α-Lipoic Acid-Based Nanozyme for Treating Acute Epilepsy

Abstract

Anti-epilepsy drugs (AEDs), a common therapeutic approach for clinically treating epilepsy, suffer from low permeability toward the blood-brain barrier (BBB), side effect risks, and a failure to regulate the pathological microenvironment. These issues hinder the complete control of epilepsy and lead to a vicious cycle of inflammation-epileptogenesis. Herein, an α-lipoic acid (LA)-based nanozyme that loads phenytoin (PHT) and complexes calcium ions (LA@PHT-Ca²⁺) is developed. This nanozyme combines the functions of delivering AEDs across the BBB and regulating undesirable microenvironments to treat epilepsy. Amphipathic LA self-assembles into stable nanoparticles in water with BBB crossing ability endowed by the transporting of LA through sodium-dependent multivitamin transporter. LA's enzyme-like and redox functions provide LA@PHT-Ca²⁺ with excellent scavenging effects on several free radicals via cascade reactions, thereby protecting neurons from oxidative stress. Moreover, Ca²⁺ disrupts neuronal respiration, resulting in reduced production of bioenergetic adenosine triphosphate and an improved hypoxic microenvironment. This leads to decreased expression of P-glycoprotein, a drug-efflux gating protein. This novel lipoic acid-based nanozyme, with intrinsic BBB crossing capability, prolonged intracellular drug retention time, and the ability to block the inflammation-epileptogenesis cycle, presents a satisfactory therapeutic effect in epileptic rats, resulting in attenuated symptoms and an improved microenvironment.