Neuronal hyperexcitability and excitotoxicity lies at the core of debilitating brain disorders such as epilepsy and traumatic brain injury, culminating in neuronal death and compromised brain function. Overcoming this challenge requires a unique approach that selectively restores normal neuronal activity and rescues neurons from impending damage. However, delivering drugs selectively to hyperexcitable neurons has been a challenge, even upon local administration. Here, we demonstrate the remarkable ability of a novel, scalable, generation‐two glucose‐dendrimer (GD2) made primarily of glucose and ethylene glycol building blocks, to specifically target hyperexcitable neurons in primary culture, ex vivo acute brain slices, and in vivo mouse models of acute seizures. Pharmacology experiments in ex vivo brain slices suggest GD2 uptake in neurons is mediated through glucose transporters (GLUT and SGLT). Inspired by these findings, we conjugated GD2 with a potent anti‐epileptic drug, valproic acid (GD2–VPA), for efficacy studies in the pilocarpine‐mouse model of seizure. When delivered intranasally, GD2–VPA significantly decreased the seizure‐severity. In summary, our findings demonstrate the unique selectivity of glucose dendrimers in targeting hyperexcitable neurons, even upon intranasal delivery, laying the foundation for neuron‐specific therapies for the precise protection and restoration of neuronal function, for targeted neuroprotection.

中文翻译：

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开发一种新型葡萄糖树枝状大分子治疗药物，针对神经系统疾病中的过度兴奋神经元

神经元过度兴奋和兴奋性毒性是导致癫痫和脑外伤等衰弱性脑部疾病的核心，最终导致神经元死亡和脑功能受损。克服这一挑战需要一种独特的方法，选择性地恢复正常的神经元活动并拯救神经元免受即将发生的损伤。然而，选择性地将药物递送至过度兴奋的神经元一直是一个挑战，即使是局部给药也是如此。在这里，我们展示了一种新型、可扩展的第二代葡萄糖树枝状聚合物（GD2）的卓越能力，该聚合物主要由葡萄糖和乙二醇组成，可以特异性地靶向原代培养物、离体急性脑切片和体内的过度兴奋神经元。急性癫痫发作的小鼠模型。离体脑切片的药理学实验表明，神经元中的 GD2 摄取是通过葡萄糖转运蛋白（GLUT 和 SGLT）介导的。受这些发现的启发，我们将 GD2 与强效抗癫痫药物丙戊酸 (GD2-VPA) 结合，在毛果芸香碱小鼠癫痫模型中进行疗效研究。当鼻内给药时，GD2-VPA 显着降低了癫痫发作的严重程度。总之，我们的研究结果证明了葡萄糖树枝状聚合物在靶向过度兴奋的神经元方面具有独特的选择性，甚至在鼻内递送时也是如此，为精确保护和恢复神经元功能的神经元特异性疗法奠定了基础，从而实现靶向神经保护。