Mannosylated fisetin/carveol lipid nanocapsules: brain-targeted dual therapy for modulation of epileptogenesis and cognitive deficits.

Pharmacological treatment of epilepsy is challenged by several barriers with the blood brain barrier (BBB) imposing the utmost restrictions to brain drug delivery. Antiepileptic drugs aim to reduce seizures frequency and severity while exerting minimal toxic effects. Herein, the merits of phytomedicine and brain targeted nanocarriers were combined for the control of seizures in a chronic epilepsy model. Fisetin (FS); a polyphenol and carveol (CAR); a limonene monoterpenoid were selected for their neuroprotective roles and co-loaded into lipid nanocapsules (FS/CAR@LNC). This was further decorated with mannose by post insertion targeting glucose transporter (GLUT-1) overexpressed on BBB (MAN-FS/CAR@LNC). The optimized MAN-FS/CAR@LNC revealed good colloidal properties with particle size (53.17 ± 4.06 nm), and low polydispersity index (0.11) and 26.9 ± 1.05 mV zeta potential. A high entrapment efficiency exceeding 99% and sustained drug release profile over 72 h were observed for both FS and CAR. In the in vivo imaging system (IVIS), MAN-FS/CAR@LNC attained 1.3-fold increase in fluorescence intensity at 5 h interval compared to FS/CAR@LNC. Following intraperitoneal administration in PTZ- induced chronic epilepsy mouse model, MAN-FS/CAR@LNC achieved maximal control of epileptic seizures accompanied with rehabilitation of locomotion, depressive and anxiety like-behaviors compared to FS/CAR and FS/CAR@LNC. Similarly, analysis of biomarkers reflecting depression and anxiety actions (brain-derived neurotrophic factor; BDNF, serotonin and glutamate) together with inflammatory markers (IL-6 and IL-1ꞵ) and histopathological assessment affirmed MAN-FS/CAR@LNC excelling in enhancing LNC brain targetability and hence seizures control. In conclusion, FS/CAR co-therapy aided with mannosylated LNC could present a compelling podium for the effective management of CNS disorders.