NQDI-1, an inhibitor of ASK1 attenuates acute perinatal hypoxic-ischemic cerebral injury by modulating cell death

Huang, Hao; Li, Sitao; Tang, Hui; Bingqing, Liu; Cai, Yujun; Shi, Changhong; Xiao, Xin

doi:10.3892/mmr.2016.5123

Cited by 16 publications

(13 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hypoxic–ischemic injury leads to the expansive neuron death and plays a key role in the development of neuron apoptosis 27 . NGR1 is isolated from Panax notoginseng , which possesses many therapeutic properties, including antiapoptotic, anti-inflammatory, and neuroprotective.…”

Section: Discussionmentioning

confidence: 99%

Notoginsenoside R1 Alleviates Oxygen–Glucose Deprivation/Reoxygenation Injury by Suppressing Endoplasmic Reticulum Calcium Release via PLC

Wang

et al. 2017

Sci Rep

View full text Add to dashboard Cite

As documented in our previous study, notoginsenoside R1 (NGR1) can inhibit neuron apoptosis and the expression of endoplasmic reticulum (ER) stress-associated pro-apoptotic proteins in hypoxic–ischemic encephalopathy. Recent evidence indicates that the Phospholipase C (PLC)/inositol 1,4,5-trisphosphate receptor (IP3R) is important for the regulation of Ca2+ release in the ER. Ca2+ imbalance can stimulate ER stress, CAMKII, and cell apoptosis. The purpose of this study was to further investigate the neuroprotective effect of NGR1 and elucidate how NGR1 regulates ER stress and cell apoptosis in the oxygen–glucose deprivation/reoxygenation (OGD/R) model. Cells were exposed to NGR1 or the PLC activator m-3M3FBS. Then, IP3R- and IP3-induced Ca2+ release (IICR) and activation of the ER stress and CaMKII signal pathway were measured. The results showed that NGR1 inhibited IICR and strengthened the binding of GRP78 with PERK and IRE1. NGR1 also alleviated the activation of the CaMKII pathway. Pretreatment with m-3M3FBS attenuated the neuroprotective effect of NGR1; IICR was activated, activation of the ER stress and CaMKII pathway was increased, and more cells were injured. These results indicate that NGR1 may suppress activation of the PLC/IP3R pathway, subsequently inhibiting ER Ca2+ release, ER stress, and CaMKII and resulting in suppressed cell apoptosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Notoginsenoside R1 Alleviates Oxygen–Glucose Deprivation/Reoxygenation Injury by Suppressing Endoplasmic Reticulum Calcium Release via PLC

Wang

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…NQDI‐1 (250 nmol per mouse;), a highly specific ASK1 inhibitor, was dissolved in DMSO (Sigma‐Aldrich) and then injected by i.c.v. into the left lateral ventricle 30 min prior to ICH induction (Hao et al, ). The control group was given the same volume of equally diluted DMSO by i.c.v.…”

Section: Methodsmentioning

confidence: 99%

The MC₄ receptor agonist RO27‐3225 inhibits NLRP1‐dependent neuronal pyroptosis via the ASK1/JNK/p38 MAPK pathway in a mouse model of intracerebral haemorrhage

Chen

Zuo

Huang

et al. 2019

British J Pharmacology

View full text Add to dashboard Cite

Background and Purpose: Inflammasome-mediated pyroptosis is an important neuronal cell death mechanism. Previous studies reported that activation of melanocortin MC 4 receptor exerted neuroprotection in several neurological diseases. Here, we have investigated the role of MC 4 receptor activation with RO27-3225 in suppressing neuronal pyroptosis after experimental intracerebral haemorrhage (ICH) and the underlying mechanism.Experimental Approach: One hundred and sixty-nine male CD1 mice were used. ICH was induced by injection of bacterial collagenase into the right-side basal ganglia.RO27-3225, a selective agonist of MC 4 receptor, was injected intraperitoneally at 1 hr after ICH. To elucidate the underlying mechanism, we used the specific MC 4 receptor antagonist HS024 and NQDI-1, a specific inhibitor of the apoptosis signalling-regulating kinase 1 (ASK1). Neurological tests, Western blot, Fluoro-Jade C, TUNEL, and immunofluorescence staining were conducted.Key Results: Expression of MC 4 receptor and the NOD-like receptor family, pyrin domain containing 1 (NLRP1) inflammasome in brain were increased after ICH. RO27-3225 treatment decreased neuronal pyroptosis and neurobehavioural deficits at 24 and 72 hr after ICH. RO27-3225 reduced the expression of p-ASK1, p-JNK, p-p38 MAPK, NLRP1 inflammasome, cleaved caspase-1, and IL-1β after ICH. HS024 pretreatment prevented the effects of RO27-3225. Similar to RO27-3225, NQDI-1 alone improved neurological functions and down-regulated ASK1/JNK/ p38MAPK expression after ICH. Conclusions and Implications: RO27-3225 suppressed NLRP1-dependent neuronal pyroptosis and improved neurological function, possibly mediated by activation of MC 4 receptor and inhibition of ASK1/JNK/p38 MAPK signalling pathways, after experimental ICH in mice. The MC 4 receptor may be a promising therapeutic target for the management of ICH. Abbreviations: ASK1, apoptosis signalling-regulating kinase 1; FJC, Fluoro-Jade C; ICH, intracerebral haemorrhage; MSH, melanocyte-stimulating hormones; NLRP1, NOD-like receptor (NLR) family, pyrin domain containing 1

show abstract

“…The importance of JNK is further supported by a recent study showing that inhibition of Apoptosis signal-regulating kinase 1 (ASK1) confers protection in HI. ASK1 activates JNK and prevented phosphorylation of JNK, TUNEL expression, and caspase-3 activation in a neonatal model of HI (Hao et al, 2016 ).…”

Section: Apoptotic Cell Deathmentioning

confidence: 99%

Cell Death in the Developing Brain after Hypoxia-Ischemia

Thornton

Leaw

Mallard

et al. 2017

Front. Cell. Neurosci.

125

View full text Add to dashboard Cite

Perinatal insults such as hypoxia–ischemia induces secondary brain injury. In order to develop the next generation of neuroprotective therapies, we urgently need to understand the underlying molecular mechanisms leading to cell death. The cell death mechanisms have been shown to be quite different in the developing brain compared to that in the adult. The aim of this review is update on what cell death mechanisms that are operating particularly in the setting of the developing CNS. In response to mild stress stimuli a number of compensatory mechanisms will be activated, most often leading to cell survival. Moderate-to-severe insults trigger regulated cell death. Depending on several factors such as the metabolic situation, cell type, nature of the stress stimulus, and which intracellular organelle(s) are affected, the cell undergoes apoptosis (caspase activation) triggered by BAX dependent mitochondrial permeabilzation, necroptosis (mixed lineage kinase domain-like activation), necrosis (via opening of the mitochondrial permeability transition pore), autophagic cell death (autophagy/Na+, K+-ATPase), or parthanatos (poly(ADP-ribose) polymerase 1, apoptosis-inducing factor). Severe insults cause accidental cell death that cannot be modulated genetically or by pharmacologic means. However, accidental cell death leads to the release of factors (damage-associated molecular patterns) that initiate systemic effects, as well as inflammation and (regulated) secondary brain injury in neighboring tissue. Furthermore, if one mode of cell death is inhibited, another route may step in at least in a scenario when upstream damaging factors predominate over protective responses. The provision of alternative routes through which the cell undergoes death has to be taken into account in the hunt for novel brain protective strategies.

show abstract

NQDI-1, an inhibitor of ASK1 attenuates acute perinatal hypoxic-ischemic cerebral injury by modulating cell death

Cited by 16 publications

References 31 publications

Notoginsenoside R1 Alleviates Oxygen–Glucose Deprivation/Reoxygenation Injury by Suppressing Endoplasmic Reticulum Calcium Release via PLC

Notoginsenoside R1 Alleviates Oxygen–Glucose Deprivation/Reoxygenation Injury by Suppressing Endoplasmic Reticulum Calcium Release via PLC

The MC₄ receptor agonist RO27‐3225 inhibits NLRP1‐dependent neuronal pyroptosis via the ASK1/JNK/p38 MAPK pathway in a mouse model of intracerebral haemorrhage

Cell Death in the Developing Brain after Hypoxia-Ischemia

Contact Info

Product

Resources

About

NQDI-1, an inhibitor of ASK1 attenuates acute perinatal hypoxic-ischemic cerebral injury by modulating cell death

Cited by 16 publications

References 31 publications

Notoginsenoside R1 Alleviates Oxygen–Glucose Deprivation/Reoxygenation Injury by Suppressing Endoplasmic Reticulum Calcium Release via PLC

Notoginsenoside R1 Alleviates Oxygen–Glucose Deprivation/Reoxygenation Injury by Suppressing Endoplasmic Reticulum Calcium Release via PLC

The MC4 receptor agonist RO27‐3225 inhibits NLRP1‐dependent neuronal pyroptosis via the ASK1/JNK/p38 MAPK pathway in a mouse model of intracerebral haemorrhage

Cell Death in the Developing Brain after Hypoxia-Ischemia

Contact Info

Product

Resources

About

The MC₄ receptor agonist RO27‐3225 inhibits NLRP1‐dependent neuronal pyroptosis via the ASK1/JNK/p38 MAPK pathway in a mouse model of intracerebral haemorrhage