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[1400W blocks death pathway of LPS-induced activated-microglia to preOLs]
Ya-Fang He1, Hui-Jin Chen, Long-Hua Qian
1Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Objective:
To explore the efficacy of inductible nitric oxide synthase (iNOS) inhibitor 1400W in vivo in blocking the death pathway of lipopolysaccharide (LPS)-induced activated-microglia to preoligodendrocytes (preOLs) in neonatal rats with infective-type periventricular leukomalacia (PVL) induced by LPS.
Methods:
Two-day-old neonatal rats were randomly divided into: a sham-operated group, an untreated PVL group, and four 1400W-treated PVL groups that were subcutaneously administrated with 20 mg/kg of 1400W at 0 h, 8 hrs, 16 hrs, and 24 hrs after LPS induction, respectively. The brain specimens were obtained 5 days after LPS induction. The pathological assessment of cerebral white matter was performed under a light microscope. Concentrations of nitric oxide (NO) were measured by nitric acid-deoxidize colorimetry. Synthesis of iNOS was determined by Western blot analysis. Peroxynitrite (ONOO(-)) level and the amount of preOLs were determined by immunocytochemistry. RETHODS: The obvious injuries of periventricular white matter, massive loss of positive O4-labelled preOLs, and increased levels of NO, ONOO(-) and iNOS were observed in neonatal rats with PVL. Compared to the untreated PVL group, the use of 1400W at 0 h, 8 hrs and 16 hrs after LPS induction significantly improved white matter injuries, reduced the levels of NO, ONOO(-) and iNOS, and increased the amount of O4-labelled preOLs. However, the use of 1400W at 24 hrs after LPS induction did not result in the improvements.
Conclusions:
iNOS inhibitor 1400W can effectively block the toxicity of LPS-activated microglia to preOLs and protect cerebral white matter through inhibiting iNOS and reducing the production of NO and ONOO(-). The use of 1400W within 16 hrs after LPS induction may provide cerebral protections in neonatal rats with PVL.
Insights
The inducible nitric oxide synthase (iNOS) inhibitor 1400W effectively protects against lipopolysaccharide (LPS)-induced brain injury in neonatal rats. Early administration of 1400W within 16 hours of LPS exposure significantly reduces white matter damage and preserves preoligodendrocytes (preOLs).
Area of Science:
- Neuroscience
- Neonatal Pathology
- Pharmacology
Context:
- Periventricular leukomalacia (PVL) is a devastating neonatal brain injury, often linked to infection and inflammation.
- Lipopolysaccharide (LPS) exposure in neonatal rats mimics aspects of infective-type PVL, leading to microglial activation and preoligodendrocyte (preOL) death.
- Inducible nitric oxide synthase (iNOS) plays a critical role in the inflammatory cascade contributing to PVL pathogenesis.
Purpose:
- To investigate the therapeutic potential of the iNOS inhibitor 1400W in a rat model of LPS-induced PVL.
- To determine if 1400W can mitigate microglial-mediated damage to preOLs and protect cerebral white matter.
- To establish the optimal therapeutic window for 1400W administration following LPS exposure.
Summary:
- Neonatal rats exposed to LPS exhibited significant white matter injury, loss of preOLs, and elevated levels of nitric oxide (NO), peroxynitrite (ONOO(-)), and iNOS.
- Administration of 1400W within 16 hours post-LPS significantly ameliorated white matter damage, reduced inflammatory markers (NO, ONOO(-), iNOS), and preserved O4-labeled preOLs.
- Treatment with 1400W at 24 hours after LPS induction did not confer significant neuroprotection, indicating a critical time-sensitive therapeutic window.
Impact:
- The study demonstrates that inhibiting iNOS with 1400W is a viable strategy for protecting the developing brain from inflammatory injury.
- Findings suggest that early intervention with iNOS inhibitors could be a promising therapeutic approach for preventing or reducing the severity of PVL in at-risk neonates.
- This research provides crucial insights into the mechanisms of PVL and highlights the importance of timely therapeutic administration.
