The lack of efficacy of IVIg may also reflect the poor CNS access owing to the presence of the Calcitriol IL-2 blood brain barrier. However, our data rather suggest that IVIg dis played significant central bioavailability after systemic administration. Indeed, a fraction of intraperitoneally administered IVIg was detected in the striatum of trea ted mice using a specific ELISA, consistent with a previ ous report where peripherally administered IVIg was also detected in APP PS1 mouse brain using immuno histochemistry. A number of studies have reported data consistent Inhibitors,Modulators,Libraries with the penetration of a fraction of sys temically administered antibodies into brain tissues lead ing to central therapeutic effect. Interaction between Fc gamma receptor and immunoglobu lins is essential for the initiation of cellular and humoral responses.

In the CNS, Fc��R are expressed on endothe lial cells, neurons, microglia, oligodendrocytes and astro cytes and the IVIg migration to critical regions of the brain, such as the striatum and SNpc in PD, might act as a central immunomodulating Inhibitors,Modulators,Libraries agent. A previous report showed that approximately Inhibitors,Modulators,Libraries 30% of pigmented SNpc neurons were IgG positive in PD patients but not in controls. This suggests that IgG can access the brain during the course of the disease. However, we found no increase in striatal IgG content in MPTP treated animals. The amount Inhibitors,Modulators,Libraries of human IgG detected in the brain of treated mice suggests that low central bioavailability is unlikely to be the sole reason for the lack of efficacy of IVIg in restoring the DAergic pathways.

After systemic injection, MPTP produces a reprodu cible lesion of the Inhibitors,Modulators,Libraries nigrostriatal DAergic pathway by causing http://www.selleckchem.com/products/Bosutinib.html oxidative stress, mitochondrial damage and neuronal cell death, as in idiopathic PD. Validation of disease modifying treatments before clinical trial initi ation is therefore often performed in MPTP treated ro dent models. However, these models are not without important limitations. First, the MPTP model used here does not generate a massive degenera tion, which is required for clinically detectable motor symptoms in humans. This explains, at least in part, why motor symptoms in the MPTP mouse model are insuffi ciently reliable for systematic assessment and were not evaluated here after IVIg treatment. To investi gate the symptomatic effects of IVIg, the use of the more expensive MPTP monkey model should be considered instead. Second, the acute mouse MPTP model does not replicate synucleinopathy or Lewy bodies, which are pathognomonic of PD. The use of other models such as the chronic infusion MPTP models or transgenic mice overexpressing human syn might be helpful for these purposes. Third, the re sponse of a mouse model to human IVIg may differ from humans.