Improving epilepsy management by targeting P2 × 7 receptor with ROS/electric responsive nanomicelles.

BACKGROUND: The intricate pathogenesis of epilepsy, characterized by abnormal neuronal discharges and neuroinflammation, underscores the critical involvement of the adenosine triphosphate (ATP)-P2X purinoceptor 7 (P2 × 7) receptor pathway in inflammation activation. To address this, a reactive oxygen species (ROS)/electric-responsive d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS)-ferrocene-poloxamer nanomicelle (TFP@A) was engineered to deliver the P2 × 7 receptor antagonist A 438,079, aiming to provide a targeted therapeutic strategy for epilepsy management. METHODS: The study meticulously designed and characterized TFP@A for precise drug delivery through various techniques including transmission electron microscopy (TEM), dynamic light scattering (DLS), and high-performance liquid chromatography (HPLC). Cellular uptake and blood-brain barrier (BBB) permeability were evaluated using fluorescein isothiocyanate (FITC)-labeled TFP@A in vitro and in a brain endothelial cell line (bEnd.3) cell BBB model. In vivo distribution and safety assessments were conducted in an epilepsy mouse model. The impact of TFP@A on epilepsy was investigated through seizure analysis, electroencephalogram (EEG) recordings, and inflammatory pathway assessment. RESULTS: TFP@A exhibited a robust drug release profile under ROS and electrical stimulation conditions. In vitro studies demonstrated its efficacy in scavenging ROS, reducing oxidative stress, and alleviating cell apoptosis in epilepsy models. Efficient cellular uptake, BBB penetration, and in vivo accumulation in the brain were observed. Notably, TFP@A effectively modulated the P2 × 7 receptor (P2 × 7R)-nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) pathway, inhibiting inflammatory mediators and promoting anti-inflammatory responses. CONCLUSION: TFP@A loaded with the P2 × 7 receptor antagonist showcases potential therapeutic benefits in suppressing NLRP3 inflammasome activation, mitigating microglial-neuron crosstalk, and ameliorating epilepsy symptoms, positioning it as a promising avenue for targeted epilepsy treatment.