Short-term effects of an endotoxin on substantia nigra dopamine neurons

Abstract

Inflammation has been implicated in the pathology of several neurodegenerative diseases, including Parkinson’s disease (PD). Studies using the endotoxin lipopolysaccharide (LPS), a potent inflammogen, show that systemic insults can trigger prolonged microglial activation and pro-inflammatory cytokine production leading to degeneration of substantia nigra (SN) dopamine (DA) neurons, mimicking idiopathic PD. Because rapid effects of LPS on SN neurons had not been investigated previously, the focus of this study is to assess time-dependent alterations in SN neuroinflammation, DAergic neurons, and neuronal signaling cascades following LPS administration. LPS (5 mg/kg, i.p.) or saline (0.9% NaCl) was administered to 8-month-old male mice. At 3hrs, 5hrs, and 12hrs post-injection, the morphology of the SN was assessed using antibodies directed against tyrosine hydroxylase (TH, DAergic marker), Iba-1 (pan-microglial marker), phospho-ERK, and phospho-CREB (signaling). LPS administration significantly reduced TH-immunoreactivity (ir) at all time-points with the greatest reduction observed at 12 h post-injection. Reduced TH-ir was accompanied by a significant increase in activated microglia at all time-points following LPS. By 12 h post-injection, LPS-treated mice exhibited activated as well as reactive microglia, which can result in neuronal damage. These data demonstrate that the initial reduction in TH-ir observed after an LPS injection was not concomitant with morphological alterations in microglial cells, even though a significant increase in phospho-ERK was observed in glial cells as soon as 3 h post-injection. It is possible that the initial alteration in DA phenotype (TH reduction) may perpetuate an inflammatory response that persists and leads to further DAergic damage.

Characterization of 11C-GSK1482160 for Targeting the P2X7 Receptor as a Biomarker for Neuroinflammation

“…To determine the morphology and spatial distribution of microglial activation, immunohistochemistry analysis against Iba1 was performed in the brains of saline-and lipopolysaccharidetreated mice. As shown in Figures 5A-5D, administration of lipopolysaccharide at 72 h resulted in a frank increase in Iba1 staining over saline, which is consistent with prior reports at earlier time points (24,25). Interestingly, the magnitude of the response as measured by image analysis of signal enhancement was consistent with Western blot analysis obtained from the lipopolysaccharide time courses at 72 h (Fig.…”

“…In the current study, brainderived protein levels of Iba1 (normalized to b-actin) in response to intraperitoneal lipopolysaccharide administration revealed a progressive rise in Iba1 content through 72 h (Fig. 4B), which is significantly longer than previously reported (23)(24)(25). It is unclear what the differences between these studies may be, but recent work on the role of gut microflora in germ-free mice suggests that elevated IL10 levels may play a role in murine immune response to lipopolysaccharide (26) and that prior exposure via gut microflora may play a substantial role in a heightened immune response.…”

Vagus nerve stimulation improves locomotion and neuronal populations in a model of Parkinson's disease

“…In order to determine the effects of VNS on microglia, the pan microglial marker Iba-1 was used [38] in the LC and SN (Figure 6). Iba-1-ir density was conducted to assess microglia using a 2-way ANOVA, which revealed an interaction between these factors in the LC, with main effects of both Lesion and Stimulation in the LC and SN (Table 1).…”

Inhibition of semicarbazide‐sensitive amine oxidase/vascular adhesion protein‐1 reduces lipopolysaccharide‐induced neuroinflammation

“…Both systemic and i.c.v. LPS induce a progressive neurodegeneration of dopaminergic neurons in the substantia nigra, suggesting a particular sensitivity of the substantia nigra to the inflammatory process and oxidative stress, whether the insult comes from within the brain or from the periphery (Liu and Hong, ; Qin et al , ; Ji et al , ; Zhou et al , ; Reinert et al , ).…”