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Lipopolysaccharide-Induced Systemic Inflammation in the Neonatal Period Increases Microglial Density and Oxidative Stress in the Cerebellum of Adult Rats.

ABSTRACT: Inflammatory processes occurring in the perinatal period may affect different brain regions, resulting in neurologic sequelae. Injection of lipopolysaccharide (LPS) at different neurodevelopmental stages produces long-term consequences in several brain structures, but there is scarce evidence regarding alterations in the cerebellum. The aim of this study was to evaluate the long-term consequences on the cerebellum of a systemic inflammatory process induced by neonatal LPS injection. For this, neonatal rats were randomly assigned to three different groups: naïve, sham, and LPS. Saline (sham group) or LPS solution (1 mg/kg) was intraperitoneally injected on alternate postnatal days (PN) PN1, PN3, PN5, and PN7. Spontaneous activity was evaluated with the open field test in adulthood. The cerebellum was evaluated for different parameters: microglial and Purkinje cell densities, oxidative stress levels, and tumor necrosis factor alpha (TNF-α) mRNA expression. Our results show that administration of LPS did not result in altered spontaneous activity in adult animals. Our data also indicate increased oxidative stress in the cerebellum, as evidenced by an increase in superoxide fluorescence by dihydroethidium (DHE) indicator. Stereological analyses indicated increased microglial density in the cerebellum that was not accompanied by Purkinje cell loss or altered TNF-α expression in adult animals. Interestingly, Purkinje cells ectopically positioned in the granular and molecular layers of the cerebellum were observed in animals of the LPS group. Our data suggest that neonatal LPS exposure causes persistent cellular and molecular changes to the cerebellum, indicating the susceptibility of this region to systemic inflammatory insults in infancy. Further investigation of the consequences of these changes and the development of strategies to avoid those should be subject of future studies.

SUBMITTER: Pires JM

PROVIDER: S-EPMC7283979 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Microglial activation after systemic infection has been suggested to mediate sepsis-associated delirium. A systematic review of animal studies suggested distinct differences between microglial activation after systemic challenge with live bacteria and lipopolysaccharide (LPS). Here, we describe a mouse model of microglial activation after systemic challenge with live Escherichia coli (E. coli) and compare results with systemic challenge with LPS. Methods: Sixty mice were intraperitoneally injected with E. coli (1 × 104 colony-forming units) and sacrificed at 12, 20, 48, and 72 h after inoculation. For 48 and 72 h time points, mice were treated with ceftriaxone. Thirty mice were intraperitoneally injected with LPS (5 mg/kg) and sacrificed 3 and 48 h after inoculation; 48 control mice were intraperitoneally injected with isotonic saline. Microglial response was monitored by immunohistochemical staining with Iba-1 antibody and flow cytometry; and inflammatory response by mRNA expression of pro- and anti-inflammatory mediators. Results: Mice infected with live E. coli showed microglial activation 72 h post-inoculation, with increased cell number in cortex (p = 0.0002), hippocampus (p = 0.003), and thalamus (p = 0.0001), but not in the caudate nucleus/putamen (p = 0.33), as compared to controls. At 72 h, flow cytometry of microglia from E. coli infected mice showed increased cell size (p = 0.03) and CD45 expression (p = 0.03), but no increase in CD11b expression, and no differences in brain mRNA expression of inflammatory mediators as compared to controls. In mice with systemic LPS stimulation, microglial cells were morphologically activated at the 48 h time point with increased cell numbers in cortex (p = 0.002), hippocampus (p = 0.0003), thalamus (p = 0.007), and caudate nucleus/putamen (p < 0.0001), as compared to controls. At 48 h, flow cytometry of microglia from LPS stimulated mice showed increased cell size (p = 0.03), CD45 (p = 0.03), and CD11b (p = 0.04) expression. Brain mRNA expression of TNF-α (p = 0.02), IL-1β (p = 0.02), and MCP-1 (p = 0.03) were increased as compared to controls. Interpretation: Systemic challenge with live E. coli causes a neuro-inflammatory response, but this response occurs at a later time point and is less vigorous as compared to LPS stimulation.The E. coli model mimics the clinical situation of infection associated delirium more closely than stimulation with supra-natural LPS.

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Lipopolysaccharide-Induced Systemic Inflammation in the Neonatal Period Increases Microglial Density and Oxidative Stress in the Cerebellum of Adult Rats.

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