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

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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Faculty Opinions recommendation of Hyperoxemia and long-term outcome after traumatic brain injury.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718076930.793482369 ◽

2013 ◽

Author(s):

Mauro Oddo ◽

Pierre Bouzat

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Term Outcome ◽

Long Term Outcome

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Long-term outcome following severe traumatic brain injury: ethical considerations

Journal of Neurosurgical Sciences ◽

10.23736/s0390-5616.18.04509-5 ◽

2018 ◽

Vol 62 (5) ◽

Author(s):

Stephen Honeybul

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Severe Traumatic Brain Injury ◽

Ethical Considerations ◽

Term Outcome ◽

Long Term Outcome

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Assessment of the Subarachnoid Hemorrhage International Trialists (SAHIT) Models for Dichotomized Long-Term Functional Outcome Prediction After Aneurysmal Subarachnoid Hemorrhage in a United Kingdom Multicenter Cohort Study

Neurosurgery ◽

10.1093/neuros/nyaa299 ◽

2020 ◽

Author(s):

Isabel C Hostettler ◽

Menelaos Pavlou ◽

Gareth Ambler ◽

Varinder S Alg ◽

Stephen Bonner ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Functional Outcome ◽

Outcome Prediction ◽

Prediction Models ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Predictive Performance ◽

Term Outcome ◽

Long Term Outcome ◽

Fisher Grade

Abstract BACKGROUND Long-term outcome after subarachnoid hemorrhage, beyond the first few months, is difficult to predict, but has critical relevance to patients, their families, and carers. OBJECTIVE To assess the performance of the Subarachnoid Hemorrhage International Trialists (SAHIT) prediction models, which were initially designed to predict short-term (90 d) outcome, as predictors of long-term (2 yr) functional outcome after aneurysmal subarachnoid hemorrhage (aSAH). METHODS We included 1545 patients with angiographically-proven aSAH from the Genetic and Observational Subarachnoid Haemorrhage (GOSH) study recruited at 22 hospitals between 2011 and 2014. We collected data on age, WNFS grade on admission, history of hypertension, Fisher grade, aneurysm size and location, as well as treatment modality. Functional outcome was measured by the Glasgow Outcome Scale (GOS) with GOS 1 to 3 corresponding to unfavorable and 4 to 5 to favorable functional outcome, according to the SAHIT models. The SAHIT models were assessed for long-term outcome prediction by estimating measures of calibration (calibration slope) and discrimination (area under the receiver-operating characteristic curve [AUC]) in relation to poor clinical outcome. RESULTS Follow-up was standardized to 2 yr using imputation methods. All 3 SAHIT models demonstrated acceptable predictive performance for long-term functional outcome. The estimated AUC was 0.71 (95% CI: 0.65-0.76), 0.73 (95% CI: 0.68-0.77), and 0.74 (95% CI: 0.69-0.79) for the core, neuroimaging, and full models, respectively; the calibration slopes were 0.86, 0.84, and 0.89, indicating good calibration. CONCLUSION The SAHIT prediction models, incorporating simple factors available on hospital admission, show good predictive performance for long-term functional outcome after aSAH.

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