Preclinical and clinical evidences have demonstrated that astroglial-derived S100B protein is a key element in neuroinflammation underlying the pathogenesis of Parkinson's disease (PD), so much as that S100B inhibitors have been proposed as promising candidates for PD targeted therapy. Pentamidine, an old-developed anti-protozoal drug, currently used for pneumocystis carinii is one of the most potent inhibitors of S100B activity, but despite this effect, is limited by its low capability to cross blood brain barrier (BBB). To overcome this problem, we developed a non-invasive intranasal delivery system, chitosan coated niosomes with entrapped pentamidine (inPentasomes), in the attempt to provide a novel pharmacological approach to ameliorate parkinsonism induced by subchronic MPTP administration in C57BL-6J mice. inPentasomes, prepared by evaporation method was administered daily by intranasal route in subchronic MPTP-intoxicated rodents and resulted in a dose-dependent manner (0.001-0.004 mg/kg) capable for a significant Tyrosine Hydroxylase (TH) positive neuronal density rescue in both striatum and substantia nigra of parkinsonian mice. In parallel, inPentasomes significantly decreased the extent of glial-related neuroinflammation through the reduction of specific gliotic markers (Iba-1, GFAP, COX-2, iNOS) with consequent PGE(2) and NO2- release reduction, in nigrostriatal system. inPentasomes-mediated S100B inhibition resulted in a RAGE/NF-kappa B pathway downstream inhibition in the nigrostriatal circuit, causing a marked amelioration of motor performances in intoxicated mice. On the basis of our results, chitosan coated niosomes loaded with pentamidine, the inPentasome system, self-candidates as a promising new intranasal approach to mitigate parkinsonism in humans and possibly paves the way for a possible clinical repositioning of pentamidine as anti-PD drug.
|Titolo:||inPentasomes: An innovative nose-to-brain pentamidine delivery blunts MPTP parkinsonism in mice|
|Parole Chiave:||Pentamidine; Parkinson's disease; Chitosan coated niosomes; Nose-to-brain delivery; Neuroinflammation; S100B-pentamidine inhibition|
|Settore Scientifico Disciplinare:||Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin)|
Settore CHIM/09 - Farmaceutico Tecnologico Applicativo
|Data di pubblicazione:||28-gen-2019|
|Digital Object Identifier (DOI):||10.1016/j.jconrel.2018.12.007|
|Appare nelle tipologie:||01 - Articolo su periodico|