Effects of chronic systemic treatment with peroxisome proliferator-activated receptor α activators on neuroinflammation induced by intracerebral injection of lipopolysaccharide in adult mice.
- Authors
- Wang, Guangming; Namura, Shobu
- Year
- 2011
- Journal
- Neuroscience research
- PMID
- 21300114
- DOI
- 10.1016/j.neures.2011.02.001
- PMCID
- PMC3092009
We examined whether chronic systemic treatment with agonists for peroxisome proliferator-activated receptor α (PPARα) influences neuroinflammation induced by lipopolysaccharide (LPS) injection into the somatosensory cortex in adult mice. Mice were pretreated with Wy-14643 or fenofibrate, both at 30 mg/kg, for 7 days. These treatment protocols increased the amount of PPARα mRNA and active form of PPARα protein in the brain. LPS injection reduced the PPARα mRNA level in the brain. On the contrary, TNFα, IL-1β, IL-6, iNOS, COX-2, ICAM-1, VCAM-1, and PECAM-1 were elevated at 6h after LPS. Wy-14643 and fenofibrate inhibited the elevations of TNFα, IL-1β, IL-6, COX-2, ICAM-1, and VCAM-1. Wy-14643, but not fenofibrate, also attenuated the iNOS elevation. At 3 days after LPS, Wy-14643 and fenofibrate showed similar inhibitions in these molecules. LPS injection also elevated IL-6 protein levels in the brain and serum at 6h, which was inhibited by fenofibrate. Histological analyses showed that Wy-14643 and fenofibrate profoundly attenuated microglia/macrophage activation, neutrophil recruitment, and neuronal injury at 3 days after LPS. These findings suggest that activation of PPARα attenuates neuroinflammation in the adult mouse brain, implicating that PPARα may be a potential therapeutic target for CNS diseases in which neuroinflammation plays a substantial role.
Photomicrographs showing Isolectin B4 staining at 3 days after LPS injection in the somatosensory cortex. LPS was at different doses: (A) 0 ng, (B) 20 ng, (C) 50 ng, and (D) 100 ng. At 20 ng, ramified microglia were mainly seen (B) while round-shape phagocytic cells were the majority at 100 ng (D). Scale bar, 250 μm (40 μm for the inlets).
LLM interpretation
This figure consists of four photomicrographs (A-D) showing Isolectin B4 staining in the somatosensory cortex following different doses of LPS injection (0 ng, 20 ng, 50 ng, and 100 ng). As the LPS dose increases, there is a visible increase in the density of stained cells, transitioning from ramified microglia at 20 ng (B) to predominantly round-shaped phagocytic cells at 100 ng (D). Each panel includes a high-magnification inlet and a scale bar (250 μm for main images, 40 μm for inlets).
Effects of Wy-14643 and fenofibrate on PPARα protein activation in non-LPS injected brains. PPARα protein activation was measured by electrophoretic mobility shift assay using nuclear protein from the brain. V, vehicle; W, Wy-14643 at 30 mg/kg; F, fenofibrate at 30 mg/kg. Experiments were done in 5 animals in each group. Data are shown mean + SD. ***P<0.001 compared to vehicle group. Statistical analysis was made by one-way ANOVA followed by Scheffe post-hoc test.
LLM interpretation
Figure A shows an electrophoretic mobility shift assay (EMSA) image with bands for three groups: vehicle (V), Wy-14643 (W), and fenofibrate (F). Figure B is a bar chart quantifying the relative levels of PPARα protein activation, showing that both Wy-14643 and fenofibrate significantly increase activation compared to the vehicle group. Statistical significance for both treatment groups is indicated by asterisks (***P<0.001).
Effects of Wy-14643 or fenofibrate on the mRNA levels of PPARα and pro-inflammatory molecules in brains before LPS injection and at 6 hours and 3 days after LPS. For the groups before LPS, the mean value from the vehicle-treated group was considered as one, and then relative expression levels in other treatment groups were calculated for each molecule. For the groups after injection, the mean value from the saline-injected group at 6 hours was considered as one. V, vehicle; W, Wy-14643 at 30 mg/kg; F, fenofibrate at 30 mg/kg. Experiments were done in 5 animals in each group. Data are shown mean + SD. #P<0.05, ##P<0.01, ###P<0.001 compared to vehicle-treated group; *P<0.05, **P<0.01, and ***P<0.001 compared to saline-injected group. Statistical analysis was made by one-way ANOVA followed by Scheffe post-hoc test.
LLM interpretation
This figure consists of nine bar charts (A-I) showing the relative mRNA expression levels of PPAR$\alpha$ and various pro-inflammatory molecules (TNF$\alpha$, IL-1$\beta$, IL-6, iNOS, COX-2, ICAM-1, VCAM-1, and PECAM-1) in the brain. Data are compared across three time points (Before, 6 hours, and 3 days) and three treatment groups: vehicle (V), Wy-14643 (W), and fenofibrate (F), with further distinctions between saline and LPS injections. Statistical significance is indicated by hashtags (#) for comparisons to the vehicle group and asterisks (*) for comparisons to the saline-injected group.
Effects of fenofibrate on IL-6 protein levels in brain (A) and serum (B) measured by ELISA at 6 hours after LPS injection. V, vehicle; W, Wy-14643 at 30 mg/kg; F, fenofibrate at 30 mg/kg. Experiments were done in 5 animals in each group. Data are shown as mean + SD. *P<0.05, **P<0.01 and ***P<0.001 compared to saline-injected group; ##P<0.01 compared to vehicle-treated LPS-injected group. Statistical analysis was made by one-way ANOVA followed by Scheffe post-hoc test.
LLM interpretation
This figure consists of two bar charts showing IL-6 protein levels in the brain (A) and serum (B) across three groups: saline-injected (-), vehicle-treated LPS-injected (V), and fenofibrate-treated LPS-injected (F). In both tissues, LPS injection significantly increased IL-6 levels compared to the saline group (***P<0.001), while treatment with fenofibrate significantly reduced these levels compared to the vehicle group (###P<0.001). The y-axes measure IL-6 concentration in ng/mg protein for the brain and ng/ml serum for the serum, with data presented as mean + SD.
LPS injection into the cortex activates microglia/macrophages and recruits neutrophils to the injection site. Fluorescent double-immunostaining showing Iba1 and IL-6 (A) and neutrophil elastase (NE) and iNOS (B) in the somatosensory cortex at 6 hours after LPS injection. Representative images taken from at least 3 animals are shown. Scale bar, 30 μm.
LLM interpretation
This figure consists of two rows of fluorescent double-immunostaining microscopy images from the somatosensory cortex 6 hours after LPS injection. Row A shows the expression and colocalization of Iba1 (green) and IL-6 (red), while Row B shows the expression and colocalization of neutrophil elastase (NE, green) and iNOS (red). The merged images on the right of each row demonstrate overlapping signals (yellow/orange), indicating the presence of both markers in the same cells. Scale bars are provided at 30 μm.
Effects of Wy-14643 and fenofibrate on histological outcomes of neuroinflammation. (A) Photomicrographs showing Iba1 immunostaining (left column) and neutrophil elastase immunostaining (right column) in the somatosensory cortex at 3 days after LPS injection. Scale bar, 200 μm (40 μm for the inlets). (B) Numbers of Ib1a immunoreactive cells at 3 days after LPS injection. (C) Numbers of neutrophil elastase immunoreactive cells at 3 days after LPS injection. (D) Numbers of Isolectin B4 stained cells at 6 hours and 3 days after LPS injection. V, vehicle; W, Wy-14643 at 30 mg/kg; F, fenofibrate at 30 mg/kg. Experiments were done in 5 animals in each group. Data are shown as mean + SD. ***P<0.001 compared to saline-injected group; #P<0.05, ###P<0.001 compared to vehicle-treated LPS-injected group. Statistical analysis was made by one-way ANOVA followed by Scheffe post-hoc test.
LLM interpretation
This figure consists of photomicrographs (A) and three bar charts (B, C, D) quantifying neuroinflammation in the somatosensory cortex following LPS injection. Photomicrographs and corresponding bar charts show that LPS injection significantly increases the number of Iba1-positive and neutrophil elastase-positive cells compared to saline, while treatment with Wy-14643 (W) or fenofibrate (F) significantly reduces these counts (P<0.001). Chart D shows that LPS increases Isolectin B4-stained cells at 6 hours and 3 days, with both W and F treatments significantly attenuating this effect (P<0.05 or P<0.001).
Effects of Wy-14643 and fenofibrate on histological outcomes of neuronal injury. (A) Fluorescent photomicrographs showing Fluoro-Jade B staining at 3 days after LPS injection. Animals were treated with either Wy-14643 or fenofibrate for 7 days before LPS and continued until brain was collected. Scale bar, 200 μm. (B) Numbers of Fluoro-Jade B stained cells at 6 hours and 3 days after LPS injection. (C) Brain tissue injury volume determined by cresyl violet staining at 3 days after LPS. (D) Graph showing effects of post-LPS treatment with fenofibrate on brain tissue injury volume at 3 days after LPS. Veh and V, vehicle; Wy and W, Wy-14643 at 30 mg/kg; F30 and F, fenofibrate at 30 mg/kg. Experiments were done in 5–7 animals in each group. Data are shown as mean + SD. ***P<0.001 compared to saline-injected group; ##P<0.01 and ###P<0.001 compared to vehicle-treated LPS-injected group. Statistical analysis was made by one-way ANOVA followed by Scheffe post-hoc test.
LLM interpretation
This figure consists of fluorescent photomicrographs (A) and three bar charts (B, C, D) evaluating the effects of Wy-14643 (Wy/W) and fenofibrate (F30/F) on LPS-induced neuronal injury. Panel A shows Fluoro-Jade B staining, with the LPS+Vehicle group exhibiting the highest density of positive cells compared to saline and treated groups. Bar charts B and C quantify Fluoro-Jade B positive cells and cresyl violet lesion volume, respectively, showing that both Wy and F significantly reduce these markers compared to the LPS+Vehicle group (##P<0.01, ###P<0.001). Panel D shows no significant difference in lesion volume between vehicle and fenofibrate when treatment is administered post-LPS.
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