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

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Abstract

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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Funding

This work was supported by grants (B.D.F) from the National Institutes of Health (NIH) (R01NS091616, R21NS106949, R25GM119975, U54RR026137, G12RR003034, U54NS060659, and S21MD000101).

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Author notes

  1. Jessica Noll and Yonggang Li contributed equally to this work.

Authors and Affiliations

  1. Division of Biomedical Sciences, University of California – Riverside School of Medicine, 900 University Ave., Riverside, CA, 92521, USA

    Jessica M. Noll, Yonggang Li, Timothy J. Distel & Byron D. Ford

  2. ICF, Atlanta, GA, 30329, USA

    Yonggang Li

  3. Fort Valley State University, 1005 State University Dr., Fort Valley, GA, 31030, USA

    Gregory D. Ford

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  1. Jessica M. Noll
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Correspondence to Byron D. Ford.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants or animals performed by any of the authors.

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The corresponding author (B.D.F.) holds patents related to the work being reported without direct corporate involvement at the time.

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Noll, J.M., Li, Y., Distel, T.J. et al. Neuroprotection by Exogenous and Endogenous Neuregulin-1 in Mouse Models of Focal Ischemic Stroke. J Mol Neurosci 69, 333–342 (2019). https://doi.org/10.1007/s12031-019-01362-4

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  • DOI: https://doi.org/10.1007/s12031-019-01362-4

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