Comparative effect of atorvastatin and risperidone on modulation of TLR4/NF-κB/NOX-2 in a rat model of valproic acid-induced autism.

IF 4.7 2区 心理学 Q1 BEHAVIORAL SCIENCES Behavioral and Brain Functions Pub Date : 2024-09-30 DOI:10.1186/s12993-024-00250-1
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
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引用次数: 0

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.

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阿托伐他汀和利培酮对丙戊酸诱发自闭症大鼠模型中TLR4/NF-κB/NOX-2调节作用的比较研究
背景:自闭症谱系障碍(ASD)是一种复杂的神经发育疾病,发病率显著上升,导致严重的痛苦。已获批准的 ASD 治疗方法只能部分改善症状,但不能完全逆转症状。开发新型疾病调节药物对于持续改善 ASD 至关重要。阿托伐他汀具有多重效应,因此在治疗神经元变性方面备受关注。本研究旨在通过丙戊酸(VPA)诱导的自闭症大鼠模型中阿托伐他汀对TLR4/NF-κB/NOX-2和细胞凋亡途径的影响,研究阿托伐他汀对自闭症的治疗效果,并将其与已获批的自闭症药物(利培酮)进行比较:在妊娠第12.5天,妊娠大鼠接受单次VPA(500 mg/kg)IP注射(VPA诱导自闭症组)、利培酮组和阿托伐他汀组;或接受生理盐水注射(正常对照组)。在出生后第 21 天,雄性后代被随机分为四组(n = 6):对照组、VPA 诱导自闭症组、利培酮组和阿托伐他汀组。利培酮和阿托伐他汀在出生后第 21 天至第 51 天期间给药。研究使用三腔试验、暗光试验和研究结束时的开阔地试验对类似自闭症的行为进行评估。研究还使用 ELISA、RT-PCR、WB 对 TLR4、NF-κB、NOX-2 和 ROS 进行了生化分析,使用苏木精和伊红进行了组织学检查,并对 CAS-3 进行了免疫组化研究:结果:产前暴露于 VPA 的雌性大鼠的雄性后代表现出明显的自闭症样行为,TLR4、NF-κB、NOX-2、ROS 和 caspase-3 表达升高。组织学分析显示大鼠的结构发生了改变。利培酮和阿托伐他汀都能有效缓解与VPA诱导的大鼠自闭症模型相关的行为、生化和结构变化。值得注意的是,阿托伐他汀组比利培酮组有更明显的改善:研究结果明确表明,阿托伐他汀可通过TLR4/NF-κB/NOX-2信号通路抑制炎症、氧化应激和细胞凋亡,从而调节VPA诱导的自闭症。阿托伐他汀可能是一种治疗自闭症的潜在药物。
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来源期刊
Behavioral and Brain Functions
Behavioral and Brain Functions 医学-行为科学
CiteScore
5.90
自引率
0.00%
发文量
11
审稿时长
6-12 weeks
期刊介绍: A well-established journal in the field of behavioral and cognitive neuroscience, Behavioral and Brain Functions welcomes manuscripts which provide insight into the neurobiological mechanisms underlying behavior and brain function, or dysfunction. The journal gives priority to manuscripts that combine both neurobiology and behavior in a non-clinical manner.
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