Abstract
Models of Parkinson's disease with neurotoxins have shown that microglial activation does not evoke a typical inflammatory response in the substantia nigra, questioning whether neuroinflammation leads to neurodegeneration. To address this issue, the archetypal inflammatory stimulus, lipopolysaccharide (LPS), was injected into the rat substantia nigra. LPS induced fever, sickness behavior, and microglial activation (OX42 immunoreactivity), followed by astrocyte activation and leukocyte infiltration (GFAP and CD45 immunoreactivities). During the acute phase of neuroinflammation, pro- and anti-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-4, and IL-10) responded differentially at mRNA and protein level. Increased NO production and lipid peroxidation occurred at 168 h after LPS injection. At this time, evidence of neurodegeneration could be seen, entailing decreased tyrosine hydroxylase (TH) immunoreactivity, irregular body contour, and prolongation discontinuity of TH+ cells, as well as apparent phagocytosis of TH+ cells by OX42+ cells. Altogether, these results show that LPS evokes a typical inflammatory response in the substantia nigra that is followed by dopaminergic neurodegeneration.
Highlights
Neuroinflammation plays a critical role in Parkinson’s disease and other neurodegenerative diseases [1, 2]
The untreated control rats maintained their body temperature at 32.65 ± 0.75°C, whereas the rats injected with LPS gradually increased their body temperature to a maximum of 38.25 ± 0.15°C detected at 8 h postinjection (Figure 1(a))
Our results provide three pieces of evidence that sustain the degeneration of dopaminergic neurons in the substantia nigra at 168 h after LPS injection: (1) the decrease in tyrosine hydroxylase (TH) immunoreactivity shown by TH immunofluorescence and immunohistochemistry assays that were performed together with glial markers (OX42 and glial fibrillary acidic protein (GFAP)) and H&E, respectively, (2) the irregular body contour and prolongation
Summary
Neuroinflammation plays a critical role in Parkinson’s disease and other neurodegenerative diseases [1, 2]. The participation of glial cells in the neuroinflammation of Parkinson’s disease has been characterized to a large extent in animal models generated by neurotoxins such as 6-hydroxydopamine (6-OHDA), 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), or rotenone [5, 16,17,18,19]. These potent neurotoxins primarily cause the death of dopaminergic neurons, so they have not favored the clarification whether neuroinflammation is the cause or consequence of dopaminergic neurodegeneration. Lipopolysaccharide (LPS) appears to be a neuroinflammatory stimulus more suitable to mimic the acute response of microglia that might occur in the early stage of Parkinson’s disease [20]
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