Neuroprotection of Botch in experimental intracerebral hemorrhage in rats
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Binbin Mei1,*, Haiying Li1,*, Juehua Zhu2,*, Junjie Yang3, Ziying Yang3, Zunjia Wen1, Xiang Li1, Haitao Shen1, Meifen Shen1 and Gang Chen1
1Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
2Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
3Institute for Cardiovascular Science and Department of Cardiovascular Surgery of The First Affiliated Hospital, Soochow University, Suzhou, Jiangsu Province, China
*These authors have contributed equally to this work
Gang Chen, email: firstname.lastname@example.org
Meifen Shen, email: email@example.com
Keywords: intracerebral hemorrhage; secondary brain injury; neuron; Botch; Notch1
Received: July 05, 2017 Accepted: August 04, 2017 Published: August 24, 2017
Notch1 maturation participates in apoptosis and inflammation following intracerebral hemorrhage (ICH). It has been reported that Botch bound to and blocked Notch1 maturation. Here we estimated the role of Botch in ICH-induced secondary brain injury and underlying mechanisms. Experimental ICH model was induced by autologous arterial blood injection in Sprague-Dawley rats, and cultured primary rat cortical neurons were exposed to oxyhemoglobin to mimic ICH in vitro. Specific small interfering RNAs and expression plasmids encoding wild type Botch and Botch with Glu115Ala mutation were exploited. The protein levels of Botch and Notch1 transmembrane intracellular domain (Notch1-TMIC) were increased within brain tissue around hematoma. Botch overexpression led to an increase in unprocessed Notch1 full-length form accompanied by a significant decrease in Notch1-TMIC, while Botch knockdown resulted in an approximately 1.5-fold increase in Notch1-TMIC. There were increased cell apoptosis, necrosis and neurobehavioral deficits after ICH, which was inhibited by Botch overexpression and enhanced by Botch knockdown. Double immunofluorescence showed a colocalization of Botch and Notch1 in the trans-Golgi. Overexpression of wild type Botch, but not Botch E115A mutant, led to an increase in the interaction between Botch and Notch1, reduced the formation and the nuclear localization of Notch1 intracellular domain, and attenuated cell apoptosis and inflammation. In conclusion, Botch exerts neuroprotection against neuronal damage via antagonizing the maturation of Notch1 in Glu115-denpendent manner. However, neuroprotection mediated by endogenous Botch is not enough to reverse ICH-induced secondary brain injury.
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