Minocycline attenuates lipopolysaccharide-induced white matter injury in the neonatal rat brain
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Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats
Published on: November 20, 2015
1Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS 39216-4505, USA.
Abstract:
Our previous studies have shown that intracerebral administration of endotoxin, lipopolysaccharide (LPS), induces selective white matter injury and hypomyelination in the neonatal rat brain and that the LPS-induced brain injury is associated with activation of microglia. To test the hypothesis that inhibition of microglial activation may protect against LPS-induced white matter injury, we examined roles of minocycline, a putative suppressor of microglial activation, on LPS-induced brain injury in the neonatal rat. A stereotactic intracerebral injection of LPS (1 mg/kg) was performed in postnatal day 5 Sprague-Dawley rats and control rats were injected with sterile saline. Minocycline (45 mg/kg) was administered intraperitoneally 12 h before and immediately after LPS injection and then every 24 h for 3 days. Inflammatory responses, activation of microglia and brain injury were examined 1 and 3 days after LPS injection. LPS injection resulted in brain injury in selective brain areas, including bilateral ventricular enlargement, cell death at the sub- and periventricular areas, loss of O4+ and O1+ oligodendrocyte (OL) immunoreactivity and hypomyelination, as indicated by decreased myelin basic protein immunostaining, in the neonatal rat brain. Minocycline administration significantly attenuated LPS-induced brain injury in these rat brains. The protective effect of minocycline was associated with suppressed microglial activation as indicated by the decreased number of activated microglial cells following LPS stimulation and with consequently decreased elevation of interleukin 1beta and tumor necrosis factor-alpha concentrations induced by LPS and a reduced number of inducible nitric oxide synthase expressing cells. Protection of minocycline was also linked with the reduction in LPS-induced oxidative stress, as indicated by 4-hydroxynonenal positive OLs. The overall results suggest that reduction in microglial activation may protect the neonatal brain from LPS-induced white matter injury and inhibition of microglial activation might be an effective approach for the therapeutic treatment of infection-induced white matter injury.
Insights
Minocycline protects the neonatal rat brain from lipopolysaccharide (LPS)-induced white matter injury by suppressing microglial activation and reducing inflammation. This suggests minocycline as a potential therapy for infection-related brain damage.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Intracerebral lipopolysaccharide (LPS) administration in neonatal rats causes white matter injury and hypomyelination, linked to microglial activation.
- Microglia play a critical role in the inflammatory response within the developing brain.
Purpose of the Study:
- To investigate the protective effects of minocycline, a microglial activation suppressor, against LPS-induced white matter injury in the neonatal rat brain.
- To determine if inhibiting microglial activation can prevent LPS-induced neuropathology.
Main Methods:
- Neonatal Sprague-Dawley rats received stereotactic intracerebral LPS injection.
- Minocycline was administered intraperitoneally before and after LPS exposure.
- Brain injury, microglial activation, inflammatory markers (interleukin-1beta, tumor necrosis factor-alpha), and oxidative stress were assessed.
Main Results:
- LPS induced significant brain injury, including ventricular enlargement, cell death, oligodendrocyte loss, and hypomyelination.
- Minocycline administration markedly attenuated LPS-induced brain injury.
- Minocycline suppressed microglial activation, reduced pro-inflammatory cytokine levels, and decreased oxidative stress markers.
Conclusions:
- Inhibition of microglial activation by minocycline effectively protects the neonatal brain from LPS-induced white matter injury.
- Targeting microglial activation represents a promising therapeutic strategy for treating infection-induced white matter damage in neonates.
