Role for HIF-1α and Downstream Pathways in Regulating Neuronal Injury after Intracerebral Hemorrhage in Diabetes

Yu, Zhe; Tang, Ling; Chen, Lifen; Li, Jinfang; Wu, Weiqiang; Chang-lin, HU

doi:10.1159/000430334

Cited by 15 publications

(9 citation statements)

References 30 publications

(37 reference statements)

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“…Also, VEGF and its subtype receptor VEGFR-2 play an important role in pathologic angiogenesis [32, 33]. Amplified HIF-1α, VEGF and VEGFR-2 have been found in the brain tissues after induction of ICH and promotion of VEGF and VEGFR-2 by stabilization of HIF-1α can improve neurological deficits and increased brain water content induced by ICH [18]. Nevertheless, results of our current study provide evidence that blocking of mTOR signal plays a beneficial role in modulating brain injuries observed in ICH via VEGF mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Role for Target of Rapamycin (mTOR) Signal Pathway in Regulating Neuronal Injury after Intracerebral Hemorrhage

Wang¹,

Zhang

2017

Cell Physiol Biochem

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Background/Aims: Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase and activation of its signal pathway plays an important role in regulating protein growth and synthesis as well as cell proliferation and survival. In the present study, we examined the contribution of mTOR signal and its downstream products to brain injuries induced by intracerebral hemorrhage (ICH) in rats. Methods: Western Blot analysis was employed to examine the protein expression of mTOR and its downstream pathway and Caspase-3. ELISA was used to measure pro-inflammatory cytokines (PICs) and vascular endothelial growth factor (VEGF). Additionally, neurological Severity Score and brain water content were used to indicate neurological function and brain edema. Results: The protein expression of p-mTOR, mTOR-mediated phosphorylation of 4E–binding protein 4 (4E-BP1), p70 ribosomal S6 protein kinase 1 (S6K1) pathways were amplified in ICH rats compared with controls. Blocking mTOR using rapamycin significantly attenuated upregulation of PICs, namely IL-1β, IL-6 and TNF-α, and Caspase-3 indicating cell apoptosis, and promoted the levels of VEGF and its subtype receptor VEGFR-2 in brain tissues. Moreover, the effects of rapamycin were linked to improvement of neurological deficits and increased brain water content observed in ICH rats. Conclusion: Activation mTOR signal is engaged in pathophysiological process during ICH and blocking mTOR pathway plays a beneficial role in regulating neuronal tissues via PIC, apoptotic Caspase-3 and VEGF mechanisms. This has pharmacological implications to target specific mTOR and its downstream signal pathway for neuronal dysfunction and vulnerability related to ICH.

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Section: Discussionmentioning

confidence: 99%

Role for Target of Rapamycin (mTOR) Signal Pathway in Regulating Neuronal Injury after Intracerebral Hemorrhage

Wang¹,

Zhang

2017

Cell Physiol Biochem

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“…The possible explanations with regard to the role hyperglycemia plays in poor outcome after ICH were stated in several previous reports [13–15,17,20], but the definite molecular mechanism remains to be elucidated [23,24]. Experimental studies showed that diffuse brain edema, perihematomal increased neuronal apoptosis, and reduced autophagy, as well as larger hematoma formation, were caused by hyperglycemia after ICH [25–27].…”

Section: Discussionmentioning

confidence: 99%

Effect of Admission Hyperglycemia on 6-Month Functional Outcome in Patients with Spontaneous Cerebellar Hemorrhage

Tao

Wang

et al. 2017

Med Sci Monit

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BackgroundCerebellar hemorrhage (CH) has a quite different treatment strategy and prognostic factors compared with supratentorial intracerebral hemorrhage (ICH). The prognostic role of hyperglycemia has been discussed mainly in cases of supratentorial hemorrhage; it remains to be elucidated following CH. We aimed to determine the association of hyperglycemia on admission with 6-month functional outcome in CH patients.Material/MethodsWe retrospectively analyzed 77 patients with acute CH between September 2010 and April 2015 in West China Hospital. Blood glucose level was measured when the patients were admitted. Primary outcome was 6-month functional outcome, which could comprehensively reflect the patient’s recovery of physical and social ability after stroke and was assessed by the modified Rankin scale (mRS). Association of hyperglycemia with functional outcome was identified in logistic regression models.ResultsThere were 50 (64.9%) patients with poor functional outcomes. Patients with poor outcome were much older (P<0.001) and had a significantly higher glucose level on admission (P<0.001), a lower Glasgow Coma Scale score (P<0.001), a larger hematoma (P=0.003), and a higher incidence of intraventricular extension (P=0.002), brainstem compression (P=0.013), and hydrocephalus (P=0.023). Multivariate analysis showed that hyperglycemia (OR 1.50, 95% CI 1.07–2.08, P=0.017 when glucose level was analyzed as a continuous variable; OR 7.46, 95% CI 1.41–39.51, P=0.018 when glucose level was dichotomized by the critical threshold of 6.78 mmol/L) emerged as an independent predictor for adverse functional outcome at 6 months.ConclusionsTo the best of our knowledge, this is the first study focusing on the relationship between hyperglycemia and long-term functional outcome after CH. The study combined with previous pertinent reports definitely indicates the poor effect of hyperglycemia on both supra- and infratentorial ICH independent of hemorrhage site. Therefore, further controlled trials are urgently needed to evaluate the benefits of glucose-lowing treatment.

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“…Also, VEGF and its subtype receptor VEGFR-2 play an important role in pathologic angiogenesis [ 20 , 21 ]. Amplified HIF-1α, VEGF and VEGFR-2 have been found in the brain tissues after induction of CA and promotion of VEGF and VEGFR-2 by stabilisation of HIF-1α can improve neurological deficits and increased brain water content induced by ICH [ 22 ]. Nevertheless, results of our current study provide evidence that blocking of mTOR signal plays a beneficial role in modulating brain injuries observed in CA rats via VEGF mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Effects of mTOR on neurological deficits after transient global ischemia

Xing

2017

Translational Neuroscience

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Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase and activation of its signal pathway plays an important role in regulating protein growth and synthesis as well as cell proliferation and survival. In the present study, we examined the contribution of mTOR and its downstream products to brain injuries and neurological deficiencies after cardiac arrest (CA) induced-transient global ischemia. CA was induced by asphyxia followed by cardiopulmonary resuscitation (CPR) in rats. Our results showed that expression of p-mTOR, mTOR-mediated phosphorylation of 4E-binding protein 4 (4E-BP1) and p70 ribosomal S6 protein kinase 1 (S6K1) pathways were amplified in CA rats compared to their controls. Blocking mTOR using rapamycin attenuated upregulation of pro-inflammatory cytokines (namely IL-1β, IL-6 and TNF-α), and Caspase-3, indicating cell apoptosis and also promoting the levels of vascular endothelial growth factor (VEGF) and its subtype receptor VEGFR-2 in the hippocampus. Moreover, the effects of rapamycin were linked to improvement of neurological deficits and increased brain water content observed in CA rats. In conclusion, activation of mTOR signal is engaged in pathophysiological process during CA-induced transient global ischemia and blocking mTOR pathway plays a beneficial role in regulating injured neuronal tissues and neurological deficits via PIC, apoptotic Caspase-3 and VEGF mechanisms. Targeting one or more of these specific mTOR pathways and its downstream signaling molecules may present new opportunities for neural dysfunction and vulnerability related to transient global ischemia.

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Role for HIF-1α and Downstream Pathways in Regulating Neuronal Injury after Intracerebral Hemorrhage in Diabetes

Cited by 15 publications

References 30 publications

Role for Target of Rapamycin (mTOR) Signal Pathway in Regulating Neuronal Injury after Intracerebral Hemorrhage

Role for Target of Rapamycin (mTOR) Signal Pathway in Regulating Neuronal Injury after Intracerebral Hemorrhage

Effect of Admission Hyperglycemia on 6-Month Functional Outcome in Patients with Spontaneous Cerebellar Hemorrhage

Effects of mTOR on neurological deficits after transient global ischemia

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