A1 adenosine receptor attenuates intracerebral hemorrhage-induced secondary brain injury in rats by activating the P38-MAPKAP2-Hsp27 pathway

Zhai, Weiwei; Chen, Dongdong; Shen, Haitao; Chen, Zhouqing; Li, Haiying; Yu, Zhengquan; Chen, Gang

doi:10.1186/s13041-016-0247-x

Cited by 25 publications

(14 citation statements)

References 55 publications

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“…A standard BCA (Beyotime Institute of Biotechnology) method was used to determine protein concentration. Then, a total of 50 μg protein each lane was subjected to SDS-PAGE (10%) and transferred to a membrane for ECL and imaging as reported previously (Zhai et al, 2016 ). The optical density was analyzed using Image J software (Rawak Software, Inc., Stuttgart, Germany).…”

Section: Methodsmentioning

confidence: 99%

PERK Pathway Activation Promotes Intracerebral Hemorrhage Induced Secondary Brain Injury by Inducing Neuronal Apoptosis Both in Vivo and in Vitro

Meng

Zhang

Dang³

et al. 2018

Front. Neurosci.

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The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) signaling pathway was reported to exert an important role in neuronal apoptosis. The present study was designed to investigate the roles of the PERK signaling pathway in the secondary brain injury (SBI) induced by intracerebral hemorrhage (ICH) and its potential mechanisms. Sprague–Dawley rats were used to establish ICH models by injecting autologous blood (100 μl), and cultured primary rat cortical neurons were exposed to oxyhemoglobin (10 μM) to mimic ICH in vitro. The PERK antagonist, GSK2606414, and inhibitor of eukaryotic translation initiation factor 2 subunit α (eIF2α) dephosphorylation, salubrinal, were used to study the roles of PERK signaling pathway in ICH-induced SBI. Our results showed that the protein levels of p-eIF2α and ATF4 were upregulated following ICH, peaking at 48 h. Application of GSK2606414 reversed this increase in vivo and in vitro, thereby preventing ICH-induced neuronal apoptosis. On the contrary, salubrinal inhibited the dephosphorylation of eIF2α, resulting in the elevation of p-eIF2α, which could activate downstream of PERK signaling and induce neuronal apoptosis and necrosis following ICH in vitro and in vivo. Thus, PERK signaling pathway plays an important role in ICH-induced apoptosis and blocking its activation has neuroprotective effects that alleviates SBI, suggesting that targeting this pathway could be a promising therapeutic strategy for improving patient outcome after ICH.

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Section: Methodsmentioning

confidence: 99%

PERK Pathway Activation Promotes Intracerebral Hemorrhage Induced Secondary Brain Injury by Inducing Neuronal Apoptosis Both in Vivo and in Vitro

Meng

Zhang

Dang³

et al. 2018

Front. Neurosci.

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“…As reported previously (Zhai et al, 2016 ), the neurons were treated with OxyHb (10 μM) to mimic ICH conditions in vitro .…”

Section: Methodsmentioning

confidence: 99%

“…Recombinant mouse netrin-1 (200 ng in 2 μL PBS) was prepared according to the manufacturer's instructions and administered via intracerebroventricular injection as previously described (Wu et al, 2008 ; Zhai et al, 2016 ).…”

Section: Methodsmentioning

confidence: 99%

Neuroprotection Exerted by Netrin-1 and Kinesin Motor KIF1A in Secondary Brain Injury following Experimental Intracerebral Hemorrhage in Rats

Wang

Zhai

et al. 2018

Front. Cell. Neurosci.

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Binding of extracellular netrin-1 to its receptors, deleted in colorectal cancer (DCC) and uncoordinated gene 5H2 (UNC5H2), inhibits apoptosis mediated by these receptors. A neuron-specific kinesin motor protein, KIF1A, has been shown to participate in netrin-1 secretion. This study aimed to identify the roles of netrin-1 and KIF1A in secondary brain injury after intracerebral hemorrhage (ICH) and the potential mechanisms. An autologous blood ICH model was established in adult male Sprague-Dawley rats, and cultured neurons were exposed to OxyHb to mimic ICH conditions in vitro. Mouse recombinant netrin-1, expression vectors encoding KIF1A, and KIF1A-specific siRNAs were administered intracerebroventricularly. After ICH, protein levels of netrin-1, DCC, and UNC5H2 increased, while protein levels of KIF1A decreased. Levels of UNC5H2 and DCC bound to netrin-1 increased after ICH but were significantly lower than the increase in total amount of protein. Administration of recombinant netrin-1 attenuated neuronal apoptosis and degeneration in ICH rats. Moreover, KIF1A overexpression increased concentrations of netrin-1 in cerebrospinal fluid and cell culture supernatant and exerted neuroprotective effects via netrin-1 and its receptor pathways. KIF1A plays a critical role in netrin-1 secretion by neurons. An increase in protein levels of netrin-1 may be a neuroprotective strategy after ICH. However, this process is almost completely abolished by ICH-induced loss of KIF1A. An exogenous increase of KIF1A may be a potential strategy for neuroprotection via the netrin-1 pathway.

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“…As described previously ( Zhai et al, 2016 ), primary neurons from SD rats were obtained and cultured. Whole brains of 17th-day rat embryos were used for preparing cell culture.…”

Section: Methodsmentioning

confidence: 99%

Phosphorylation at S153 as a Functional Switch of Phosphatidylethanolamine Binding Protein 1 in Cerebral Ischemia-Reperfusion Injury in Rats

Zhong

Yao

et al. 2017

Front. Mol. Neurosci.

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This study aimed to estimate the role of phosphatidylethanolamine binding protein 1 (PEBP1) in cerebral ischemia-reperfusion (I/R) injury and the underlying mechanisms. Middle cerebral artery occlusion/reperfusion (MCAO/R) model in adult male Sprague Dawley rats (250–280 g) were established and cultured neurons were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) to mimic I/R injury in vitro. Expression vectors encoding wild-type PEBP1 and PEBP1 with Ser153Ala mutation (S153A), PEBP1 specific siRNAs, and human recombinant PEBP1 (rhPEBP1) were administered intracerebroventricularly. Endogenous PEBP1 level and its phosphorylation at Ser153 were increased within penumbra tissue and cultured neurons after I/R, accompanied by decreased interaction between PEBP1 and Raf-1. There was a trend toward increased Raf-1/MEK/ERK/NF-κB signaling pathway and phosphatidylcholine-phospholipase C (PC-PLC) activity after I/R, which was enhanced by wild-type PEBP1overexpression and rhPEBP1 treatment and inhibited by PEBP1 (S153A) overexpression. And PEBP1 (S153A) overexpression increased its interaction with Raf-1, reduced infarct size, neuronal death and inflammation, and improved neurological function after I/R, while wild-type PEBP1overexpression exerted opposite effects, suggesting that phosphorylation at Ser153 may exert as a functional switch of PEBP1 by switching PEBP1 from Raf-1 inhibition to PC-PLC activation following I/R. Compared with PEBP1 knockdown, PEBP1 (S153A) overexpression exerted a better rescue effect on I/R injury, which further proved that PEBP1 may be a good protein gone bad with phosphorylation at S153 as a functional switch following I/R. Collectively, our findings suggest that PEBP1 contributed to neuronal death and inflammation after I/R. Selective inhibition of PEBP1 phosphorylation may be a novel approach to ameliorate I/R injury.

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A1 adenosine receptor attenuates intracerebral hemorrhage-induced secondary brain injury in rats by activating the P38-MAPKAP2-Hsp27 pathway

Cited by 25 publications

References 55 publications

PERK Pathway Activation Promotes Intracerebral Hemorrhage Induced Secondary Brain Injury by Inducing Neuronal Apoptosis Both in Vivo and in Vitro

PERK Pathway Activation Promotes Intracerebral Hemorrhage Induced Secondary Brain Injury by Inducing Neuronal Apoptosis Both in Vivo and in Vitro

Neuroprotection Exerted by Netrin-1 and Kinesin Motor KIF1A in Secondary Brain Injury following Experimental Intracerebral Hemorrhage in Rats

Phosphorylation at S153 as a Functional Switch of Phosphatidylethanolamine Binding Protein 1 in Cerebral Ischemia-Reperfusion Injury in Rats

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