Nigrostriatal Inflammation Is Associated with Nonmotor Symptoms in an Experimental Model of Prodromal Parkinson's Disease.

Recent evidence has supported a pathogenic role for neuroinflammation in Parkinson's disease (PD). Inflammatory response has been associated with symptoms and subtypes of PD. However, it is unclear whether immune changes are involved in the initial pathogenesis of PD, leading to the non-motor symptoms (NMS) observed in its prodromal stage. The current study aimed to characterize the behavioral and cognitive changes in a toxin-induced model of prodromal PD-like syndrome. We also sought to investigate the role of neuroinflammation in prodromal PD-related NMS. Male mice were subjected to bilateral intranasal infusion with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or saline (control group), followed by comprehensive behavioral, pathological and neurochemical analysis. Intranasal MPTP infusion was able to cause the loss of dopaminergic neurons in the substantia nigra (SN). In parallel, it induced impairment in olfactory discrimination and social memory consolidation, compulsive and anxiety-like behaviors, but did not influence motor performance. Iba-1 and GFAP expressions were increased in the SN, suggesting an activated state of microglia and astrocytes. Consistent with this, MPTP mice had increased levels of IL-10 and IL-17A, and decreased levels of BDNF and TrkA mRNA in the SN. The striatum showed increased IL-17A, BDNF, and NFG levels compared to control mice. In conclusion, neuroinflammation may play an important role in the early stage of experimental PD-like syndrome, leading to cognitive and behavioral changes. Our results also indicate that intranasal administration of MPTP may represent a valuable mouse model for prodromal PD.

Physicochemical Characterization and Skin Permeation of Cationic Transfersomes Containing the Synthetic Peptide PnPP-19.

BACKGROUND: PnPP-19 is a 19-amino-acid synthetic peptide previously described as a novel drug for the treatment of erectile dysfunction. OBJECTIVE: The aim of this work was to evaluate the physicochemical properties of cationic transfersomes containing PnPP-19 and the skin permeation of free PnPP-19 and PnPP-19-loaded transfersomes. METHODS: Three different liposomal preparation methods were evaluated. Cationic transfersomes contained egg phosphatidyl choline: stearylamine (9:1 w/w) and Tween 20 (84.6:15.4 lipid:Tween, w/w). Lipid concentration varied from 20 to 40 mM. We evaluated the entrapment percentage, mean diameter, zeta potential and stability at 4 °C of the formulations. The skin permeation assays were performed with abdominal human skin using Franz diffusion cell with 3 cm2 diffusion area at 32 °C and a fluorescent derivative of the peptide, containing 5-TAMRA, bound to PnPP-19 C-terminal region, where an extra lysine was inserted. RESULTS: Our results showed variable entrapment efficiencies, from 6% to 30%, depending on the preparation method and the lipid concentration used. The reverse phase evaporation method using a total lipid concentration equal to 40 mM led to the best entrapment percentage (30.2 + 4.5%). Free PnPP-19 was able to permeate skin at a rate of 10.8 ng/cm2/h. However, PnPP-19 was specifically hydrolyzed by skin proteases, generating a fragment of 15 amino acid residues. Encapsulated PnPP-19 permeated the skin at a rate of 19.8 ng/cm2/h. CONCLUSION: The encapsulation of PnPP-19 in cationic transfersomes protected the peptide from degradation, favoring its topical administration.