Abstract
BackgroundIschemic stroke is a major disease that threatens human health in ageing population. Increasing evidence has shown that neuroinflammatory mediators play crucial roles in the pathophysiology of cerebral ischemia injury. Notch signaling is recognized as the cell fate signaling but recent evidence indicates that it may be involved in the inflammatory response in activated microglia in cerebral ischemia. Previous report in our group demonstrated hypertonic saline (HS) could reduce the release of interleukin-1 beta and tumor necrosis factor-alpha in activated microglia, but the underlying molecular and cellular mechanisms have remained uncertain. This study was aimed to explore whether HS would partake in regulating production of proinflammatory mediators through Notch signaling.ResultsHS markedly attenuated the expression of Notch-1, NICD, RBP-JK and Hes-1 in activated microglia both in vivo and in vitro. Remarkably, HS also reduced the expression of iNOS in vivo, while the in vitro levels of inflammatory mediators Phos-NF-κB, iNOS and ROS were reduced by HS as well.ConclusionOur results suggest that HS may suppress of inflammatory mediators following ischemia/hypoxic through the Notch signaling which operates synergistically with NF-κB pathway in activated microglia. Our study has provided the morphological and biochemical evidence that HS can attenuate inflammation reaction and can be neuroprotective in cerebral ischemia, thus supporting the use of hypertonic saline by clinicians in patients with an ischemia stroke.
Highlights
Ischemic stroke is a major disease that threatens human health in ageing population
The second cleavage by γ-secretase enzyme complex releases the Notch intracellular domain (NICD), which translocates into the nucleus where it binds to recombination signal sequence-binding protein J (RBP-JK), causing the transcriptional activation of Notch targeting genes including the Hairy-Enhancer of Split (HES) and HES-related proteins (HERP) genes [11,12,13]
Pharmacological inhibition of Notch signaling attenuates the expression of Phos-NF-κB, inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS)
Summary
Ischemic stroke is a major disease that threatens human health in ageing population. Increasing evidence has shown that neuroinflammatory mediators play crucial roles in the pathophysiology of cerebral ischemia injury. Zeng et al BMC Neurosci (2017) 18:32 species (ROS) are widely thought to be derived from activated microglia, which is the main resident immune cells within the central nervous system (CNS) that play an important role in the development of inflammatory response after cerebral ischemic insults [5,6,7]. It seems to be a progressing therapeutic strategy to suppress the excessive inflammatory mediators driven by activated-microglia in cerebral ischemia. In light of the above, Notch signaling may be a novel and important target to reduce inflammatory response and improve the function in ischemic stroke
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