Therapeutic Effect of LEV in a Propionic Acid-Induced Autism Model via AMPK/SIRT1 Pathway

IF 1.6 4区医学 Q3 DEVELOPMENTAL BIOLOGY

International Journal of Developmental Neuroscience Pub Date : 2025-09-19 DOI:10.1002/jdn.70055

Tarık Mecit, İlknur Altuntaş, Mümin Alper Erdoğan, Yiğit Uyanıkgil, Oytun Erbaş

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Abstract

Objectives

In this study, we aimed to evaluate the therapeutic effect of levetiracetam (LEV), an antiepileptic drug used in the treatment of both focal and generalized epilepsy, in a propionic acid (PPA)-induced autism model by assessing social deficits, learning and memory impairments, and their neurochemical correlates. We further examined the involvement of the AMPK/SIRT1 signalling pathway as a potential molecular mechanism.

Material and Methods

Thirty male Wistar albino rats were allocated into three groups: normal control (n = 10), PPA + saline (n = 10) and PPA + LEV (n = 10). Autism-like features were induced by intraperitoneal PPA administration (250 mg/kg/day, 5 days). LEV was administered orally (100 mg/kg/day) for 15 days. Behavioural performance (three-chamber sociability test, open-field test, passive avoidance learning), biochemical markers (malondialdehyde [MDA], tumour necrosis factor-alpha [TNF-α], brain-derived neurotrophic factor [BDNF], AMPK, and SIRT1) and histopathological changes (neuronal counts in CA1, CA3, Purkinje cells; GFAP immunostaining) were evaluated.

Results

In the sociability test, social interaction time decreased by 51.6% in the PPA + saline group compared to controls (67.2% ± 2.4% vs. 32.5% ± 2.1%), while LEV increased it by 121.8% vs. PPA + saline (72.1% ± 4.5%). Open-field ambulation decreased by 83% in PPA + saline (17.3 ± 3.2 vs. 2.9 ± 0.8) and increased by 158% with LEV (7.5 ± 2.16). Passive avoidance latency decreased by 76% in PPA + saline (245.9 ± 17.5 s vs. 59.2 ± 20.8 s) and increased by 180% with LEV (165.7 ± 18.3 s). MDA levels increased by 187% in PPA + saline vs. controls (49.9 ± 1.4 vs. 143.5 ± 4.7 nmol/g protein) and decreased by 31% with LEV (98.6 ± 5.4). TNF-α increased by 1012% in PPA + saline (13.1 ± 0.9 vs. 145.8 ± 10.6 pg/mg protein) and decreased by 39% with LEV (88.4 ± 3.9). BDNF decreased by 52% in PPA + saline (5.21 ± 0.9 vs. 2.48 ± 0.3 pg/mg protein) and increased by 88% with LEV (4.66 ± 0.5). AMPK decreased by 62% in PPA + saline (113.5 ± 6.3 vs. 43.2 ± 7.5 pg/mg protein) and increased by 73% with LEV (74.8 ± 2.1). SIRT1 decreased by 75% in PPA + saline (4.65 ± 0.5 vs. 1.17 ± 1.1 pg/mg protein) and increased by 132% with LEV (2.72 ± 0.8). Histologically, CA1 neuronal counts decreased by 35% in PPA + saline (67.2 ± 2.04 vs. 43.8 ± 1.1) and increased by 38% with LEV (60.5 ± 1.3). CA3 neuronal counts decreased by 31% in PPA + saline (48.5 ± 3.2 vs. 33.7 ± 1.9) and increased by 31% with LEV (44.2 ± 0.8). Purkinje cells decreased by 53% in PPA + saline (26.2 ± 0.5 vs. 12.2 ± 0.8) and increased by 68% with LEV (20.5 ± 1.1). GFAP indices in CA1, CA3 and cerebellum were elevated in PPA + saline (31.6 ± 2.4 vs. 47.5 ± 1.2; 33.4 ± 1.1 vs. 48.2 ± 0.7; 21.2 ± 1.6 vs. 32.3 ± 0.9) and reduced with LEV (40.3 ± 0.6; 39.5 ± 0.8; 28.5 ± 1.4, respectively).

These therapeutic effects were accompanied by marked upregulation of the AMPK/SIRT1 pathway, which was suppressed in the PPA + saline group.

Conclusion

LEV treatment ameliorated PPA-induced behavioural, biochemical and histological impairments, likely via anti-inflammatory, antioxidant and neuroprotective mechanisms involving activation of the AMPK/SIRT1 pathway. These findings support LEV as a potential therapeutic candidate for autism spectrum disorder.

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LEV通过AMPK/SIRT1通路在丙酸诱导的自闭症模型中的治疗作用

目的：在本研究中，我们旨在通过评估社交缺陷、学习和记忆障碍及其神经化学相关因素，评估左乙拉西坦（LEV）在丙酸（PPA）诱导的自闭症模型中的治疗效果。左乙拉西坦是一种抗癫痫药物，用于治疗局灶性和全面性癫痫。我们进一步研究了AMPK/SIRT1信号通路作为潜在的分子机制的参与。材料与方法：雄性Wistar白化大鼠30只，随机分为正常对照组（n = 10）、PPA +生理盐水组（n = 10）和PPA + LEV组（n = 10）。腹腔注射PPA （250 mg/kg/天，5天）诱导自闭症样特征。口服LEV （100 mg/kg/天）15天。评估行为表现（三室社交测试、开场测试、被动回避学习）、生化指标（丙二醛[MDA]、肿瘤坏死因子-α [TNF-α]、脑源性神经营养因子[BDNF]、AMPK和SIRT1）和组织病理学变化（CA1、CA3、浦肯野细胞的神经元计数；GFAP免疫染色）。结果：在社交能力测试中，PPA +生理盐水组的社交时间比对照组减少51.6%(67.2%±2.4%比32.5%±2.1%)，而LEV组的社交时间比PPA +生理盐水组增加121.8%（72.1%±4.5%）。PPA +生理盐水组野外活动减少83%(17.3±3.2 vs. 2.9±0.8)，LEV组增加158%（7.5±2.16）。PPA +生理盐水组被动回避潜伏期减少76%(245.9±17.5 s vs 59.2±20.8 s)， LEV组被动回避潜伏期增加180%（165.7±18.3 s）。与对照组相比，PPA +生理盐水组MDA水平升高了187%(49.9±1.4比143.5±4.7 nmol/g protein)， LEV组MDA水平下降了31%（98.6±5.4）。PPA +生理盐水组TNF-α升高1012%（13.1±0.9 vs. 145.8±10.6 pg/mg蛋白），LEV组TNF-α降低39%（88.4±3.9）。PPA +生理盐水组BDNF降低52%（5.21±0.9 vs 2.48±0.3 pg/mg蛋白），LEV组BDNF升高88%（4.66±0.5）。PPA +生理盐水组AMPK降低62%（113.5±6.3 vs. 43.2±7.5 pg/mg蛋白），LEV组AMPK升高73%（74.8±2.1）。PPA +生理盐水组SIRT1降低75%（4.65±0.5 vs. 1.17±1.1 pg/mg蛋白），LEV组SIRT1升高132%（2.72±0.8）。组织学上，PPA +生理盐水组CA1神经元计数减少35%(67.2±2.04 vs. 43.8±1.1)，LEV组CA1神经元计数增加38%（60.5±1.3）。PPA +生理盐水组CA3神经元计数减少31%(48.5±3.2比33.7±1.9)，LEV组CA3神经元计数增加31%（44.2±0.8）。PPA +生理盐水组浦肯野细胞减少53%(26.2±0.5 vs 12.2±0.8)，LEV组浦肯野细胞增加68%（20.5±1.1）。PPA +生理盐水组CA1、CA3和小脑GFAP指数升高（31.6±2.4 vs. 47.5±1.2;33.4±1.1 vs. 48.2±0.7;21.2±1.6 vs. 32.3±0.9），LEV组GFAP指数降低（分别为40.3±0.6;39.5±0.8;28.5±1.4）。这些治疗效果伴随着AMPK/SIRT1通路的显著上调，而这在PPA +生理盐水组中被抑制。结论：LEV治疗可能通过激活AMPK/SIRT1通路的抗炎、抗氧化和神经保护机制改善ppa诱导的行为、生化和组织学损伤。这些发现支持LEV作为自闭症谱系障碍的潜在治疗候选药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

International Journal of Developmental Neuroscience 医学-发育生物学

CiteScore

3.30

自引率

5.60%

发文量

审稿时长

6-12 weeks

期刊介绍： International Journal of Developmental Neuroscience publishes original research articles and critical review papers on all fundamental and clinical aspects of nervous system development, renewal and regeneration, as well as on the effects of genetic and environmental perturbations of brain development and homeostasis leading to neurodevelopmental disorders and neurological conditions. Studies describing the involvement of stem cells in nervous system maintenance and disease (including brain tumours), stem cell-based approaches for the investigation of neurodegenerative diseases, roles of neuroinflammation in development and disease, and neuroevolution are also encouraged. Investigations using molecular, cellular, physiological, genetic and epigenetic approaches in model systems ranging from simple invertebrates to human iPSC-based 2D and 3D models are encouraged, as are studies using experimental models that provide behavioural or evolutionary insights. The journal also publishes Special Issues dealing with topics at the cutting edge of research edited by Guest Editors appointed by the Editor in Chief. A major aim of the journal is to facilitate the transfer of fundamental studies of nervous system development, maintenance, and disease to clinical applications. The journal thus intends to disseminate valuable information for both biologists and physicians. International Journal of Developmental Neuroscience is owned and supported by The International Society for Developmental Neuroscience (ISDN), an organization of scientists interested in advancing developmental neuroscience research in the broadest sense.