Comparative effect of atorvastatin and risperidone on modulation of TLR4/NF-κB/NOX-2 in a rat model of valproic acid-induced autism
Abstract Background Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is significantly increasing, resulting in severe distress. The approved treatment for ASD only partially improves the sympoms, but it does not entirely reverse the symptoms. Developing novel disease-mod...
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BMC
2024-09-01
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| Series: | Behavioral and Brain Functions |
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| Online Access: | https://doi.org/10.1186/s12993-024-00250-1 |
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| author | Eman A. E. Farrag Mona H. Askar Zienab Abdallah Safinaz M. Mahmoud Eman A. Abdulhai Eman Abdelrazik Eman Mohamad El Nashar Faten Mohammed Alasiri Asma Nasser Saeed Alqahtani Mamdouh Eldesoqui Ali M. Eldib Alshimaa Magdy |
| author_facet | Eman A. E. Farrag Mona H. Askar Zienab Abdallah Safinaz M. Mahmoud Eman A. Abdulhai Eman Abdelrazik Eman Mohamad El Nashar Faten Mohammed Alasiri Asma Nasser Saeed Alqahtani Mamdouh Eldesoqui Ali M. Eldib Alshimaa Magdy |
| author_sort | Eman A. E. Farrag |
| collection | DOAJ |
| description | Abstract Background Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is significantly increasing, resulting in severe distress. The approved treatment for ASD only partially improves the sympoms, but it does not entirely reverse the symptoms. Developing novel disease-modifying drugs is essential for the continuous improvement of ASD. Because of its pleiotropic effect, atorvastatin has been garnered attention for treating neuronal degeneration. The present study aimed to investigate the therapeutic effects of atorvastatin in autism and compare it with an approved autism drug (risperidone) through the impact of these drugs on TLR4/NF-κB/NOX-2 and the apoptotic pathway in a valproic acid (VPA) induced rat model of autism. Methods On gestational day 12.5, pregnant rats received a single IP injection of VPA (500 mg/kg), for VPA induced autism, risperidone and atorvastatin groups, or saline for control normal group. At postnatal day 21, male offsprings were randomly divided into four groups (n = 6): control, VPA induced autism, risperidone, and atorvastatin. Risperidone and atorvastatin were administered from postnatal day 21 to day 51. The study evaluated autism-like behaviors using the three-chamber test, the dark light test, and the open field test at the end of the study. Biochemical analysis of TLR4, NF-κB, NOX-2, and ROS using ELISA, RT-PCR, WB, histological examination with hematoxylin and eosin and immunohistochemical study of CAS-3 were performed. Results Male offspring of prenatal VPA-exposed female rats exhibited significant autism-like behaviors and elevated TLR4, NF-κB, NOX-2, ROS, and caspase-3 expression. Histological analysis revealed structural alterations. Both risperidone and atorvastatin effectively mitigated the behavioral, biochemical, and structural changes associated with VPA-induced rat model of autism. Notably, atorvastatin group showed a more significant improvement than risperidone group. Conclusions The research results unequivocally demonstrated that atorvastatin can modulate VPA-induced autism by suppressing inflammation, oxidative stress, and apoptosis through TLR4/NF-κB/NOX-2 signaling pathway. Atorvastatin could be a potential treatment for ASD. Graphical Abstract |
| format | Article |
| id | doaj-art-17798aeae1c64d59be7712322f04f615 |
| institution | Kabale University |
| issn | 1744-9081 |
| language | English |
| publishDate | 2024-09-01 |
| publisher | BMC |
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| series | Behavioral and Brain Functions |
| spelling | doaj-art-17798aeae1c64d59be7712322f04f6152025-01-19T12:33:16ZengBMCBehavioral and Brain Functions1744-90812024-09-0120112010.1186/s12993-024-00250-1Comparative effect of atorvastatin and risperidone on modulation of TLR4/NF-κB/NOX-2 in a rat model of valproic acid-induced autismEman A. E. Farrag0Mona H. Askar1Zienab Abdallah2Safinaz M. Mahmoud3Eman A. Abdulhai4Eman Abdelrazik5Eman Mohamad El Nashar6Faten Mohammed Alasiri7Asma Nasser Saeed Alqahtani8Mamdouh Eldesoqui9Ali M. Eldib10Alshimaa Magdy11Department of Clinical Pharmacology, Faculty of Medicine, Mansoura UniversityDepartment of Medical Physiology, Faculty of Medicine, Mansoura UniversityDepartment of Medical Physiology, Faculty of Medicine, Mansoura UniversityDepartment of Medical Histology and Cell Biology, Faculty of Medicine, Mansoura UniversityDepartment of Pediatrics, Faculty of Medicine, Mansoura, UniversityDepartment of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Mansoura UniversityDepartment of Anatomy, College of Medicine, King Khalid UniversityKing Fahad Armed Forces HospitalBin Rushed CenterDepartment of Basic Medical Sciences, College of Medicine, AlMaarefa UniversityDepartment of Zoology, Faculty of Science, Damanhour UniversityDepartment of Medical Biochemistry, Faculty of Medicine, Mansoura UniversityAbstract Background Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is significantly increasing, resulting in severe distress. The approved treatment for ASD only partially improves the sympoms, but it does not entirely reverse the symptoms. Developing novel disease-modifying drugs is essential for the continuous improvement of ASD. Because of its pleiotropic effect, atorvastatin has been garnered attention for treating neuronal degeneration. The present study aimed to investigate the therapeutic effects of atorvastatin in autism and compare it with an approved autism drug (risperidone) through the impact of these drugs on TLR4/NF-κB/NOX-2 and the apoptotic pathway in a valproic acid (VPA) induced rat model of autism. Methods On gestational day 12.5, pregnant rats received a single IP injection of VPA (500 mg/kg), for VPA induced autism, risperidone and atorvastatin groups, or saline for control normal group. At postnatal day 21, male offsprings were randomly divided into four groups (n = 6): control, VPA induced autism, risperidone, and atorvastatin. Risperidone and atorvastatin were administered from postnatal day 21 to day 51. The study evaluated autism-like behaviors using the three-chamber test, the dark light test, and the open field test at the end of the study. Biochemical analysis of TLR4, NF-κB, NOX-2, and ROS using ELISA, RT-PCR, WB, histological examination with hematoxylin and eosin and immunohistochemical study of CAS-3 were performed. Results Male offspring of prenatal VPA-exposed female rats exhibited significant autism-like behaviors and elevated TLR4, NF-κB, NOX-2, ROS, and caspase-3 expression. Histological analysis revealed structural alterations. Both risperidone and atorvastatin effectively mitigated the behavioral, biochemical, and structural changes associated with VPA-induced rat model of autism. Notably, atorvastatin group showed a more significant improvement than risperidone group. Conclusions The research results unequivocally demonstrated that atorvastatin can modulate VPA-induced autism by suppressing inflammation, oxidative stress, and apoptosis through TLR4/NF-κB/NOX-2 signaling pathway. Atorvastatin could be a potential treatment for ASD. Graphical Abstracthttps://doi.org/10.1186/s12993-024-00250-1Valproic acidAutismAtorvastatinRisperidoneTLR4NF-κB |
| spellingShingle | Eman A. E. Farrag Mona H. Askar Zienab Abdallah Safinaz M. Mahmoud Eman A. Abdulhai Eman Abdelrazik Eman Mohamad El Nashar Faten Mohammed Alasiri Asma Nasser Saeed Alqahtani Mamdouh Eldesoqui Ali M. Eldib Alshimaa Magdy Comparative effect of atorvastatin and risperidone on modulation of TLR4/NF-κB/NOX-2 in a rat model of valproic acid-induced autism Behavioral and Brain Functions Valproic acid Autism Atorvastatin Risperidone TLR4 NF-κB |
| title | Comparative effect of atorvastatin and risperidone on modulation of TLR4/NF-κB/NOX-2 in a rat model of valproic acid-induced autism |
| title_full | Comparative effect of atorvastatin and risperidone on modulation of TLR4/NF-κB/NOX-2 in a rat model of valproic acid-induced autism |
| title_fullStr | Comparative effect of atorvastatin and risperidone on modulation of TLR4/NF-κB/NOX-2 in a rat model of valproic acid-induced autism |
| title_full_unstemmed | Comparative effect of atorvastatin and risperidone on modulation of TLR4/NF-κB/NOX-2 in a rat model of valproic acid-induced autism |
| title_short | Comparative effect of atorvastatin and risperidone on modulation of TLR4/NF-κB/NOX-2 in a rat model of valproic acid-induced autism |
| title_sort | comparative effect of atorvastatin and risperidone on modulation of tlr4 nf κb nox 2 in a rat model of valproic acid induced autism |
| topic | Valproic acid Autism Atorvastatin Risperidone TLR4 NF-κB |
| url | https://doi.org/10.1186/s12993-024-00250-1 |
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