Development and Evaluation of Novel Metformin Derivative Metformin Threonate for Brain Ischemia Treatment.
Development and Evaluation of Novel Metformin Derivative Metformin Threonate for Brain Ischemia Treatment.
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DOI：
10.3389/fphar.2022.879690
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发表时间：
2022
影响因子：
5.6
通讯作者：
Zhen, Xuechu
中科院分区：
文献类型：
--
作者：
Zhang, Gufang;Chen, Shuangshuang;Jia, Jia;Liu, Chun;Wang, Weipeng;Zhang, Hongjian;Zhen, Xuechu
流行病学数据显示，服用二甲双胍的糖尿病患者在卒中后神经功能恢复期间表现出较低的卒中发生率和较好的功能结局。我们以前证明，长期缺血后二甲双胍给药可改善实验性脑缺血的功能恢复。然而，二甲双胍在实验动物或卒中患者中对脑缺血急性期的有益作用很少，这限制了二甲双胍在卒中中的应用。我们推测，细胞对盐酸二甲双胍的缓慢摄取可能导致急性卒中缺乏疗效。我们最近开发了一种新的二甲双胍衍生物，二甲双胍苏糖酸盐（SHY-01）并获得专利。体内和培养细胞中的药代动力学特征显示，二甲双胍从SHY-01中的摄取和蓄积比盐酸二甲双胍更快。因此，SHY-01处理表现出更有效和快速的AMP活化蛋白激酶（AMPK）活化。此外，与盐酸二甲双胍相比，SHY-01对小胶质细胞活化的抑制作用更强，神经保护作用更强。SHY-01给药对实验性中风的神经功能恢复也有上级有益作用，并对急性脑缺血提供强有力的保护，减少梗死体积和死亡率，以及改善大鼠的感觉运动和认知功能。总的来说，这些结果表明SHY-01具有改善的药代动力学和药理学特征，并对急性中风和长期神经损伤产生更有效的保护作用。我们认为SHY-01是一种非常有前途的治疗缺血性脑卒中的候选药物。
Epidemiologic data reveal that diabetes patients taking metformin exhibit lower incidence of stroke and better functional outcomes during post-stroke neurologic recovery. We previously demonstrated that chronic post-ischemic administration of metformin improved functional recovery in experimental cerebral ischemia. However, few beneficial effects of metformin on the acute phase of cerebral ischemia were reported either in experimental animals or in stroke patients, which limits the application of metformin in stroke. We hypothesized that slow cellular uptake of metformin hydrochloride may contribute to the lack of efficacy in acute stroke. We recently developed and patented a novel metformin derivative, metformin threonate (SHY-01). Pharmacokinetic profile in vivo and in cultured cells revealed that metformin is more rapidly uptaken and accumulated from SHY-01 than metformin hydrochloride. Accordingly, SHY-01 treatment exhibited more potent and rapid activation of AMP-activated protein kinase (AMPK). Furthermore, SHY-01 elicited a stronger inhibition of microglia activation and more potent neuroprotection when compared to metformin hydrochloride. SHY-01 administration also had superior beneficial effects on neurologic functional recovery in experimental stroke and offered strong protection against acute cerebral ischemia with reduced infarct volume and mortality, as well as the improved sensorimotor and cognitive functions in rats. Collectively, these results indicated that SHY-01 had an improved pharmacokinetic and pharmacological profile and produced more potent protective effects on acute stroke and long-term neurological damage. We propose that SHY-01 is a very promising therapeutic candidate for cerebral ischemic stroke.
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中年晚期的二甲双胍治疗可通过减轻小胶质细胞活化和增强海马自噬来改善认知功能。
影响因子：
7.8
作者：
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影响因子：
7.8
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影响因子：
6.9
作者：
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影响因子：
4.7
作者：
Chen, Xiaoling;Wu, Wen;Chen, Long
通讯作者：
Chen, Long
影响因子：
24
作者：
Jadhav, Sachin;Ferrell, William;Sattar, Naveed
通讯作者：
Sattar, Naveed