Evaluation of neuregulin-1's neuroprotection against ischemic injury in rats using diffusion tensor imaging

Wang, Silun; Li, Yonggang; Paudyal, Ramesh; Ford, Byron D.; Zhang, Xiaodong

doi:10.1016/j.mri.2018.07.002

Cited by 9 publications

(7 citation statements)

References 60 publications

(80 reference statements)

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“…Compared with controls, i.a. administration of NRG-1 drastically reduced infarct volume after MCAO in mice as we and others previously showed in rats (Guo et al 2006;Li et al 2007;Shyu et al 2004;Wang et al 2015Wang et al , 2018Xu et al 2004Xu et al , 2005Xu et al , 2006. The percentage of total infarct volume to the ipsilateral hemisphere in vehicle-treated animals was 41%.…”

Section: Resultssupporting

confidence: 79%

“…Neuregulins have been implicated in normal brain function, as well as in neuroprotection following cerebral ischemia. Previous studies from our laboratory and others demonstrated that neuregulin-1 (NRG-1) reduced ischemia-induced neuronal death in a rat focal stroke model by~90% with a therapeutic window of > 13 h (Guo et al 2006;Li et al 2007;Shyu et al 2004;Wang et al 2015Wang et al , 2018Xu et al 2004Xu et al , 2005Xu et al , 2006. NRG-1 administration also resulted in a significant improvement of neurological function (Iaci et al 2010;Xu et al 2006).…”

Section: Introductionmentioning

confidence: 97%

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Neuroprotection by Exogenous and Endogenous Neuregulin-1 in Mouse Models of Focal Ischemic Stroke

Noll

Distel

et al. 2019

J Mol Neurosci

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Identifying novel neuroprotectants that can halt or reverse the neurological effects of stroke is of interest to both clinicians and scientists. We and others previously showed the pre-clinical neuroprotective efficacy of neuregulin-1 (NRG-1) in rats following focal brain ischemia. In this study, we examined neuroprotection by exogenous and endogenous NRG-1 using a mouse model of ischemic stroke. C57BL6 mice were subjected to middle cerebral artery occlusion (MCAO) followed by reperfusion. NRG-1 or vehicle was infused intra-arterially (i.a.) or intravenously (i.v.) after MCAO and before the onset of reperfusion. NRG-1 treatment (16 μg/kg; i.a.) reduced cerebral cortical infarct volume by 72% in mice when delivered post-ischemia. NRG-1 also inhibited neuronal injury as measured by Fluoro Jade B labeling and rescued NeuN immunoreactivity in neurons. Neuroprotection by NRG-1 was also observed in mice when administered i.v. (100 μg/kg) in both male and female mice. We investigated whether endogenous NRG-1 was neuroprotective using male and female heterozygous NRG-1 knockout mice (NRG-1+/−) compared with wild-type mice (WT) littermates. NRG-1+/− and WT mice were subjected to MCAO for 45 min, and infarct size was measured 24 h following MCAO. NRG-1+/− mice displayed a sixfold increase in cortical infarct size compared with WT mice. These results demonstrate that NRG-1 treatment mitigates neuronal damage following cerebral ischemia. We further showed that reduced endogenous NRG-1 results in exacerbated neuronal injury in vivo. These findings suggest that NRG-1 represents a promising therapy to treat stroke in human patients.

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Section: Resultssupporting

confidence: 79%

Section: Introductionmentioning

confidence: 97%

Neuroprotection by Exogenous and Endogenous Neuregulin-1 in Mouse Models of Focal Ischemic Stroke

Noll

Distel

et al. 2019

J Mol Neurosci

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“…Work from our laboratory and others demonstrated that NRG-1 reduced ischemia-induced neuronal death and inflammation in rodent focal stroke models by up to 90% ( Shyu et al, 2004 ; Xu et al, 2004 ; Guo et al, 2006 ; Xu et al, 2006 ; Li et al, 2007 , 2008 , 2009 ; Guan et al, 2015 ; Wang et al, 2015 ; Simmons et al, 2016 ; Ji et al, 2017 ; Surles-Zeigler et al, 2018 ; Wang et al, 2018 ; Noll et al, 2019 ; Cui et al, 2023 ). These finding have been demonstrated by seven independent laboratories.…”

Section: Rationale For Neuregulin-1 Clinical Studies For Strokementioning

confidence: 84%

The case for neuregulin-1 as a clinical treatment for stroke

Noll,

Sherafat,

Ford

et al. 2024

Front. Cell. Neurosci.

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Ischemic stroke is the leading cause of serious long-term disability and the 5th leading cause of death in the United States. Revascularization of the occluded cerebral artery, either by thrombolysis or endovascular thrombectomy, is the only effective, clinically-approved stroke therapy. Several potentially neuroprotective agents, including glutamate antagonists, anti-inflammatory compounds and free radical scavenging agents were shown to be effective neuroprotectants in preclinical animal models of brain ischemia. However, these compounds did not demonstrate efficacy in clinical trials with human patients following stroke. Proposed reasons for the translational failure include an insufficient understanding on the cellular and molecular pathophysiology of ischemic stroke, lack of alignment between preclinical and clinical studies and inappropriate design of clinical trials based on the preclinical findings. Therefore, novel neuroprotective treatments must be developed based on a clearer understanding of the complex spatiotemporal mechanisms of ischemic stroke and with proper clinical trial design based on the preclinical findings from specific animal models of stroke. We and others have demonstrated the clinical potential for neuregulin-1 (NRG-1) in preclinical stroke studies. NRG-1 significantly reduced ischemia-induced neuronal death, neuroinflammation and oxidative stress in rodent stroke models with a therapeutic window of >13 h. Clinically, NRG-1 was shown to be safe in human patients and improved cardiac function in multisite phase II studies for heart failure. This review summarizes previous stroke clinical candidates and provides evidence that NRG-1 represents a novel, safe, neuroprotective strategy that has potential therapeutic value in treating individuals after acute ischemic stroke.

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“…NRG1 was transduced through the receptor tyrosine-protein kinase erythroblastic oncogene B (ErbB) family to regulate downstream pathways PI3K–AKT and PI3K–extracellular-signal-regulated kinase signaling pathway. It had been demonstrated NRG1 signaling involved in NPCs activation [ 38 ], neuroprotective effects [ 39 , 40 ], neuroinflammatory modulation [ 41 , 42 ], and angiogenesis [ 43 ]. Through Western blot, the expression of NRG1 and AKT, typically activated in the EBP-bFGF/ECM group, was verified compared with the other 2 groups.…”

Section: Discussionmentioning

confidence: 99%

Engineered Basic Fibroblast Growth Factor Specifically Bonded with Injectable Extracellular Matrix Hydrogel for the Functional Restoration of Cerebral Ischemia in Rats

Shi,

Liu,

Sun

et al. 2024

Biomater Res

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Cerebral ischemia was one of the leading causes of mortality and disability worldwide. Extracellular matrix (ECM) hydrogel held great potential to replace volumetric brain tissue loss following ischemic injury but with limited regenerative effect for functional restoration when implanted alone. In the present study, an engineered basic fibroblast growth factor (EBP-bFGF) was constructed, which fused a specific ECM-binding peptide (EBP peptide) with bFGF. The recombinant EBP-bFGF showed typical binding capacity with ECM without affecting the bioactivity of bFGF both in vitro and in vivo. Furthermore, the EBP-bFGF was used for bioactive modification of ECM hydrogel to repair cerebral ischemia. The combination of EBP-bFGF and ECM hydrogels could realize the sustained release of bFGF in the ischemic brain and improve the regenerative effect of ECM, which protected the survival of neurons, enhanced angiogenesis, and decreased the permeability of blood–brain barrier, ultimately promoted the recovery of motor function. In addition, transcriptome analysis revealed neuregulin-1/AKT pathway involved in this process. Therefore, EBP-bFGF/ECM hydrogel would be a promising therapeutic strategy for cerebral ischemia.

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Evaluation of neuregulin-1's neuroprotection against ischemic injury in rats using diffusion tensor imaging

Cited by 9 publications

References 60 publications

Neuroprotection by Exogenous and Endogenous Neuregulin-1 in Mouse Models of Focal Ischemic Stroke

Neuroprotection by Exogenous and Endogenous Neuregulin-1 in Mouse Models of Focal Ischemic Stroke

The case for neuregulin-1 as a clinical treatment for stroke

Engineered Basic Fibroblast Growth Factor Specifically Bonded with Injectable Extracellular Matrix Hydrogel for the Functional Restoration of Cerebral Ischemia in Rats

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