Neuropilin-1 is a molecular target of the transcription factor E2F1 and is involved in cerebral ischemia–induced neuronal death

ABSTRACT The nuclear transcription factor E2F1 plays an important role in modulating neuronal death in response to excitotoxicity and cerebral ischemia. Here, by comparing gene expression in brain cortices from E2F1+/+ and E2F1−/− mice using a custom high-density DNA microarray, we identified a group of putative E2F1 target genes that might be responsible for ischemia-induced E2F1-dependent neuronal death. Neuropilin 1 (NRP-1), a receptor for semaphorin 3A-mediated axon growth cone collapse and retraction, was confirmed to be a direct target of E2F1 based on (i) the fact that the NRP-1 promoter sequence contains an E2F1 binding site, (ii) reactivation of NRP-1 expression in E2F1−/− neurons when the E2F1 gene was replaced, (iii) activation of the NRP-1 promoter by E2F1 in a luciferase reporter assay, (iv) electrophoretic mobility gel shift analysis confirmation of the presence of an E2F binding sequence in the NRP-1 promoter, and (v) the fact that a chromatin immunoprecipitation assay showed that E2F1 binds directly to the endogenous NRP-1 promoter. Interestingly, the temporal induction in cerebral ischemia-induced E2F1 binding to the NRP-1 promoter correlated with the temporal-induction profile of NRP-1 mRNA, confirming that E2F1 positively regulates NRP-1 during cerebral ischemia. Functional analysis also showed that NRP-1 receptor expression was extremely low in E2F1−/− neurons, which led to the diminished response to semaphorin 3A-induced axonal shortening and neuronal death. An NRP-1 selective peptide inhibitor provided neuroprotection against oxygen-glucose deprivation. Taken together, these findings support a model in which E2F1 targets NRP-1 to modulate axonal damage and neuronal death in response to cerebral ischemia.

Download Full-text

Modulation of Neuronal Death by the Transcription Factor E2F1 in Experimental Stroke

Maturation Phenomenon in Cerebral Ischemia V ◽

10.1007/978-3-642-18713-1_1 ◽

2004 ◽

pp. 3-12

Author(s):

J. P. MacManus ◽

M. Jian ◽

E. Preston ◽

J. Webster ◽

B. Zurakowski

Keyword(s):

Transcription Factor ◽

Neuronal Death ◽

Experimental Stroke ◽

Transcription Factor E2f1

Download Full-text

A Water-Ethanol Extract from the Willow Bracket Mushroom, Phellinus igniarius (Higher Basidiomycetes), Reduces Transient Cerebral Ischemia-Induced Neuronal Death

International Journal of Medicinal Mushrooms ◽

10.1615/intjmedmushrooms.v17.i9.80 ◽

2015 ◽

Vol 17 (9) ◽

pp. 879-889 ◽

Cited By ~ 4

Author(s):

Jin Hee Kim ◽

Bo Young Choi ◽

Hyun Jung Kim ◽

In Yeol Kim ◽

Bo Eun Lee ◽

...

Keyword(s):

Cerebral Ischemia ◽

Neuronal Death ◽

Ethanol Extract ◽

Transient Cerebral Ischemia ◽

Phellinus Igniarius

Download Full-text

Inhibition of MLKL-dependent necroptosis via downregulating interleukin-1R1 contributes to neuroprotection of hypoxic preconditioning in transient global cerebral ischemic rats

Journal of Neuroinflammation ◽

10.1186/s12974-021-02141-y ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Lixuan Zhan ◽

Xiaomei Lu ◽

Wensheng Xu ◽

Weiwen Sun ◽

En Xu

Keyword(s):

Plasma Membrane ◽

Cerebral Ischemia ◽

Neuronal Death ◽

Interleukin 1 ◽

Hypoxic Preconditioning ◽

Global Cerebral Ischemia ◽

Free Calcium ◽

Membrane Translocation ◽

Vessel Occlusion ◽

Transient Global Cerebral Ischemia

Abstract Background Our previous study indicated that hypoxic preconditioning reduced receptor interacting protein (RIP) 3-mediated necroptotic neuronal death in hippocampal CA1 of adult rats after transient global cerebral ischemia (tGCI). Although mixed lineage kinase domain-like (MLKL) has emerged as a crucial molecule for necroptosis induction downstream of RIP3, how MLKL executes necroptosis is not yet well understood. In this study, we aim to elucidate the molecular mechanism underlying hypoxic preconditioning that inactivates MLKL-dependent neuronal necroptosis after tGCI. Methods Transient global cerebral ischemia was induced by the four-vessel occlusion method. Twenty-four hours before ischemia, rats were exposed to systemic hypoxia with 8% O2 for 30 min. Western blotting was used to detect the expression of MLKL and interleukin-1 type 1 receptor (IL-1R1) in CA1. Immunoprecipitation was used to assess the interactions among IL-1R1, RIP3, and phosphorylated MLKL (p-MLKL). The concentration of intracellular free calcium ion (Ca2+) was measured using Fluo-4 AM. Silencing and overexpression studies were used to study the role of p-MLKL in tGCI-induced neuronal death. Results Hypoxic preconditioning decreased the phosphorylation of MLKL both in neurons and microglia of CA1 after tGCI. The knockdown of MLKL with siRNA decreased the expression of p-MLKL and exerted neuroprotective effects after tGCI, whereas treatment with lentiviral delivery of MLKL showed opposite results. Mechanistically, hypoxic preconditioning or MLKL siRNA attenuated the RIP3-p-MLKL interaction, reduced the plasma membrane translocation of p-MLKL, and blocked Ca2+ influx after tGCI. Furthermore, hypoxic preconditioning downregulated the expression of IL-1R1 in CA1 after tGCI. Additionally, neutralizing IL-1R1 with its antagonist disrupted the interaction between IL-1R1 and the necrosome, attenuated the expression and the plasma membrane translocation of p-MLKL, thus alleviating neuronal death after tGCI. Conclusions These data support that the inhibition of MLKL-dependent neuronal necroptosis through downregulating IL-1R1 contributes to neuroprotection of hypoxic preconditioning against tGCI.

Download Full-text

Transient Cerebral Ischemia Induces Active Astrocytosis Without Distinct Neuronal Death in the Gerbil Main Olfactory Bulb: A Long-Term Analysis

Neurochemical Research ◽

10.1007/s11064-010-0219-y ◽

2010 ◽

Vol 35 (10) ◽

pp. 1588-1598 ◽

Cited By ~ 3

Author(s):

Jung Hoon Choi ◽

Ki-Yeon Yoo ◽

Choong Hyun Lee ◽

Ok kyu Park ◽

Bing Chun Yan ◽

...

Keyword(s):

Cerebral Ischemia ◽

Olfactory Bulb ◽

Neuronal Death ◽

Transient Cerebral Ischemia ◽

Main Olfactory Bulb ◽

Term Analysis

Download Full-text

Early immature neuronal death is partially involved in memory impairment induced by cerebral ischemia

Behavioural Brain Research ◽

10.1016/j.bbr.2016.04.019 ◽

2016 ◽

Vol 308 ◽

pp. 75-82 ◽

Cited By ~ 2

Author(s):

Jee Hyun Yi ◽

So Yeon Cho ◽

Se Jin Jeon ◽

Ji Wook Jung ◽

Man Seok Park ◽

...

Keyword(s):

Cerebral Ischemia ◽

Neuronal Death ◽

Memory Impairment

Download Full-text

Carvacrol Attenuates Hippocampal Neuronal Death after Global Cerebral Ischemia via Inhibition of Transient Receptor Potential Melastatin 7

Cells ◽

10.3390/cells7120231 ◽

2018 ◽

Vol 7 (12) ◽

pp. 231 ◽

Cited By ~ 6

Author(s):

Dae Hong ◽

Bo Choi ◽

A Kho ◽

Song Lee ◽

Jeong Jeong ◽

...

Keyword(s):

Cerebral Ischemia ◽

Neuronal Death ◽

Transient Receptor Potential ◽

Therapeutic Potential ◽

Receptor Potential ◽

Global Cerebral Ischemia ◽

Neuroprotective Effects ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor ◽

Zinc Translocation

Over the last two decades, evidence supporting the concept of zinc-induced neuronal death has been introduced, and several intervention strategies have been investigated. Vesicular zinc is released into the synaptic cleft, where it then translocates to the cytoplasm, which leads to the production of reactive oxygen species and neurodegeneration. Carvacrol inhibits transient receptor potential melastatin 7 (TRPM7), which regulates the homeostasis of extracellular metal ions, such as calcium and zinc. In the present study, we test whether carvacrol displays any neuroprotective effects after global cerebral ischemia (GCI), via a blockade of zinc influx. To test our hypothesis, we used eight-week-old male Sprague–Dawley rats, and a GCI model was induced by bilateral common carotid artery occlusion (CCAO), accompanied by blood withdrawal from the femoral artery. Ischemic duration was defined as a seven-minute electroencephalographic (EEG) isoelectric period. Carvacrol (50 mg/kg) was injected into the intraperitoneal space once per day for three days after the onset of GCI. The present study found that administration of carvacrol significantly decreased the number of degenerating neurons, microglial activation, oxidative damage, and zinc translocation after GCI, via downregulation of TRPM7 channels. These findings suggest that carvacrol, a TRPM7 inhibitor, may have therapeutic potential after GCI by reducing intracellular zinc translocation.

Download Full-text