Hanna_2023_Expert.Opin.Drug.Deliv__

OBJECTIVES: Oxaliplatininduces chemobrain in cancer patients/survivors. Nutraceuticalnaringin has antioxidant and anti-inflammatory properties with low oralbioavailability. Our aim was to formulate naringin in chitosan nanoparticles fornose to brain delivery and assess its neuroprotective effect against oxaliplatin-inducedchemobrain in rats. METHODS: Naringinchitosan nanoparticles were prepared by ionic gelation. Rats were administeredoral naringin (80 mg/kg), intranasal naringin (0.3 mg/kg) or intranasal naringin-loadedchitosan nanoparticles (0.3 mg/kg). Naringin's neuroprotective efficacy wasassessed based on behavioral tests, histopathology, and measuring oxidativestress and inflammatory markers. RESULTS: Selectednanoparticles formulation showed drug loading of 5%, size of 150 nm and werecationic. Intranasal naringin administration enhanced memory function,inhibited hippocampal acetylcholinesterase activity, and corrected oxaliplatin-inducedhistological changes. Moreover, it reduced malondialdehyde and elevated reducedglutathione hippocampal levels. Furthermore, it decreased levels of inflammatorymarkers: NF-kB and TNF-alpha by 1.25-fold.Upstream to this inflammatory status, intranasal naringin downregulated thehippocampal protein levels of two pathways: cGAS/STINGand HMGB1/RAGE/TLR2/MYD88. CONCLUSION: Intranasalnaringin-loaded chitosan nanoparticles showed superior amelioration ofoxaliplatin-induced chemobrain in rats at a dose 267-fold lower to thatadministered orally. The potential involvement of cGAS/STINGand HMGB1/RAGE/TLR2/MYD88 pathways in the mechanistic process of eitheroxaliplatin-induced chemobrain or naringin-mediated neuroprotection was evidenced.