Development of a novel glucose‐dendrimer based therapeutic targeting hyperexcitable neurons in neurological disorders

Abstract 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.