阿托伐他汀和利培酮对丙戊酸诱导自闭症大鼠 TLR4/NF-κB/NOX-2 调节的比较作用。
Comparative effect of atorvastatin and risperidone on modulation of TLR4/NF-κB/NOX-2 in a rat model of valproic acid-induced autism.
机构信息
Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, 31516, Egypt.
Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
出版信息
Behav Brain Funct. 2024 Sep 30;20(1):26. doi: 10.1186/s12993-024-00250-1.
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.
背景
自闭症谱系障碍（ASD）是一种复杂的神经发育疾病，其发病率显著增加，导致严重的痛苦。目前批准的 ASD 治疗方法仅部分改善症状，但不能完全逆转症状。开发新型疾病修饰药物对于 ASD 的持续改善至关重要。由于阿托伐他汀具有多效性，因此它已被用于治疗神经元退行性变。本研究旨在通过这些药物对 TLR4/NF-κB/NOX-2 和凋亡通路的影响，研究阿托伐他汀在自闭症中的治疗作用，并将其与一种已批准的自闭症药物（利培酮）进行比较，在丙戊酸（VPA）诱导的自闭症大鼠模型中。
方法
在妊娠第 12.5 天，给孕鼠单次腹腔注射 VPA（500mg/kg），用于 VPA 诱导的自闭症、利培酮和阿托伐他汀组，或生理盐水用于对照正常组。在出生后第 21 天，雄性后代随机分为四组（n=6）：对照组、VPA 诱导的自闭症、利培酮和阿托伐他汀组。从出生后第 21 天到第 51 天给予利培酮和阿托伐他汀。研究结束时，使用三箱测试、暗光测试和旷场测试评估自闭症样行为。使用 ELISA、RT-PCR、WB 进行 TLR4、NF-κB、NOX-2 和 ROS 的生化分析，进行苏木精和伊红组织学检查和 CAS-3 的免疫组织化学研究。
结果
产前 VPA 暴露的雌性大鼠的雄性后代表现出明显的自闭症样行为和升高的 TLR4、NF-κB、NOX-2、ROS 和 caspase-3 表达。组织学分析显示结构改变。利培酮和阿托伐他汀均能有效减轻 VPA 诱导的自闭症大鼠模型的行为、生化和结构变化。值得注意的是，阿托伐他汀组的改善比利培酮组更显著。
结论
研究结果明确表明，阿托伐他汀通过 TLR4/NF-κB/NOX-2 信号通路抑制炎症、氧化应激和细胞凋亡，可调节 VPA 诱导的自闭症。阿托伐他汀可能是 ASD 的一种潜在治疗方法。
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