The influence of microglia on the pathogenesis of Parkinson's disease

Neuroinflammation in the pathophysiology of Parkinson’s disease and therapeutic evidence of anti-inflammatory drugs

“…The specific antigens that trigger the adaptive immune response and lymphocytic infiltration have not been identified but likely include oxidatively-modified a-synuclein, particularly the nitrated form, released from dying neurons 13,14 . Activation of microglia, the resident immune cells of the CNS, has been evidenced in post-mortem brains of PD patients, mainly in the SN and putamen, the most affected areas in this disease, but also in hippocampus and many cortical areas such as transentorhinal, cingulate and temporal cortices, where neuronal loss is also important 5,15,16 . Microglia can be activated by molecules released by dying dopaminergic neurons such as a-synuclein aggregates, ATP, matrix metalloproteinase-3 (MMP-3) and neuromelanin.…”

“…Microglia can be activated by molecules released by dying dopaminergic neurons such as a-synuclein aggregates, ATP, matrix metalloproteinase-3 (MMP-3) and neuromelanin. Lipopolysaccharide (LPS) also activates microglia both in vitro and in vivo 5 . Several studies support the hypothesis that activation of the nuclear factor kappa-B (NF-kB) plays an important role in PD pathogenesis.…”

“…When NF-kB is activated, it enters the nucleus and stimulates the gene transcription of several proinflammatory factors including inducible nitric oxide synthase (iNOS), interleukin (IL)-1b, IL-6, cyclooxigenase 2 (COX-2) and tumor necrosis factor-a (TNF-a by the microglia 19,20 . Probably because of this, the proinflammatory cytokines IL-1b, TNF-a, IL-2 and IL-6 are expressed at higher levels in PD post-mortem brains as well as in cerebrospinal fluid (CSF) and serum of PD patients, compared with age-matched controls 5 . In addition, the inflammatory process associated with an increase in COX-2 expression and elevated concentrations of prostaglandin E2 (PGE2) have been implicated in the deleterious events that leads to neuronal degeneration in PD 21 .…”

“…The disease is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), loss of their ascending projections to the striatum (caudate and putamen), and consequent decrease of striatal dopamine (DA) content, which leads to severe locomotion difficulties and cardinal motor symptoms such as tremor at rest, rigidity, postural instability and slowness of body movements (bradykinesia) 4,5 . By the time a patient is diagnosed, approximately 60% of SNpc neurons are degenerated and 80% of striatal DA content is depleted 4,5 . In addition to neuronal damage, PD is characterized by the presence of proteinaceous inclusions called Lewy bodies and Lewy neurites, mainly in the SNpc 6 .…”

Neurotrophic factors for the treatment of Parkinson's disease

“…Approximately 5% of PD cases are caused by heritable genetic mutations. The remaining cases are sporadic and of unknown origin, although many theories have been proposed to explain the cause of dopaminergic neuronal death which occurs in PD, such as environmental toxins, mitochondrial dysfunction with resulting oxidative stress, and inflammatory mechanisms [4,5].…”