myelin-basic-protein and Infections

Periventricular white matter injury (PWMI) is very common in survivors of premature birth, and the final outcomes are a reduction in myelinated neurons leading to white matter hypomyelination. How and (or) why the oligodendrocyte lineage develops abnormally and myelination is reduced is a hot topic in the field. This study focuses on the effect of intrauterine inflammation on the proliferation of oligodendrocyte lineage cells and the underlying mechanisms. Lipopolysaccharide (LPS) (300 μg/kg) was intraperitoneally injected into pregnant Sprague-Dawley rats at embryonic days 19 and 20 to establish a rat model of intrauterine infection-induced white matter injury. Corpus callosum tissues were collected at postnatal day 14 (P14) to quantify the number of oligodendrocytes, the number and proliferation of oligodendrocyte precursor cells (OPCs), and the expression of myelin proteins (MBP and PLP). Furthermore, the expression of Wnt and Notch signaling-related proteins was analyzed. The results showed that the number of oligodendrocytes in the corpus callosum tissues of LPS-treated rats was reduced, and the expression levels of myelinating proteins were down-regulated. Further analysis showed that the Notch signaling pathway was down-regulated in the LPStreated group. These results indicate that intrauterine LPS may inhibit the proliferation of OPCs by down-regulating the Notch rather than the Wnt signaling pathway, leading to hypomyelination of white matter.

Topics: Animals; Animals, Newborn; Brain; Brain Injuries; Cell Lineage; Cell Proliferation; Corpus Callosum; Female; Gene Expression Regulation, Developmental; Humans; Infections; Leukoencephalopathies; Lipopolysaccharides; Myelin Basic Protein; Myelin Proteolipid Protein; Oligodendrocyte Precursor Cells; Pregnancy; Rats; Receptors, Notch; Signal Transduction

Periventricular leukomalacia, the predominant pathological lesion underlying cerebral palsy in premature infants, is thought to be the result of hypoxic-ischemic injury to the cerebral white matter. The main cell type injured is the developing oligodendrocyte (OL), which has been shown to be more sensitive than mature OLs to both excitotoxic and oxidative mechanisms of injury. A maturation dependence of OL vulnerability to cystine deprivation-induced glutathione depletion has been previously demonstrated in culture. We hypothesized that mitochondria could be involved in this toxicity by generating superoxide and that increased superoxide dismutase (SOD) activity in mature OLs may account for their greater resistance. Cystine deprivation toxicity was found to be associated with mitochondrial dysfunction and intracellular superoxide accumulation in developing OLs. CuZnSOD protein expression and enzyme activity was similar along the OL lineage. In contrast, MnSOD was up-regulated in mature OLs, as manifested by a 53% increase in its expression and a four-fold increase in its activity. Overexpressing MnSOD in developing OLs was associated with a protective effect on mitochondrial membrane potential and a decrease in cell death induced by mild cystine deprivation. The greater challenge presented by total cystine deprivation was resistant to MnSOD overexpression and appeared to be related to hydrogen peroxide toxicity. These data suggest a primary involvement of superoxide in glutathione depletion toxicity in developing OLs, and suggest an important role for MnSOD in the resistance observed in mature OLs.

Topics: Adenosine Triphosphate; Aldehydes; Animals; Animals, Newborn; Antioxidants; Benzimidazoles; Blotting, Western; Carbocyanines; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; Catalase; Cell Count; Cell Survival; Cells, Cultured; Cerebral Cortex; Cysteine; Dose-Response Relationship, Drug; Drug Interactions; Free Radicals; Green Fluorescent Proteins; Humans; Hydrogen Peroxide; Immunohistochemistry; Infections; Intracellular Space; Ionophores; Luminescent Proteins; Mitochondria; Myelin Basic Protein; O Antigens; Oligodendroglia; Oxidative Stress; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Time Factors; Up-Regulation

Topics: Adjuvants, Immunologic; Animals; Antigens; Autoimmune Diseases; Disease Models, Animal; Humans; Infections; Myelin Basic Protein; Myelin P2 Protein; Neuritis; Vaccines