Microglia as a posible pathomechanism in Parkinson's diseases

It has been suggested that neuroinflammatory mechanisms augment the progression of Parkinson's disease (PD): Apart from the massive loss of dopaminergic neurons, PD brains also show a conspicuous microglial reaction accompanied by elevated cytokine levels and upregulation of inflammatory-associated factors. However, endogenous factors initiating microglial activation are largely unknown. We therefore investigated the effects of human neuromelanin (NM) on the release of neurotoxic mediators and the underlying signaling pathways from rat microglia in vitro. The addition of NM to microglial cultures induced positive chemotactic effects, activated the proinflammatory transcription factor nuclear factor kappaB (NF-kappaB) via phosphorylation and degradation of the inhibitor protein kappaB (IkappaB), and led to an up-regulation of tumor necrosis factor alpha, interleukin-6, and nitric oxide. The impairment of NF-kappaB function by the IkappaB kinase inhibitor sulfasalazine was paralleled by a decline in neurotoxic mediators. We propose that, in PD, NM plays a crucial role in the cascade of events leading to nerve cell death, thus propagating the neurodegenerative process. We summarize and discuss the latest findings regarding neuroinflammatory aspects in PD.