Effects of neural stem cell‐derived extracellular vesicles on neuronal protection and functional recovery in the rat model of middle cerebral artery occlusion

2019 ◽  
Vol 38 (4) ◽  
pp. 373-383 ◽  
Author(s):  
Marzieh Mahdavipour ◽  
Gholamreza Hassanzadeh ◽  
Elham Seifali ◽  
Keywan Mortezaee ◽  
Hadi Aligholi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Neural Stem Cell ◽  
Extracellular Vesicles ◽  
Functional Recovery ◽  
Rat Model ◽  
Artery Occlusion ◽  
Neuronal Protection ◽  
Cerebral Artery Occlusion

scholarly journals Ischemic Succinate Accumulation Inhibits Neural Stem Cell Proliferation after Cerebral Ischemia/Reperfusion via Inducing Cdc42 Succinylation

2021 ◽  
Author(s):  
Linyan Huang ◽  
Juyun Ma ◽  
Jinxiu Song ◽  
Jingjing Xu ◽  
Haidi Fan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Stem Cell ◽  
Middle Cerebral Artery ◽  
Reperfusion Injury ◽  
Middle Cerebral Artery Occlusion ◽  
Neural Stem Cell ◽  
Artery Occlusion ◽  
Ischemic Reperfusion Injury ◽  
Ischemic Reperfusion ◽  
Cerebral Artery Occlusion

Abstract BackgroundNeural stem cell proliferation is a critical process in endogenous neurogenesis after ischemic/reperfusion injury. Ischemic succinate accumulation causes cerebral damage due to excess reactive oxygen species production. However, it remains elusive whether ischemic succinate accumulation affects neural stem cell proliferation.MethodsIn this study, we established rat middle cerebral artery occlusion model to mimic ischemic/reperfusion injury in vivo. Primary neural stem cell and neural stem cell line C17.2 were challenged with oxygen-glucose deprivation and reoxygenation. The level of succinate was assessed by liquid chromatography–mass spectrometry analysis. Cell proliferation was tested by cell counting kit 8. The infarct volume was measured by 2,3,5-Triphenyltetrazolium chloride staining. G protein coupled receptor GPR91 was detected by immunofluorescence. Sirtuin 5 knockdown was performed with Sirt 5 siRNA transfection. Cdc42 GTPase activity and succinylation were evaluated by co-immunoprecipitation.ResultsWe showed that succinate increased in the serum and brain (cortex and hippocampus) in middle cerebral artery occlusion rats. oxygen-glucose deprivation also induced abundant succinate in neural stem cell. Diethyl succinate inhibited C17.2 cell proliferation. Intraperitoneal administration of DS (800mg/kg) increased the infarct volume in middle cerebral artery occlusion rats. Besides, Diethyl succinate increases Cdc42 succinylation but represses Rho family GTPase Cdc42 activity, without affecting the level of its receptor G protein-coupled receptor-91 in neural stem cells. Increasing Cdc42 succinylation by desuccinylacylase Sirt5 knockdown inhibited GTPase Cdc42 activity. Accordingly, Cdc42 inhibtor ML141 also inhibited C17.2 proliferation.ConclusionsOur observations showed that accumulation of succinate inhibited neural stem cell proliferation by inducing Cdc42 succinylation, which reduced Cdc42 GTPase activity and was detrimental for neurogenesis after ischemic/reperfusion injury. Our data revealed a new mechanism that ischemic succinate accumulation aggrevated cerebral ischemic/reperfusion injury.

scholarly journals Neuroprotective Effects of Cerebral Ischemic Preconditioning in a Rat Middle Cerebral Artery Occlusion Model: The Role of the Notch Signaling Pathway

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Li Chen ◽  
Kuan Huang ◽  
Rong Wang ◽  
Qiong Jiang ◽  
Zhenghua Wu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Notch Signaling ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Signaling Pathway ◽  
Neural Stem Cell ◽  
Notch Signaling Pathway ◽  
Artery Occlusion ◽  
Neuroprotective Effects ◽  
Cerebral Artery Occlusion

Cerebral ischemia-reperfusion (I/R) injury is a major problem worldwide. The Notch signaling pathway plays an important role in neural progenitor cell differentiation and in the inflammatory response after central nervous system injury. This study evaluated whether the neuroprotective effect of cerebral ischemic preconditioning (cIPC) is mediated by the preactivation of the Notch signaling pathway. A rat middle cerebral artery occlusion/reperfusion (MCAO/R) model and glucose deprivation/reoxygenation (OGD/R) cell model were constructed to detect the neuroprotective effects of cIPC. In in vivo experiments, cIPC reduces the neurological functional deficit, cerebral infarction, and cellular apoptosis in the hippocampus induced by middle cerebral artery occlusion/reperfusion (MCAO/R), thus indicating that cIPC can improve neurologic function. Moreover, cIPC can reveal the expression peak of Jagged1, Notch1, NICD, and Hes1 protein, thereby indicating that cIPC can preactivate Notch signaling. However, cIPC-induced improvements in neurologic function are compromised by the γ-secretase inhibitor N-(N-(3,5-difluorophenacetyl)-1-alanyl)-S-phenylglycine t-butyl ester (DAPT). In in vitro experiments, OGD preconditioning (OGDPC) can clearly upregulate Notch1 expression in the OGD/R-treated neuron and neural stem cell. Notch1 pre-overexpression can decrease neuron death and apoptosis under OGD/R treatment. Notch1 pre-overexpression can decrease the percentage of G1 stage cells and increase the percentage of S stage cells in OGD/R-treated neural stem cell. Furthermore, Notch1 pre-knockdown has the opposite effect on cell survival, apoptosis, and cycle in both OGD/R-treated neuron and neural stem cell. In conclusion, our results demonstrate that the neuroprotective effects of cIPC in a rat MCAO/R model are mediated by the preactivation of the Notch signaling pathway.

Reliability of behavioral tests in the middle cerebral artery occlusion model of rat

2018 ◽  
Vol 53 (5) ◽  
pp. 478-490 ◽  
Author(s):  
Junghoon Yu ◽  
Jinkyoo Moon ◽  
Joonyoung Jang ◽  
Jee In Choi ◽  
Jooeun Jung ◽  
...  
Keyword(s):  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Rat Model ◽  
Artery Occlusion ◽  
Behavioral Tests ◽  
Walking Test ◽  
Satisfactory Level ◽  
Cylinder Test ◽  
Cerebral Artery Occlusion

Stroke is one of the leading causes of death and disability worldwide, and its incidence is increasing. To overcome impairment from stroke, translational research for developing new therapeutic technologies has been conducted and middle cerebral artery occlusion (MCAo) in rat is the representative model. Since recovery from neurological impairment in contralateral limbs caused by brain damage is the major goal of treatment, behavioral tests that assess the relevant function are used. To determine therapeutic effect, obtaining reliable results of behavioral assessment is a prerequisite. However, studies on the reliability of behavioral tests in the MCAo rat model and necessity of prior training have not yet been reported. In this study, the authors investigate relative and absolute inter-rater reliabilities of modified neurological severity score (mNSS), cylinder test, and grid-walking test before training and repeated training every week until the reliability of results reached a satisfactory level. The training included repeated learning of the scoring system and decreasing disagreements among the raters. For MCAo modeling, adult male Sprague-Dawley rats were subjected to 90 min of transient MCAo. Six raters conducted behavioral tests via observation of video-recording on sham-operated and MCAo model rats at 3 or 7 days after the intervention. An independent experimenter randomly numbered each video clip to blind the experiment. The results of reliabilities were unacceptable before training and improved to a satisfactory level after 6 weeks of training in all of the tests. In conclusion, mNSS, cylinder test, and grid-walking test on the MCAo rat model are reliable evaluation methods after conducting appropriate training.

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