Inflammation in Parkinson's disease: the role of activated microglia

Abstract

Glial inflammation was viewed previously as a bystander effect, or epiphenomenon, with inflammation occurring when damaged neurons elicit an activation response by glia. However, an accumulating body of evidence has challenged this perspective and indicates an active role of neuroinflammation in the pathophysiology of neurodegenerative disorders as Parkinson's disease (PD). Agents suppressing microglial activation are attracting attention as candidate drugs for neuroprotection in PD: While different mechanisms including environmental toxins and genetic factors initiate neuronal damage in the basal ganglia in PD, there is now unequivocal evidence that activation of neuroinflammatory cells, especially microglia 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) the degenerative process continues for years in absence of the toxin. Large numbers of reactive microglia have been observed in the substantia nigra of PD patients, indicating that this inflammatory process aggravates 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: 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, chemotaxis and microglial activation in PD with subsequent release of proinflammatory and possible neurotoxic mediators like NO, TNF-alpha and IL-6. The addition of human NM to microglial cell cultures induced positive chemotactic effects, and led to an upregulation of TNF-alpha, IL-6 and NO. To further investigate the possible role of NM in the pathogenesis of PD we conducted in vivo experiments which showed that microglial cells become activated and neurotoxic after injection of human neuromelanin (NM) into the substantia nigra as compared to control animals injected with gold particles of comparable size and weight. 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.