media S.A.
2025-05-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1571008/full |
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| author | Basma A. Yasseen Hadeer Abdelkhalek Sara Gohar Sara Gohar Yasmin Hatem Hajar El-Sayed Aya A. Elkhodiry Aya Galal Aya Samir Aya Samir Nouran Al-Shehaby Malak W. Elbenhawi Rehab Hamdy Christine S. Prince Azza G. Kamel Mohamed A. Badawy Ghada F. Soliman Soha Aly ElMorsy Tamer M. Gamal El-Din Ebtehal El-Demerdash Ebtehal El-Demerdash Sameh S. Ali Engy A. Abdel-Rahman Engy A. Abdel-Rahman |
| author_facet | Basma A. Yasseen Hadeer Abdelkhalek Sara Gohar Sara Gohar Yasmin Hatem Hajar El-Sayed Aya A. Elkhodiry Aya Galal Aya Samir Aya Samir Nouran Al-Shehaby Malak W. Elbenhawi Rehab Hamdy Christine S. Prince Azza G. Kamel Mohamed A. Badawy Ghada F. Soliman Soha Aly ElMorsy Tamer M. Gamal El-Din Ebtehal El-Demerdash Ebtehal El-Demerdash Sameh S. Ali Engy A. Abdel-Rahman Engy A. Abdel-Rahman |
| author_sort | Basma A. Yasseen |
| collection | DOAJ |
| description | IndroductionImpaired 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.MethodsHere, 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.ResultsOur 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.DiscussionThese results suggest that targeting the NOX-ROS pathway may be a potential therapeutic strategy for ASD. |
| format | Article |
| id | doaj-art-2d416655d6c54048aa87b5eec532df15 |
| institution | DOAJ |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-2d416655d6c54048aa87b5eec532df152025-08-20T03:21:34ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-05-011610.3389/fphar.2025.15710081571008Prenatal modulation of NADPH-oxidase reverses the deranged GABA switch and rescues behavioral deficits in valproate ASD rat modelBasma A. Yasseen0Hadeer Abdelkhalek1Sara Gohar2Sara Gohar3Yasmin Hatem4Hajar El-Sayed5Aya A. Elkhodiry6Aya Galal7Aya Samir8Aya Samir9Nouran Al-Shehaby10Malak W. Elbenhawi11Rehab Hamdy12Christine S. Prince13Azza G. Kamel14Mohamed A. Badawy15Ghada F. Soliman16Soha Aly ElMorsy17Tamer M. Gamal El-Din18Ebtehal El-Demerdash19Ebtehal El-Demerdash20Sameh S. Ali21Engy A. Abdel-Rahman22Engy A. Abdel-Rahman23Tumor Biology Research Program, Research Department, Children’s Cancer Hospital Egypt, Cairo, EgyptTumor Biology Research Program, Research Department, Children’s Cancer Hospital Egypt, Cairo, EgyptTumor Biology Research Program, Research Department, Children’s Cancer Hospital Egypt, Cairo, EgyptCancer Research UK Scotland Institute, Glasgow, United KingdomTumor Biology Research Program, Research Department, Children’s Cancer Hospital Egypt, Cairo, EgyptTumor Biology Research Program, Research Department, Children’s Cancer Hospital Egypt, Cairo, EgyptTumor Biology Research Program, Research Department, Children’s Cancer Hospital Egypt, Cairo, EgyptPreclinical and Translational Research Center, Faculty of Pharmacy, Ain Shams University, Cairo, EgyptTumor Biology Research Program, Research Department, Children’s Cancer Hospital Egypt, Cairo, EgyptDepartment of Biotechnology, Faculty of Science, Cairo University, Cairo, EgyptTumor Biology Research Program, Research Department, Children’s Cancer Hospital Egypt, Cairo, EgyptTumor Biology Research Program, Research Department, Children’s Cancer Hospital Egypt, Cairo, EgyptTumor Biology Research Program, Research Department, Children’s Cancer Hospital Egypt, Cairo, EgyptTumor Biology Research Program, Research Department, Children’s Cancer Hospital Egypt, Cairo, EgyptTumor Biology Research Program, Research Department, Children’s Cancer Hospital Egypt, Cairo, EgyptTumor Biology Research Program, Research Department, Children’s Cancer Hospital Egypt, Cairo, EgyptDepartment of Medical Pharmacology, Faculty of Medicine, Cairo University, Cairo, EgyptDepartment of Medical Pharmacology, Faculty of Medicine, Cairo University, Cairo, EgyptDepartment of Pharmacology, University of Washington, Seattle, WA, United StatesPreclinical and Translational Research Center, Faculty of Pharmacy, Ain Shams University, Cairo, EgyptDepartment of Pharmacology, Faculty of Pharmacy, Ain-Shams University, Cairo, EgyptTumor Biology Research Program, Research Department, Children’s Cancer Hospital Egypt, Cairo, EgyptTumor Biology Research Program, Research Department, Children’s Cancer Hospital Egypt, Cairo, EgyptDepartment of Pharmacology, Faculty of Medicine, Assiut University, Assiut, EgyptIndroductionImpaired 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.MethodsHere, 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.ResultsOur 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.DiscussionThese results suggest that targeting the NOX-ROS pathway may be a potential therapeutic strategy for ASD.https://www.frontiersin.org/articles/10.3389/fphar.2025.1571008/fullASDGABA D/H switchsynaptosomesKCC2NOXshikonin |
| spellingShingle | Basma A. Yasseen Hadeer Abdelkhalek Sara Gohar Sara Gohar Yasmin Hatem Hajar El-Sayed Aya A. Elkhodiry Aya Galal Aya Samir Aya Samir Nouran Al-Shehaby Malak W. Elbenhawi Rehab Hamdy Christine S. Prince Azza G. Kamel Mohamed A. Badawy Ghada F. Soliman Soha Aly ElMorsy Tamer M. Gamal El-Din Ebtehal El-Demerdash Ebtehal El-Demerdash Sameh S. Ali Engy A. Abdel-Rahman Engy A. Abdel-Rahman Prenatal modulation of NADPH-oxidase reverses the deranged GABA switch and rescues behavioral deficits in valproate ASD rat model Frontiers in Pharmacology ASD GABA D/H switch synaptosomes KCC2 NOX shikonin |
| title | Prenatal modulation of NADPH-oxidase reverses the deranged GABA switch and rescues behavioral deficits in valproate ASD rat model |
| title_full | Prenatal modulation of NADPH-oxidase reverses the deranged GABA switch and rescues behavioral deficits in valproate ASD rat model |
| title_fullStr | Prenatal modulation of NADPH-oxidase reverses the deranged GABA switch and rescues behavioral deficits in valproate ASD rat model |
| title_full_unstemmed | Prenatal modulation of NADPH-oxidase reverses the deranged GABA switch and rescues behavioral deficits in valproate ASD rat model |
| title_short | Prenatal modulation of NADPH-oxidase reverses the deranged GABA switch and rescues behavioral deficits in valproate ASD rat model |
| title_sort | prenatal modulation of nadph oxidase reverses the deranged gaba switch and rescues behavioral deficits in valproate asd rat model |
| topic | ASD GABA D/H switch synaptosomes KCC2 NOX shikonin |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1571008/full |
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