Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
Department of Drug Radiation Research, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo, Egypt.
Toxicol Appl Pharmacol. 2024 Aug;489:116994. doi: 10.1016/j.taap.2024.116994. Epub 2024 Jun 8.
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.
辐射诱导的认知障碍最近引起了科学界的兴趣，越来越多的癌症患者在治疗方案中需要全脑照射 (WBI)。西格列汀 (SAXA) 是一种二肽基肽酶-4 (DPP-4) 抑制剂，对多种神经退行性疾病表现出有效的神经保护作用。因此，本研究旨在研究 SAXA 缓解 WBI 诱导的认知缺陷的疗效。雄性 Sprague Dawley 大鼠分为对照组、接受 20Gy γ 射线照射的 WBI 组、用 SAXA（10mg/kg，口服，每日一次）治疗三周的 SAXA 组和接受 20Gy γ 射线照射然后用 SAXA（10mg/kg，口服，每日一次）治疗的 WBI/SAXA 组。在行为测试中，SAXA 有效逆转了 20Gy WBI 引起的记忆恶化和运动功能障碍，并保持了照射大鼠海马组织的正常组织学结构。从机制上讲，SAXA 通过降低脂质过氧化作用抑制 WBI 诱导的海马氧化应激，同时恢复过氧化氢酶抗氧化活性。此外，SAXA 通过下调促凋亡 Bcl-2 相关 X 蛋白 (Bax) 和上调抗凋亡 B 细胞淋巴瘤 2 (Bcl-2) 表达来阻断辐射诱导的海马神经元凋亡，最终减少 cleaved caspase 3 的表达。此外，SAXA 通过上调脑源性神经营养因子 (BDNF) 的表达促进海马神经发生。SAXA 的这些有价值的神经保护能力与激活蛋白激酶 B (Akt)、环磷酸腺苷反应元件结合蛋白 (CREB) 以及上调沉默调节蛋白 1 (SIRT-1) 的表达有关。SAXA 成功减轻了 WBI 引发的认知功能障碍，减轻了氧化损伤和神经元凋亡，并通过激活 Akt/CREB/BDNF/SIRT-1 信号通路增强了神经发生。SAXA 的这些富有成效的神经修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。
