Design and evaluation of chrysin-loaded nanoemulsion against lithium/pilocarpine-induced status epilepticus in rats; emphasis on formulation, neuronal excitotoxicity, oxidative stress, microglia polarization, and AMPK/SIRT-1/PGC-1α pathway

The present study aims to formulate and evaluate the efficacy of chrysin-loaded nanoemulsion (CH NE) against lithium/pilocarpine-induced epilepsy in rats, as well as, elucidate its effect on main epilepsy pathogenesis cornerstones; neuronal hyperactivity, oxidative stress, and neuroinflammation. NEs were characterized by droplet size, zeta potential, pH, in vitro release, accelerated and long-term stability studies. Anti-convulsant efficacy of the optimized formula and underlying mechanisms involved were assessed and compared to that from CH suspension given orally at a 30 folds higher dose. Optimized formula displayed a droplet size of 48.09 ± 0.83 nm, PDI 0.25 ± 0.011, sustained release, and good stability. CH treatment reduced seizures scoring, corrected behavioral and histological changes induced by Li/Pilo. Moreover, CH restored neurotransmitters balance and oxidative stress markers levels. Besides, CH induced microglia polarization from M1 to M2 hindering inflammation induced by Li/Pilo. Also, CH restored energy metabolism homeostasis via regulating protein expression of AMPK/SIRT-1/PGC-1α pathway markers. CH NE formulation was found to significantly enhance drug delivery to rats’ hippocampus compared to CH suspension. Our findings prove the therapeutic efficacy of CH NE at a lower dose which could be a potential brain targeting platform to combat epilepsy.