Limb Remote Ischemic Conditioning Promotes Neurogenesis after Cerebral Ischemia by Modulating miR-449b/Notch1 Pathway in Mice

Abstract

Neurogenesis plays an important role in the prognosis of stroke patients and is known to be promoted by the activation of the Notch1 signaling pathway. Studies on the airway epithelium have shown that miR-449b represses the Notch pathway. The study aimed to investigate whether limb remote ischemic conditioning (LRIC) was able to promote neurogenesis in cerebral ischemic mice, and to investigate the role of the miR-449b/Notch1 pathway in LRIC-induced neuroprotection. Male C57BL/6 mice (22–25 g) were subjected to transient middle cerebral artery occlusion (MCAO), and LRIC was performed in the bilateral lower limbs immediately after MCA occlusion. Immunofluorescence staining was performed to assess neurogenesis. The cell line NE-4C was used to elucidate the proliferation of neuronal stem cells in 8% O2. After LRIC treatment on day 28, mice recovered neurological function. Neuronal precursor proliferation was enhanced in the SVZ, and neuronal precursor migration was enhanced in the basal ganglia on day 7. LRIC promoted the improvement of neurological function in mice on day 28, promoted neuronal precursor proliferation in the SVZ, and enhanced neuronal precursor migration in the basal ganglia on day 7. The neurological function score was negatively correlated with the number of BrdU-positive/DCX-positive cells in the SVZ and striatum. LRIC promoted activated Notch1 protein expression in the SVZ and substantially downregulated miR-449b levels in the SVZ and plasma. In vitro, miR-449b was found to target Notch1. Lentivirus-mediated miR-449b knockdown increased Notch1 levels in NE-4C cells and increased proliferation in the cells. The effects of miR-449b inhibition on neurogenesis were ablated by the application of Notch1 shRNA. Our study showed that LRIC promoted the proliferation and migration of neural stem cells after MCAO, and these effects were modulated by the miR-449b/Notch1 pathway.

Remote Ischaemic Conditioning for Neurological Disorders – A Systematic Review and Narrative Synthesis

“…Conducting trials in paediatric patients will avoid potentially obstructive comorbidities and therefore give us a clearer understanding of the impact of RIC. Moreover, the ndings are expected to contribute to our understanding of the underlying mechanisms of action of RIC therapy and whether RIC promotes neuroplasticity and restoration as previously suggested [132][133][134][135][136][137].…”

“…Changes in molecular markers suggest both therapeutic options work by promoting Neuroplasticity, Synaptogenesis and Angiogenesis [57,135,[138][139][140][141]. Exercise has been established as an effective rehabilitation method in stroke, studies have shown that it improves memory loss, neurological function and is neuroprotective [131][132][133][134][135][136][137][138][139][140][141][142][143][144]. However, compliance levels to exercise in post stroke patients is low due to physical limitations, anxiety, lack of accessible facilities, lack of progress and the presence of comorbidities [145].…”

Hypoxic Preconditioning Modulates BDNF and Its Signaling through DNA Methylation to Promote Learning and Memory in Mice

“…The protective effect of HPC on the nervous system is evident. HPC has been found to be able to regulate the process of HIF signaling, 3 neurogenesis, 17 and autophagy 18 through various mechanisms, thus exerting an obviously protective effect on neurons. More importantly, HPC may also protect the overall function of the nervous system, such as learning and memory.…”