The impact of neuronal Notch-1/JNK pathway on intracerebral hemorrhage-induced neuronal injury of rat model

Abstract

Notch signaling is a highly conserved pathway that regulates cell fate decisions during embryonic development. Notch activation endangers neurons by modulating NF-κB and HIF-1α pathways, however, the role of Notch signaling in activating JNK/c-Jun following intracerebral hemorrhage (ICH) has not been investigated. In this study, we used rat ICH models and thrombin-induced cell models to investigate the potential role of Notch-1/JNK signals. Our findings revealed that Notch-1 and JNK increased in hematoma-surrounding neurons tissues following ICH during ischemic conditions (all p<0.05). Besides, the expression of active caspase-3 protein was also up-regulated after ICH. According to in-vitro assays, the expression of Notch-1, p-JNK, and active caspase-3 were all up-regulated in cell viability-decreasing ICH cell models (all p<0.05). However, blocking of either Notch-1 or JNK suppressed the phosphorylation of JNK and the expression of active caspase-3, and cell viability was obviously ameliorated. In conclusion, this work suggested Notch-1 activates JNK pathway to induce the active caspase-3, leading to neuronal injury when intracerebral hemorrhage or ischemia occurred. Thus the Notch-1/JNK signal pathway has an important role in ICH process, and may be a therapeutic target to prevent brain injury.

Distinct peripheral blood monocyte and neutrophil transcriptional programs following intracerebral hemorrhage and different etiologies of ischemic stroke

“…These included: Relaxin signaling, involved in vasodilation and angiogenesis 103 with predicted activation of VEGF-A, MMP9, and angiogenesis; GNRH signaling, which has a role in neurodegeneration 104 ; NGF signaling which may be neuroprotective after ICH 105 ; and Notch signaling which modulates neuronal injury, apoptosis, angiogenesis, and BBB function following experimental ICH. 106 , 107 As in monocytes, the interferon pathway was significantly suppressed in ICH neutrophils along with IL-1 and α-adrenergic signaling pathways in our previous study. 21 IL-1 is a proinflammatory neutrophil mediator in ICH and represents a promising ICH treatment target 108–110 (clinical trial NCT03737344).…”

Interplay between Notch and p53 promotes neuronal cell death in ischemic stroke

“…26 Notch-mediated neuronal cell fate determination or other events could be influenced not only by Hes but also by NICD's interaction with other targets, such as NF-kB, 4,27 HIF-1a 5,28 and c-Jun. 12,29 A pro-apoptotic role for Notch in focal ischemic stroke was supported by studies showing that mice overexpressing Notch1 antisense (NAS) and normal mice treated with inhibitors of the Notch-activating enzyme, g-secretase, exhibit reduced damage to brain cells and improved functional outcome. [3][4][5] Consequently, the mechanisms underlying Notchmediated apoptosis in ischemic stroke were further investigated here.…”

White Matter Injury after Intracerebral Hemorrhage: Pathophysiology and Therapeutic Strategies

“…JNK is a member of the mitogen-activated protein kinase (MAPK) superfamily, which has already been widely investigated due to its active actions in response to various stimuli, such as the exposure to inflammatory cytokines (Kumar et al, 2015 ). JNK is activated in ICH animal models primarily by iron, and iron chelator can reduce the free iron contents in the CSF, suppress JNK activation, reduce WMI and improve neurological deficits (Yatsushige et al, 2007 ; Wan et al, 2009 ; Ni et al, 2015 ; Chen et al, 2016 ; Zou et al, 2017 ). Furthermore, the inhibition of JNK could deactivate inflammation, attenuate brain edema and improve functional outcome after ICH (Ohnishi et al, 2007 ; Michel-Monigadon et al, 2010 ).…”