Nanoformulated ellagic acid ameliorates pentylenetetrazol-induced experimental epileptic seizures by modulating oxidative stress, inflammatory cytokines and apoptosis in the brains of male mice.

The present study evaluated the neuroprotective and antiepileptic efficacy of ellagic acid (EA) encapsulated in calcium-alginate nanoparticles (Ca²⁺-ALG NPs) in pentylenetetrazol (PTZ)-induced seizures in male mice. EA was encapsulated in ALG NPs using a nanospray drying method followed by ionotropic crosslinking with Ca²⁺. Characterization of the developed Ca²⁺-crosslinked EA-ALG NPs showed spherical, high stability NPs; successful loading of EA within crosslinked ALG NPs; and sustained release of EA. Male Swiss albino mice were divided into ten groups as follows; Group I- (control), Group II (50 mg EA /kg) - (EA), Group III polyethylene glycol (PEG), Group IV EA NPs (50 mg/kg) - (EA NP), Group (50 mg/kg alginate) V void V NPs - (void NPs), Group VI: (37.5 PTZ mg/kg) -(PTZ), Group VII: PTZ and EA - (PTZ-EA). Group VIII: animals received PTZ and PEG concurrently (PTZ-PEG). Group IX; animals received PTZ and void NPs concurrently - (PTZ-void). Group X: animals received PTZ and EA NPs concurrently (PTZ-EA NPs). PTZ was used to induce experimental epilepsy. Ca²⁺-ALG NPs prevented seizures throughout the experimental period and had a more prominent effect than free EA did. Ca²⁺-ALG NPs prevented increased glutamate, decreased GABA concentrations and ameliorated increased amyloid-β and homocysteine levels in the serum and brain. Ca²⁺-EA-ALG NPs were superior to free EA in improving increased IL-6 and TNF-α. Ca²⁺-ALG NPs ameliorated PTZ-induced oxidative stress, as evidenced by decreased 4HNE levels and enhanced GSH, GR and GPx levels in the brain. These changes were accompanied by amelioration of apoptosis and its regulating proteins, including Cytochrome C, P53, Bax, Bcl2 and caspase-3 and caspase-9, and protected against DNA damage. Histological examination of the hippocampus confirmed that the neuroprotective effect of Ca²⁺-EA-ALG NPs was superior and more effective than that of free EA.