Neuroprotective effects of saxagliptin against radiation-induced cognitive impairment: Insights on Akt/CREB/SIRT1/BDNF signaling pathway

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY Toxicology and applied pharmacology Pub Date : 2024-06-08 DOI:10.1016/j.taap.2024.116994

Ashrakt H. Abdelhamid , Eman M. Mantawy , Riham S. Said , Ebtehal El-Demerdash

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Abstract

Radiation-induced cognitive impairment has recently fueled scientific interest with an increasing prevalence of cancer patients requiring whole brain irradiation (WBI) in their treatment algorithm. Saxagliptin (SAXA), a dipeptidyl peptidase-IV (DPP-IV) inhibitor, has exhibited competent neuroprotective effects against varied neurodegenerative disorders. Hence, this study aimed at examining the efficacy of SAXA in alleviating WBI-induced cognitive deficits. Male Sprague Dawley rats were distributed into control group, WBI group exposed to 20 Gy ϒ-radiation, SAXA group treated for three weeks with SAXA (10 mg/kg. orally, once daily), and WBI/SAXA group exposed to 20 Gy ϒ-radiation then treated with SAXA (10 mg/kg. orally, once daily). SAXA effectively reversed memory deterioration and motor dysfunction induced by 20 Gy WBI during behavioural tests and preserved normal histological architecture of the hippocampal tissues of irradiated rats. Mechanistically, SAXA inhibited WBI-induced hippocampal oxidative stress via decreasing lipid peroxidation while restoring catalase antioxidant activity. Moreover, SAXA abrogated radiation-induced hippocampal neuronal apoptosis through downregulating proapoptotic Bcl-2 Associated X-protein (Bax) and upregulating antiapoptotic B-cell lymphoma 2 (Bcl-2) expressions and eventually diminishing expression of cleaved caspase 3. Furthermore, SAXA boosted hippocampal neurogenesis by upregulating brain-derived neurotrophic factor (BDNF) expression. These valuable neuroprotective capabilities of SAXA were linked to activating protein kinase B (Akt), and cAMP-response element-binding protein (CREB) along with elevating the expression of sirtuin 1 (SIRT-1). SAXA successfully mitigated cognitive dysfunction triggered by WBI, attenuated oxidative injury, and neuronal apoptosis, and enhanced neurogenesis through switching on Akt/CREB/BDNF/SIRT-1 signaling axes. Such fruitful neurorestorative effects of SAXA provide an innovative therapeutic strategy for improving the cognitive capacity of cancer patients exposed to radiotherapy.

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沙格列汀对辐射所致认知障碍的神经保护作用：对Akt/CREB/SIRT1/BDNF信号通路的启示

最近，随着需要进行全脑照射（WBI）治疗的癌症患者越来越多，辐射诱发的认知障碍引起了科学界的关注。沙克列汀（SAXA）是一种二肽基肽酶-IV（DPP-IV）抑制剂，对各种神经退行性疾病具有良好的神经保护作用。因此，本研究旨在探讨 SAXA 在缓解 WBI 引起的认知障碍方面的功效。雄性 Sprague Dawley 大鼠被分为对照组、暴露于 20 Gy ϒ 辐射的 WBI 组、口服 SAXA（10 毫克/千克，每日一次）治疗三周的 SAXA 组，以及暴露于 20 Gy ϒ 辐射然后口服 SAXA（10 毫克/千克，每日一次）治疗的 WBI/SAXA 组。在行为测试中，SAXA能有效逆转20 Gy WBI诱导的记忆衰退和运动功能障碍，并保留辐照大鼠海马组织的正常组织学结构。从机理上讲，SAXA通过降低脂质过氧化反应抑制了WBI诱导的海马氧化应激，同时恢复了过氧化氢酶的抗氧化活性。此外，SAXA 还能通过下调促凋亡的 Bcl-2 相关 X 蛋白（Bax）和上调抗凋亡的 B 细胞淋巴瘤 2（Bcl-2）的表达，最终降低裂解的 Caspase 3 的表达，从而抑制辐射诱导的海马神经元凋亡。此外，SAXA 还能通过上调脑源性神经营养因子（BDNF）的表达来促进海马神经发生。SAXA 的这些宝贵的神经保护功能与激活蛋白激酶 B（Akt）和 cAMP 反应元件结合蛋白（CREB）以及提高 sirtuin 1（SIRT-1）的表达有关。通过切换 Akt/CREB/BDNF/SIRT-1 信号轴，SAXA 成功缓解了 WBI 引发的认知功能障碍，减轻了氧化损伤和神经元凋亡，并增强了神经发生。SAXA 卓有成效的神经恢复作用为改善接受放疗的癌症患者的认知能力提供了一种创新的治疗策略。

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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.