The findings from the current study concluded a cytokine-dependent regulation of astroglial CXCL10 and iNOS expression by alpha-synuclein and neuromelanin. Alpha-synuclein induced the expression of CXCL10 in both IL-1beta- and TNFalpha-stimulated astroglial cells, however, this enhancement by alpha-synuclein was not demonstrated for the mRNA. Studies revealed the ability of alpha-synuclein to mediate an increase in mRNA stability, which may be, in part, the mechanism responsible for the increase in CXCL10 protein expression. The NF-kappaB signaling pathway was not activated by alpha-synuclein under similar treatments that induced CXCL10 expression yet was activated in the presence of other alpha-synuclein concentrations, suggesting the expression of other inflammatory mediators besides CXCL10 may be modulated by alpha-synuclein. Alpha-synuclein also increased astroglial iNOS expression, further supporting the inflammation-mediated effects by alpha-synuclein.

Investigation of role of NM on astroglial chemokine expression revealed a down-regulation of CXCL10 protein expression with a reduction in NF-kappaB activation, suggesting a possible mechanism responsible for decrease in CXCL10 protein. NM enhanced cytokine-induced iNOS expression in the presence of astrocytes; however, further studies need to be conducted to understand the mechanism.

Overall, the findings provide an initial understanding of the effects of PD-associated molecules and inflammation on human brain cells. The regulation of astroglial-derived inflammatory mediators by extracellular alpha-synuclein and neuromelanin may play a role in PD-associated neuroinflammation. The observations provide novel information that may be useful in identifying molecular targets for therapeutic intervention in PD.