title: Intranasal Piperine-Loaded Chitosan Nanoparticles as Brain-Targeted Therapy in Alzheimer's Disease: Optimization, Biological Efficacy, and Potential Toxicity.
abstract: Piperine (PIP) is a phytopharmaceutical with reported neuroprotective potential in Alzheimer's disease (AD). Oral PIP delivery suffers from its hydrophobicity and pre-systemic metabolism. In this article, mono-disperse intranasal chitosan nanoparticles (CS-NPs) were elaborated for brain targeting of PIP. Formula optimization was based on particle size (PS), zeta potential (ZP), polydispersity index (PDI), % entrapment efficiency (% EE), release studies, and transmission electron microscopy. AD was induced in 48 male Wistar rats on which full behavioral and biochemical testing was conducted. Brain toxicity was assessed based on Caspase-3 assay for apoptosis and tumor necrosis factor for inflammation. Spherical NPs with optimum % EE (81.70), PS (248.50 nm), PDI (0.24), and ZP (+56.30 mV) were elaborated. PIP-NPs could significantly improve cognitive functions as efficient as standard drug (donpezil injection) with additional advantages of dual mechanism (Ach esterase inhibition and antioxidant effect). CS-NPs could significantly alleviate PIP nasal irritation and showed no brain toxicity. This work was the first to report additional mechanism of PIP in AD via anti-apoptosis and anti-inflammatory effects. To conclude, mucoadhesive CS-NPs were successfully tailored for effective, safe, and non-invasive PIP delivery with 20-folds decrease in oral dose, opening a gate for a future with lower AD morbidity.
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
authors.forename: Yosra S R
authors.initials: YS
authors.lastname: Elnaggar
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
authors.forename: Samar M
authors.initials: SM
authors.lastname: Etman
authors.affiliation: Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
authors.forename: Doaa A
authors.initials: DA
authors.lastname: Abdelmonsif
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
authors.forename: Ossama Y
authors.initials: OY
authors.lastname: Abdallah
mesh_terms: D000281:Administration, Intranasal; D000470:Alkaloids / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D052117:Benzodioxoles / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D001927:Brain Diseases / Q000139:chemically induced / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D048271:Chitosan; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects; D016503:Drug Delivery Systems; D008297:Male; D053758:Nanoparticles; D010316:Particle Size; D010880:Piperidines / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D053284:Polyunsaturated Alkamides / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000470:Alkaloids; D000975:Antioxidants; D052117:Benzodioxoles; D002800:Cholinesterase Inhibitors; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D014409:Tumor Necrosis Factor-alpha; D048271:Chitosan; C505410:Casp3 protein, rat; D053148:Caspase 3; C008922:piperine
keywords: Alzheimer's disease; chitosan; drug targeting; nanotechnology; nasal drug delivery; polymeric drug delivery systems