Year of publication:
Journal title abbreviated:
CURR PHARM DESIGN
Journal title long:
Current pharmaceutical design : a timely review journal on recent advances in drug design
Agents suppressing microglial activation are attracting attention as candidate drugs for neuroprotection in Parkinson s disease (PD): While different mechanisms including environmental toxins and genetic factors initiate neuronal damage in the substantia nigra and striatum in PD, there is unequivocal evidence that activation of neuroinflammatory cells aggravates this neurodegenerative process. It was shown that following an acute exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and other toxins the degenerative process continues for years in absence of the toxin. Reactive microglia has been observed in the substantia nigra of patients with PD, indicating that this inflammatory process might aggravate neurodegeneration. By releasing various kinds of noxious factors such as cytokines or proinflammatory molecules microglia may damage CNS cells. The stimuli triggering microgliosis in Parkinsonian syndromes are unknown so far: However, analysis of neuronal loss in PD patients shows that it is not uniform but that neurons containing neuromelanin (NM) are predominantly involved. We hypothesized that extraneuronal melanin might trigger microgliosis, microglial chemotaxis and microglial activation in PD with subsequent release of neurotoxic mediators. The addition of human NM to microglial cell cultures induced positive chemotactic effects, activated the pro-inflammatory transcription factor nuclear factor kappa B (NF-kappaB) via phosphorylation and degradation of the inhibitor protein kappaB (IkappaB), and led to an upregulation of TNF-alpha, IL-6 and NO. These findings demonstrate a crucial role of NM in the pathogenesis of Parkinson''s disease by augmentation of microglial activation, leading to a vicious cycle of neuronal death, exposure of additional neuromelanin and chronification of inflammation. Antiinflammatory drugs may be one of the new approaches in the treatment of PD.