Role of Inflammation in MPTP-Induced Dopaminergic Neuronal Death

摘要

Parkinson's Disease (PD) is the second most common neurodegenerative disease that affects our aging population. One of the most consistent pathological features of this disorder is neuroinflammation which is characterized by a significant presence of activated microglia, a prominent astrocytosis and the up-regulation of certain enxymes known to produce toxic compounds in the substantia nigra pars compacta (SNpc) of the brain. We, as researchers of PD, have asked the question what does the presence of neuroinflammation have to do with PD. The answers may be that this neuroinflammation is the root cause of the progressive nature of PD. Based on what we know from pathological studies and using the MPTP (1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine) mouse model of PD, which replicates almost all of the hallmarks of PD and produces an oxidative stress in the substantia nigra (SN) of the brain, we examined the role of inflammation in MPTP-induced dopaminergic neuron death in the MPTP-treated mouse. We found that indeed both microglia and astrocytes are activated in the SNpc, that certain enzymes, such as NADPH oxidase and inducible nitric oxide synthase that produce toxic compounds such as the superoxide and nitric oxide are up-regulated in this area following MPTP administration and that the cyclooxygenase type II (COX-2) enzyme is involved here. These findings were documented to be present in the human PD brain. Furthermore, we showed that we could mitigate the MPTP-induced up-regulation of these toxic producing enzymes by pharmacological means through the use of specific blockers of these enzymes. In covering all bases, noting that it is the neuromelanin-containing dopaminergic neuron in the SNpc that is dying in PD, thus spilling their contents into the microenvironment surrounding the dopaminergic neuron, we investigated the role of neuromelanin in the production of inflammation in the SNpc of rats.