Sustained release of a model water-soluble compound via dry powder aerosolizable acetalated dextran microparticles.

Objective: To design and characterize aerosol microparticles (MP) to provide sustained release of the water-soluble compound sulforhodamine B (SRB) and achieve effective aerosol dispersion. Significance: Modulating the release of water-soluble compounds remains a challenge in pulmonary drug delivery. Methods: SRB and water made up an aqueous solution, while acetalated dextran (Ac-Dex) and isopropyl alcohol made up an organic solution. The two solutions were mixed together, and the solution was spray dried to produce MP. MP were characterized for morphology, size, release kinetics, aerosol dispersion, and cellular interactions. Results: Ac-Dex MP exhibited corrugated morphology and aerodynamic diameters from 2.06 to 2.86 µm. MP deposited in all stages of a Next Generation Impactor, with >90% fine particle fraction. MP exhibited encapsulation efficiencies >129% with SRB loading values up to 16.7 µg SRB/mg MP. MP exhibited sustained release of SRB at pH 7 and fast release at pH 5. In vitro experiments showed minimal cytotoxicity, successful uptake of MP in epithelial cells, and no disruption to the integrity of epithelial monolayers. Conclusions: Ac-Dex MP systems demonstrated the ability to provide sustained the release of a water-soluble therapeutic in addition to effective aerosol dispersion for pulmonary applications.

Early inhibition of TNFalpha increases 6-hydroxydopamine-induced striatal degeneration.

Evidence suggests that tumor necrosis factor alpha (TNF) is a leading cause of dopaminergic neuronal cell death. TNF also, however, has neuroprotective effects. Thus, TNF might have a dual role following injury: immediate release after injury is protective, whereas chronic increases are detrimental. In the present study, 6-hydroxydopamine was used to lesion the dorsal striatum in male Fisher 344 rats at 2 different time points. Group 1 received a daily injection of TNFalpha antisense oligodeoxyribonucleotide (ODN) or control on days 1 through 7 post-lesion. Group 2 received a daily injection of TNF antisense ODN or control on days 5 through 15 post-lesion. Rats were killed on the day following the last injection of TNF antisense ODN. Injection of TNF antisense ODN on days 1 through 7 increased the area of the tyrosine-hydroxylase-negative zone ipsilateral to the injection when compared to controls. In contrast, when inhibition of TNF was delayed, the area of tyrosine hydroxylase loss was significantly reduced. These findings suggest that TNF release is neuroprotective in the early stages of injury but becomes neurotoxic when chronically induced.

Pomegranate's Neuroprotective Effects against Alzheimer's Disease Are Mediated by Urolithins, Its Ellagitannin-Gut Microbial Derived Metabolites.

Pomegranate shows neuroprotective effects against Alzheimer's disease (AD) in several reported animal studies. However, whether its constituent ellagitannins and/or their physiologically relevant gut microbiota-derived metabolites, namely, urolithins (6H-dibenzo[b,d]pyran-6-one derivatives), are the responsible bioactive constituents is unknown. Therefore, from a pomegranate extract (PE), previously reported by our group to have anti-AD effects in vivo, 21 constituents, which were primarily ellagitannins, were isolated and identified (by HPLC, NMR, and HRESIMS). In silico computational studies, used to predict blood-brain barrier permeability, revealed that none of the PE constituents, but the urolithins, fulfilled criteria required for penetration. Urolithins prevented ß-amyloid fibrillation in vitro and methyl-urolithin B (3-methoxy-6H-dibenzo[b,d]pyran-6-one), but not PE or its predominant ellagitannins, had a protective effect in Caenorhabditis elegans post induction of amyloid ß(1-42) induced neurotoxicity and paralysis. Therefore, urolithins are the possible brain absorbable compounds which contribute to pomegranate's anti-AD effects warranting further in vivo studies on these compounds.