Neuroprotective effect of PPAR gamma agonist in rat model of autism spectrum disorder: Role of Wnt/β-catenin pathway

IF 5.3 2区 医学 Q1 CLINICAL NEUROLOGY Progress in Neuro-Psychopharmacology & Biological Psychiatry Pub Date : 2024-08-22 DOI:10.1016/j.pnpbp.2024.111126
Arushi Sandhu , Kajal Rawat , Vipasha Gautam , Anil Kumar , Antika Sharma , Alka Bhatia , Sandeep Grover , Lokesh Saini , Lekha Saha
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Abstract

Background

The clinical manifestation of autism spectrum disorder (ASD) is linked to the disruption of fundamental neurodevelopmental pathways. Emerging evidences claim to have an upregulation of canonical Wnt/β-catenin pathway while downregulation of PPARγ pathway in ASD. This study aims to investigate the therapeutic potential of pioglitazone, a PPARγ agonist, in rat model of ASD. The study further explores the possible role of PPARγ and Wnt/β-catenin pathway and their interaction in ASD by using their modulators.

Material and methods

Pregnant female Wistar rats received 600 mg/kg of valproic acid (VPA) to induce autistic symptoms in pups. Pioglitazone (10 mg/kg) was used to evaluate neurobehaviors, relative mRNA expression of inflammatory (IL-1β, IL-6, IL-10, TNF-α), apoptotic markers (Bcl-2, Bax, & Caspase-3) and histopathology (H&E, Nissl stain, Immunohistochemistry). Effect of pioglitazone was evaluated on Wnt pathway and 4 μg/kg dose of 6-BIO (Wnt modulator) was used to study the PPARγ pathway.

Results

ASD model was established in pups as indicated by core autistic symptoms, increased neuroinflammation, apoptosis and histopathological neurodegeneration in cerebellum, hippocampus and amygdala. Pioglitazone significantly attenuated these alterations in VPA-exposed rats. The expression study results indicated an increase in key transcription factor, β-catenin in VPA-rats suggesting an upregulation of canonical Wnt pathway in them. Pioglitazone significantly downregulated the Wnt signaling by suppressing the expression of Wnt signaling-associated proteins. The inhibiting effect of Wnt pathway on PPARγ activity was indicated by downregulation of PPARγ-associated protein in VPA-exposed rats and those administered with 6-BIO.

Conclusion

In the present study, upregulation of canonical Wnt/β-catenin pathway was demonstrated in ASD rat model. Pioglitazone administration significantly ameliorated these symptoms potentially through its neuroprotective effect and its ability to downregulate the Wnt/β-catenin pathway. The antagonism between the PPARγ and Wnt pathway offers a promising therapeutic approach for addressing ASD.

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PPAR gamma 激动剂对自闭症谱系障碍大鼠模型的神经保护作用:Wnt/β-catenin通路的作用
背景:自闭症谱系障碍(ASD)的临床表现与基本神经发育途径的破坏有关。新的证据表明,在自闭症谱系障碍中,典型的Wnt/β-catenin通路上调,而PPARγ通路下调。本研究旨在探讨 PPARγ 激动剂吡格列酮在 ASD 大鼠模型中的治疗潜力。本研究通过使用 PPARγ 和 Wnt/β-catenin 通路的调节剂,进一步探讨 PPARγ 和 Wnt/β-catenin 通路在 ASD 中的可能作用及其相互作用:妊娠雌性 Wistar 大鼠接受 600 mg/kg 丙戊酸(VPA)诱导幼鼠出现自闭症症状。用吡格列酮(10 毫克/千克)评估神经行为、炎症(IL-1β、IL-6、IL-10、TNF-α)、凋亡标志物(Bcl-2、Bax 和 Caspase-3)的相对 mRNA 表达和组织病理学(H&E、Nissl 染色、免疫组化)。评估了吡格列酮对 Wnt 通路的影响,并使用 4 μg/kg 剂量的 6-BIO(Wnt 调节剂)研究 PPARγ 通路:结果:幼鼠自闭症模型的建立表现为核心自闭症症状、神经炎症、细胞凋亡增加以及小脑、海马和杏仁核的组织病理学神经变性。吡格列酮能明显减轻暴露于 VPA 的大鼠的这些变化。表达研究结果表明,VPA 大鼠体内的关键转录因子 β-catenin 增加,表明它们体内的典型 Wnt 通路上调。吡格列酮通过抑制 Wnt 信号转导相关蛋白的表达,明显降低了 Wnt 信号转导。在暴露于 VPA 的大鼠和服用 6-BIO 的大鼠中,PPARγ 相关蛋白的下调表明了 Wnt 通路对 PPARγ 活性的抑制作用:结论:本研究表明,在ASD大鼠模型中,典型Wnt/β-catenin通路上调。服用吡格列酮可明显改善这些症状,这可能是由于吡格列酮具有神经保护作用,并能下调 Wnt/β-catenin 通路。PPARγ和Wnt通路之间的拮抗作用为解决ASD问题提供了一种很有前景的治疗方法。
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来源期刊
CiteScore
12.00
自引率
1.80%
发文量
153
审稿时长
56 days
期刊介绍: Progress in Neuro-Psychopharmacology & Biological Psychiatry is an international and multidisciplinary journal which aims to ensure the rapid publication of authoritative reviews and research papers dealing with experimental and clinical aspects of neuro-psychopharmacology and biological psychiatry. Issues of the journal are regularly devoted wholly in or in part to a topical subject. Progress in Neuro-Psychopharmacology & Biological Psychiatry does not publish work on the actions of biological extracts unless the pharmacological active molecular substrate and/or specific receptor binding properties of the extract compounds are elucidated.
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