Abstract
Recent studies revealed that folic acid deficiency (FD) increased the likelihood of stroke and aggravated brain injury after focal cerebral ischaemia. The microglia‐mediated inflammatory response plays a crucial role in the complicated pathologies that lead to ischaemic brain injury. However, whether FD is involved in the activation of microglia and the neuroinflammation after experimental stroke and the underlying mechanism is still unclear. The aim of the present study was to assess whether FD modulates the Notch1/nuclear factor kappa B (NF‐κB) pathway and enhances microglial immune response in a rat middle cerebral artery occlusion‐reperfusion (MCAO) model and oxygen‐glucose deprivation (OGD)‐treated BV‐2 cells. Our results exhibited that FD worsened neuronal cell death and exaggerated microglia activation in the hippocampal CA1, CA3 and Dentate gyrus (DG) subregions after cerebral ischaemia/reperfusion. The hippocampal CA1 region was more sensitive to ischaemic injury and FD treatment. The protein expressions of proinflammatory cytokines such as tumour necrosis factor‐α, interleukin‐1β and interleukin‐6 were also augmented by FD treatment in microglial cells of the post‐ischaemic hippocampus and in vitro OGD‐stressed microglia model. Moreover, FD not only dramatically enhanced the protein expression levels of Notch1 and NF‐κB p65 but also promoted the phosphorylation of pIkBα and the nuclear translocation of NF‐κB p65. Blocking of Notch1 with N‐[N‐(3, 5‐difluorophenacetyl)‐l‐alanyl]‐S‐phenylglycine t‐butyl ester partly attenuated the nuclear translocation of NF‐κB p65 and the protein expression of neuroinflammatory cytokines in FD‐treated hypoxic BV‐2 microglia. These results suggested that Notch1/NF‐κB p65 pathway‐mediated microglial immune response may be a molecular mechanism underlying cerebral ischaemia‐reperfusion injury worsened by FD treatment.
Highlights
Stroke is a type of acute cerebrovascular neuropathology with a high rate of disability, mortality and morbidity
We showed that folic acid deficiency (FD) induced significant cell injury and microglial activation in hippocampus after cerebral ischaemia‐reperfusion
It was for the first time validated in microglial cultures exposed to oxygen‐glucose deprivation (OGD) and rat middle cerebral artery occlusion‐reperfusion (MCAO) model that there was the relationship between FD and microglial‐induced neu‐ roinflammation, which may occur via Notch/NF‐κB p65 pathway regulation
Summary
Stroke is a type of acute cerebrovascular neuropathology with a high rate of disability, mortality and morbidity. Inhibition of Notch signalling reduced the cell numbers of activated microglia, decreased the expression of proin‐ flammatory cytokines and the cerebral infarct size and improved functional outcome in a model of focal ischaemic stroke.[14,15] In addition, the transcriptional factor nuclear factor kappa B (NF‐κB) which is widely known as a key transcriptional factor is associated with the activation of microglia and the subsequent inflamma‐ tory responses following cerebral ischaemia.[16] Cao et al showed that Notch‐1 and NF‐κB p65 signalling pathways operated in syn‐ ergy in regulating the production of proinflammatory mediators in lipopolysaccharide (LPS)‐activated microglia.[17] More specifi‐ cally, Notch signalling can amplify the proinflammatory response of microglia by enhancing the NF‐κB p65 signalling.[18] we hypothesized that folic acid modulates the production of proin‐ flammatory cytokines in activated microglial cells by Notch‐1 and NF‐κB/p65 signalling pathways In this study, both rat MCAO model and in vitro oxygen‐glucose deprivation (OGD) BV2 cells were used to observe the effect of FD on activation of microglia, and investigate the impact of FD on the Notch‐1/NF‐κB p65 pathway. We examined the regional hippocampal sensitivity to ischaemic injury combined with FD
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
