n-(n-(3-5-difluorophenacetyl)alanyl)phenylglycine-tert-butyl-ester and Brain-Injuries

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.

Topics: Animals; Brain Injuries; Brain Ischemia; Cell Line; Cytokines; Dipeptides; Folic Acid Deficiency; Glucose; Hippocampus; Infarction, Middle Cerebral Artery; Inflammation; Male; Mice; Microglia; Neurons; Oxygen; Rats, Sprague-Dawley; Receptor, Notch1; Signal Transduction; Transcription Factor RelA

Hyperoxia exposure can cause dramatic release of proinflammatory cytokines, leading to neuronal apoptosis and inducing white matter damage in newborn mouse brains. Some studies indicated that the Notch activation was provoked during inflammation and might regulate adaptive and innate immune responses. Moreover, the pathway also regulated oligodendrocyte maturation which was disrupted in neonatal mice after hyperoxia exposure. This study sought to investigate whether the Notch signalling activation contributed to immature brain damage after hyperoxia exposure. Cellular changes in the white matter (WM) of neonatal wild-type mice exposed to 80% oxygen from postnatal day 3 (P3) to day 5 (P5) were determined. Moreover, in order to further confirm the relationship between the Notch signalling pathway and hyperoxia-induced periventricular white matter injury, mice were pre-treated with a γ-secretase inhibitor (N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester, DAPT), which inhibits activation of the Notch pathway before exposure to hyperoxia. The results suggested that expression of myelin basic protein (MBP) increased in P12 mice subjected to hyperoxia after DAPT pretreatment. Moreover, hyperoxia could cause mature oligodendrocytes (MBP+) counts decreased with an obvious inverse increase in OPCs (NG2+) after hyperoxia on P12, DAPT pretreatment significantly ameliorated disruption of oligodendrocytes maturation induced by hyperoxia. Our results also demonstrated that DAPT could reduce memory impairment induced by hyperoxia exposure. Taken together, these results suggest that hyperoxia exposure induces both brain damage in the developing brain and behavioural abnormalities through the Notch signalling activation. And modulation of γ-secretase, selectively interfering with the Notch signalling pathway, could improve adverse outcomes induced by hyperoxia.

Topics: Animals; Animals, Newborn; Brain; Brain Injuries; Dipeptides; Hyperoxia; Learning; Mice, Inbred C57BL; Oligodendroglia; Receptor, Notch1; Signal Transduction