Semaglutide ameliorated autism-like behaviors and DNA repair efficiency in male BTBR mice by recovering DNA repair gene expression

IF 5.3 2区 医学 Q1 CLINICAL NEUROLOGY
Marwa H. Hussein, Alaa A. Alameen, Mushtaq A. Ansari, Shakir D. AlSharari, Sheikh F. Ahmad, Mohamed S.M. Attia, Wedad S. Sarawi, Ahmed Nadeem, Saleh A. Bakheet, Sabry M. Attia
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引用次数: 0

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is marked by impaired social interactions, and increased repetitive behaviors. There is evidence of genetic changes in ASD, and several of these altered genes are linked to the process of DNA repair. Therefore, individuals with ASD must have improved DNA repair efficiency to mitigate risks associated with ASD. Despite numerous milestones in ASD research, the disease remains incurable, with a high occurrence rate and substantial financial burdens. This motivates scientists to search for new drugs to manage the disease. Disruption of glucagon-like peptide-1 (GLP-1) signaling, a regulator in neuronal development and maintains homeostasis, has been associated with the pathogenesis and progression of several neurological disorders, such as ASD. Our study aimed to assess the impact of semaglutide, a new GLP-1 analog antidiabetic medication, on behavioral phenotypes and DNA repair efficiency in the BTBR autistic mouse model. Furthermore, we elucidated the underlying mechanism(s) responsible for the ameliorative effects of semaglutide against behavioral problems and DNA repair deficiency in BTBR mice. The current results demonstrate that repeated treatment with semaglutide efficiently decreased autism-like behaviors in BTBR mice without affecting motor performance. Semaglutide also mitigated spontaneous DNA damage and enhanced DNA repair efficiency in the BTBR mice as determined by comet assay. Moreover, administering semaglutide recovered oxidant-antioxidant balance in BTBR mice. Semaglutide restored the disrupted DNA damage/repair pathways in the BTBR mice by reducing Gadd45a expression and increasing Ogg1 and Xrcc1 expression at both the mRNA and protein levels. This suggests that semaglutide holds great potential as a novel therapeutic candidate for treating ASD traits.

塞马鲁肽通过恢复 DNA 修复基因的表达,改善雄性 BTBR 小鼠的自闭症样行为和 DNA 修复效率
自闭症谱系障碍(ASD)是一种复杂的神经发育障碍,主要表现为社交互动障碍和重复行为增多。有证据表明,自闭症的基因发生了变化,其中几个发生变化的基因与 DNA 修复过程有关。因此,患有 ASD 的个体必须提高 DNA 修复效率,才能降低与 ASD 相关的风险。尽管 ASD 研究取得了众多里程碑式的进展,但该疾病仍无法治愈,发病率高,经济负担巨大。这促使科学家们寻找新的药物来控制这种疾病。胰高血糖素样肽-1(GLP-1)信号传导是神经元发育和维持体内平衡的调节因子,它的中断与 ASD 等多种神经系统疾病的发病和进展有关。我们的研究旨在评估一种新型 GLP-1 类似物抗糖尿病药物塞马鲁肽对 BTBR 自闭症小鼠模型的行为表型和 DNA 修复效率的影响。此外,我们还阐明了塞马鲁肽改善 BTBR 小鼠行为问题和 DNA 修复缺陷的潜在机制。目前的研究结果表明,反复使用塞马鲁肽能有效减少 BTBR 小鼠的自闭症样行为,而不影响运动能力。通过彗星试验测定,塞马鲁肽还能减轻BTBR小鼠的自发性DNA损伤,提高DNA修复效率。此外,服用塞马鲁肽还能恢复BTBR小鼠体内的氧化-抗氧化平衡。通过在mRNA和蛋白质水平上降低Gadd45a的表达、增加Ogg1和Xrcc1的表达,塞马鲁肽恢复了BTBR小鼠被破坏的DNA损伤/修复途径。这表明,塞马鲁肽作为治疗ASD特征的新型候选疗法具有巨大潜力。
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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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