Osteopontin attenuates early brain injury through regulating autophagy‐apoptosis interaction after subarachnoid hemorrhage in rats

Sun, Chengmei; Enkhjargal, Budbazar; Reis, Cesar; Zhou, Keren; Xie, Zhiyi; Wu, Lingyun; Zhang, Tongyu; Zhu, Qiquan; Tang, Jiping; Jiang, Xiao-dan; Zhang, Junyi

doi:10.1111/cns.13199

Cited by 28 publications

(32 citation statements)

References 41 publications

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“…Apoptosis is triggered if p62-mediated autophagy is prohibited (Goodall et al, 2016). Cheng et al suggested that the neuronal apoptosis was inhibited by recombinant OPN via enhancing autophagy in subarachnoid hemorrhage-induced brain injury (Sun et al, 2019). Moreover, previous studies also proved that autophagy induction alleviated apoptosis in Parkinson's disease (Lin et al, 2014) and stroke (Wu et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Eugenol Attenuates Cerebral Ischemia-Reperfusion Injury by Enhancing Autophagy via AMPK-mTOR-P70S6K Pathway

et al. 2020

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Eugenol, as an active compound isolated from Acorus gramineus, has been shown to protect against cerebral ischemia-reperfusion (I/R) injury. Nonetheless, the detailed neuroprotective mechanisms of eugenol in cerebral I/R injury have not been elaborated. In the present study, cerebral I/R injury model was established by middle cerebral artery occlusion (MCAO) in rats. HT22 cells were subjected to oxygen-glucose deprivation/ reperfusion (OGD/R) to mimic cerebral I/R injury in vitro. The results showed that eugenol pre-treatment relieved cerebral I/R injury as evidenced by improving neurological deficits and reducing infarct volume. Autophagy was induced by MCAO, which was further promoted by eugenol administration. Moreover, rapamycin, an activator of autophagy, promoted eugenol-induced decreases in neurological score, infarct volume, brain water content, and apoptosis. However, pretreatment with 3-MA, an inhibitor of autophagy, led to the opposite results. Similarly, eugenol pretreatment increased the viability and restrained apoptosis of OGD/R-challenged HT22 cells. OGD/R-induced autophagy was strengthened by eugenol. Mechanically, eugenol promoted autophagy through regulating AMPK/mTOR/P70S6K signaling pathway in vivo and in vitro. In conclusion, pretreatment with eugenol attenuated cerebral I/R injury by inducing autophagy via AMPK/mTOR/ P70S6K signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Eugenol Attenuates Cerebral Ischemia-Reperfusion Injury by Enhancing Autophagy via AMPK-mTOR-P70S6K Pathway

et al. 2020

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“…OPN is a neuroprotective glycoprotein expressed in various types of cells. Our previous studies showed that endogenous OPN expression increased after SAH induction [21,35]. Moreover, exogenous OPN treatment showed protective effects against vasospasm and blood-brain barrier disruption after SAH through integrin receptor-dependent activation of MKP-1 and MAPK phosphatase in astrocytes and endothelial cells [18,36].…”

Section: Discussionmentioning

confidence: 99%

“…Vehicle or rOPN was delivered via the nasal route 1 h after SAH induction, and brain samples were collected 24 h after SAH. The intranasal rOPN dosage was selected based on previous studies [7,21].…”

Section: Methodsmentioning

confidence: 99%

“…Vehicle or rOPN was delivered via the intranasal route 1 h after SAH induction as previously described [21]. Rats under 2% isoflurane anesthesia were placed in a supine position and a total volume of 30 μL PBS or rOPN was administered alternately into the left and right nares, 5 μL each time with an interval of 2 min between each administration.…”

Section: Methodsmentioning

confidence: 99%

“…After rOPN administration, there were elevated autophagy protein expressions and a decreased apoptosis level in the perforated side of rat brains 24 h after SAH. We also observed an interaction between autophagy initiator Beclin 1 and apoptosis-related protein Caspase-3 which could be regulated by rOPN administration at 24 h after SAH [21]. However, the molecular mechanism involved in OPN-enhanced autophagy after SAH has not been studied yet.…”

Section: Introductionmentioning

confidence: 99%

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Osteopontin-Enhanced Autophagy Attenuates Early Brain Injury via FAK–ERK Pathway and Improves Long-Term Outcome after Subarachnoid Hemorrhage in Rats

Sun

Enkhjargal

Reis

et al. 2019

Cells

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Osteopontin (OPN) enhances autophagy, reduces apoptosis, and attenuates early brain injury (EBI) after a subarachnoid hemorrhage (SAH). A total of 87 Sprague–Dawley rats were subjected to sham or SAH operations to further investigate the signaling pathway involved in osteopontin-enhanced autophagy during EBI, and the potential effect of recombinant OPN (rOPN) administration to improve long-term outcomes after SAH. Rats were randomly divided into five groups: Sham, SAH + Vehicle (PBS, phosphate-buffered saline), SAH + rOPN (5 μg/rat recombinant OPN), SAH + rOPN + Fib-14 (30 mg/kg of focal adhesion kinase (FAK) inhibitor-14), and SAH + rOPN + DMSO (dimethyl sulfoxide). Short-term and long-term neurobehavior tests were performed, followed by a collection of brain samples for assessment of autophagy markers in neurons, pathway proteins expression, and delayed hippocampal injury. Western blot, double immunofluorescence staining, Nissl staining, and Fluoro-Jade C staining assay were used. Results showed that rOPN administration increased autophagy in neurons and improved neurobehavior in a rat model of SAH. With the administration of FAK inhibitor-14 (Fib-14), neurobehavioral improvement and autophagy enhancement induced by rOPN were abolished, and there were consistent changes in the phosphorylation level of ERK1/2. In addition, early administration of rOPN in rat SAH models improved long-term neurobehavior results, possibly by alleviating hippocampal injury. These results suggest that FAK–ERK signaling may be involved in OPN-enhanced autophagy in the EBI phase after SAH. Early administration of rOPN may be a preventive and therapeutic strategy against delayed brain injury after SAH.

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Protective mechanism of FoxO1 against early brain injury after subarachnoid hemorrhage by regulating autophagy

et al. 2021

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Introduction:Early brain injury (EBI) plays a key role in the devastating outcomes after subarachnoid hemorrhage (SAH). Autophagy and apoptosis may share a common molecular inducer that regulates the process of cell death. FoxO1, as a key regulator of neuronal autophagy which is involved in apoptosis, has not been reported in SAH rats.This work was to investigate the protective and anti-inflammatory effects of FoxO1 on EBI after SAH by regulating autophagy. Methods:In this study, we constructed the SAH model. In experiment I, low dose (50 μl of 1 × 10 8 IU/ml) or high dose (50 μl of 1 × 10 10 IU/ml) of FoxO1 gene overexpressed adenovirus vector was injected into the lateral ventricle of rats before SAH. In experiment II, we reported the effect of FoxO1 overexpress on nerve function recovery, oedema, BBB leakage, neuronal death in rats after SAH through autophagy regulation.Post-SAH evaluation included neurological function score, brain water content, evans blue exosmosis, pathological changes, inflammatory response and apoptosis. Results:The experiment I showed that either low or high dose of ad-FoxO1 could significantly improve nerve function, reduce cerebral water content and reduce bloodbrain barrier (BBB) destruction in rats, indicating that ad-FoxO1 had a protective effect on brain injury in rats EBI after SAH. In addition, ad-FoxO1 promoted autophagy in rat hippocampal tissue, as evidenced by accumulation of LC3II/I and Beclin-1 and degradation of p62. Furthermore, ad-FoxO1 inhibited the inflammatory response and apoptosis of rat hippocampal neurons after SAH. The experiment II showed that both ad-FoxO1 and rapamycin attenuated the injury of nerve function in rats after SAH, and this synergistic effect further reduced cerebral edema and evansblue extravasation, decreased hippocampus neuronal cell apoptosis, and declined inflammatory response.However, this was contrary to the results of chloroquine. These findings suggested that FoxO1 regulated the neural function of EBI after SAH through the autophagy pathway. Conclusions:The findings in this study was beneficial for identifying the novel therapeutic target for the treatment of SAH.

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Osteopontin attenuates early brain injury through regulating autophagy‐apoptosis interaction after subarachnoid hemorrhage in rats

Cited by 28 publications

References 41 publications

Eugenol Attenuates Cerebral Ischemia-Reperfusion Injury by Enhancing Autophagy via AMPK-mTOR-P70S6K Pathway

Eugenol Attenuates Cerebral Ischemia-Reperfusion Injury by Enhancing Autophagy via AMPK-mTOR-P70S6K Pathway

Osteopontin-Enhanced Autophagy Attenuates Early Brain Injury via FAK–ERK Pathway and Improves Long-Term Outcome after Subarachnoid Hemorrhage in Rats

Protective mechanism of FoxO1 against early brain injury after subarachnoid hemorrhage by regulating autophagy

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