Lin Xiaojing, Zhang Kangli, Li Chenyi, Liu Kewei, Sun Yanping, Wu Wei, Liu Kai, Yi Xeuqing, Wang Xiaowen, Qu Zixuan, Liu Xiaohong, Xing Yao, Walker M J, Gong Qinglei, Liu Ruoxu, Xu Xiaoming, Lin Cheng-Hsien, Sun Gang
Key Laboratory of Military Medical Psychology and Stress Biology of PLA, Jinan, Shandong Province, PR China.
Department of General Medicine, The 960th Hospital of Joint Logistics Support Force of PLA, Shandong Province, PR China.
Eur J Pharmacol. 2024 Jul 5;974:176631. doi: 10.1016/j.ejphar.2024.176631. Epub 2024 Apr 30.
Dasatinib and quercetin (D & Q) have demonstrated promise in improving aged-related pathophysiological dysfunctions in humans and mice. Herein we aimed to ascertain whether the heat stress (HS)-induced cognitive deficits in aged or even young adult male mice can be reduced by D & Q therapy.
Before the onset of HS, animals were pre-treated with D & Q or placebo for 3 consecutive days every 2 weeks over a 10-week period. Cognitive function, intestinal barrier permeability, and blood-brain barrier permeability were assessed.
Compared to the non-HS young adult male mice, the HS young adult male mice or the aged male mice had significantly lesser extents of the exacerbated stress reactions, intestinal barrier disruption, endotoxemia, systemic inflammation and oxidative stress, blood-brain barrier disruption, hippocampal inflammation and oxidative stress, and cognitive deficits evaluated at 7 days post-HS. All the cognitive deficits and other syndromes that occurred in young adult HS mice or in aged HS mice were significantly attenuated by D & Q therapy (P < 0.01). Compared to the young adult HS mice, the aged HS mice had significantly (P < 0.01) higher severity of cognitive deficits and other related syndromes.
First, our data show that aged male mice are more vulnerable to HS-induced cognitive deficits than those of the young adult male mice. Second, we demonstrate that a combination of D and Q therapy attenuates cognitive deficits in heat stressed aged or young adult male mice via broad normalization of the brain-gut-endotoxin axis function.
达沙替尼和槲皮素（D&Q）已显示出改善人类和小鼠与年龄相关的病理生理功能障碍的前景。在此，我们旨在确定D&Q疗法是否能减轻热应激（HS）诱导的老年甚至年轻成年雄性小鼠的认知缺陷。
在HS开始前，动物每2周连续3天接受D&Q或安慰剂预处理，为期10周。评估认知功能、肠道屏障通透性和血脑屏障通透性。
与非HS年轻成年雄性小鼠相比，HS年轻成年雄性小鼠或老年雄性小鼠在HS后7天评估的应激反应加剧、肠道屏障破坏、内毒素血症、全身炎症和氧化应激、血脑屏障破坏、海马炎症和氧化应激以及认知缺陷的程度明显较轻。D&Q疗法显著减轻了年轻成年HS小鼠或老年HS小鼠出现的所有认知缺陷和其他综合征（P<0.01）。与年轻成年HS小鼠相比，老年HS小鼠的认知缺陷和其他相关综合征的严重程度明显更高（P<0.01）。
首先，我们的数据表明，老年雄性小鼠比年轻成年雄性小鼠更容易受到HS诱导的认知缺陷的影响。其次，我们证明，D和Q联合疗法通过广泛恢复脑-肠-内毒素轴功能，减轻热应激老年或年轻成年雄性小鼠的认知缺陷。
