Restarting synaptic remodeling and structural network: New treatment strategies for epilepsy.

Abstract

Oxidative stress and lysosomal dysfunction are considered as critical contributors to epileptogenesis and its progression. These processes create a self-perpetuating cycle that worsens neuronal hyperexcitability, neuroinflammation, and synaptic pathology, while simultaneously impairing neural stem cell survival and neuroregeneration, which includes neurogenesis, synaptic remodeling, and circuit repair. Traditional treatments merely suppress discharges but overlook the synaptic damage, loss of inhibitory interneurons, and exhaustion of neural stem cells caused by oxidative stress and lysosomal dysfunction, making it difficult for the network structure to self-repair. The purpose of this review is to explore a new paradigm "Restarting synaptic remodeling and structural network: A novel strategy for neuroregeneration in epilepsy." This review clearly outlines the mechanisms through which oxidative stress and lysosomal dysfunction damage synapses, neurons, and neural stem cells, as well as the reinforcing feedback loop that these two processes create within the epileptic network. In terms of nerve repair, a "dual-target repair" strategy can be implemented. On one hand, this involves using an activator of nuclear factor erythroid 2-related factor 2 combined with antioxidants to eliminate reactive oxygen species and protect existing synapses. On the other hand, it includes employing transcription factor EB agonists, mTOR inhibitors, or gene/enzyme replacement therapies to restore lysosomal degradation function, clear aggregates, and rebuild the inhibitory microenvironment. Taken together, the oxidative stress-lysosomal dysfunction-neuroregeneration axis provides a unifying framework that integrates molecular pathology with failed neural repair, offering a novel perspective for developing next-generation therapies aimed at both seizure reduction and circuit restoration. This paradigm shift emphasizes the potential of neuroregenerative strategies to restart synaptic remodeling and repair structural network in epilepsy and related neurodegenerative disorders.