We performed an in silico, in vitro, and in vivo assessment of a potassium 2-[2-(2-oxo-4-phenylpyrrolidin-1-yl) acetamido]ethanesulfonate (compound 1) as a potential prodrug for cognitive function improvement in ischemic brain injury. Using in silico methods, we predicted the pharmacological efficacy and possible safety in rat models. In addition, in silico data showed neuroprotective features of compound 1, which were further supported by in vitro experiments in a glutamate excitotoxicity-induced model in newborn rat cortical neuron cultures. Next, we checked whether compound 1 is capable of crossing the blood–brain barrier in intact and ischemic animals. Compound 1 improved animal behavior both in intact and ischemic rats and, even though the concentration in intact brains was low, we still observed a significant anxiety reduction and activity escalation. We used molecular docking and molecular dynamics to support our hypothesis that compound 1 could affect the AMPA receptor function. In a rat model of acute focal cerebral ischemia, we studied the effects of compound 1 on the behavior and neurological deficit. An in vivo experiment demonstrated that compound 1 significantly reduced the neurological deficit and improved neurological symptom regression, exploratory behavior, and anxiety. Thus, here, for the first time, we show that compound 1 can be considered as an agent for restoring cognitive functions.

中文翻译：

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一种新型苯基吡咯烷衍生物：合成及对实验性缺血性中风大鼠认知功能的影响

我们对 2-[2-(2-oxo-4-phenylpyrrolidin-1-yl) acetamido]乙磺酸钾（化合物1）进行了计算机模拟、体外和体内评估，作为改善认知功能的潜在前药缺血性脑损伤。使用计算机方法，我们预测了大鼠模型中的药理功效和可能的安全性。此外，计算机数据显示了化合物1 的神经保护特性，这得到了在新生大鼠皮层神经元培养物中谷氨酸兴奋性毒性诱导模型的体外实验的进一步支持。接下来，我们检查了化合物1是否能够穿过完整和缺血动物的血脑屏障。化合物1改善了完整和缺血大鼠的动物行为，即使完整大脑中的浓度很低，我们仍然观察到焦虑显着减少和活动升级。我们使用分子对接和分子动力学来支持我们的假设，即化合物1可以影响 AMPA 受体功能。在急性局灶性脑缺血大鼠模型中，我们研究了化合物1对行为和神经功能缺损的影响。一项体内实验表明，化合物1显着减少了神经功能缺损并改善了神经症状消退、探索性行为和焦虑。因此，在这里，我们第一次证明化合物1可以被认为是恢复认知功能的代理。