Elsevier

Neuroscience

Volume 416, 15 September 2019, Pages 198-206
Neuroscience

Research Article
Colivelin Rescues Ischemic Neuron and Axons Involving JAK/STAT3 Signaling Pathway

https://doi.org/10.1016/j.neuroscience.2019.07.020Get rights and content

Highlights

  • Colivelin decreased neurological deficits and infarct lesion after brain ischemia.

  • Colivelin inhibited axonal damage and neuronal death after ischemic stroke.

  • Colivelin increased anti-apoptotic genes level via JAK/STAT3.

  • Colivelin may serve as a single or adjunct therapy in ischemic stroke.

Abstract

Colivelin is a neuroprotective humanin family peptide with potent long-term capacity against Aβ deposition, neuronal apoptosis, and synaptic plasticity deficits in neurodegenerative disease. We seek to investigate whether this effect of Colivelin also govern ischemic brain injury, and potential mechanism underlying the Colivelin-mediated action on ischemic neurons. We adopted 60 min induction of transient focal cerebral ischemia and reperfusion in mice. We found that relative to mice receiving vehicle, Colivelin administration decreased the neurological deficits and infarct lesion induced by brain ischemia. Colivelin inhibited axonal damage and neuronal death in brain tissue, which was associated with elevated anti-apoptotic gene expression in ischemic neurons as well as increased axonal growth up until two-weeks post-stroke. Moreover, Colivelin activated STAT3 signaling, which may partially contribute to its beneficial effect against neuronal death and axon growth. In conclusion, Colivelin induce anti-apoptotic genes up-regulation, and activate JAK/STAT3 signaling after ischemic stroke, which may contribute to its effects of rescuing ischemic neuronal death and axonal remodeling. This study may justify further works to examine Colivelin as a single or adjunct therapy in ischemic stroke.

Section snippets

INTRODUCTION

Cerebral ischemia and subsequent neurological deficits gravely afflict stroke patients. Current therapies for acute ischemic stroke are limited to intravenous administration of tissue plasminogen activator (tPA) which is further restricted by a short therapeutic window and strict inclusion criteria(Hacke et al., 2008, Ahmad and Graham, 2010, Lees et al., 2010, Chamorro et al., 2012). Endovascular thrombectomy (EVT), with the aid of CT/MRI perfusion imaging, show significant outcome improvement

Animals

Male C57BL/6 mice were purchased from Taconic (Oxnard, CA, USA). For all experiments, 10- to 12-week-old, 20 to 25 g, age-matched male littermates were used between experimental groups. All mice were randomly assigned to each experiment. Mice were housed no more than 5 animals per cage under standardized light–dark cycle conditions with access to food and water ad libitum. All animal experiments were performed in accordance with the recommendations of the Guide for the Care and Use of

Colivelin reduces infarct volume and improves neurological deficits after MCAO

Wild type C57BL/6 mice were intraperitoneally injected with Colivelin (1 mg/kg) or vehicle (20% ethyl alcohol) 30 min prior to sham or MCAO procedures, and continuous 6 days with daily administration. To determine the impact of Colivelin on ischemic brain injury, neurodeficits, infarct lesion volume and brain edema of MCAO mice receiving Colivelin or vehicle were examined. From day 1 to day 14 post ischemia and reperfusion, Colivelin administration resulted in improved motor and cognitive

Discussion

In this study, we describe the beneficial effect of Colivelin in mouse model of ischemic stroke as evidenced by improved neurodeficits, reduced lesion size and attenuated neuronal apoptosis. Colivelin treatment results in accelerated growth of midline-crossing axons, which is highly correlated with improved clinical outcome. Moreover, activation of STAT3 signaling might be involved in the beneficial mechanism of Colivelin.

The use of neuroprotective agents in stroke has been a notable failure of

Declarations of interest

None.

Funding

This study was supported in part by National Science Foundation of China grant 81771274, 91642205, and 81830038.

Acknowledgments

We would like to thank Samuel Xiang-Yu Shi (Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA) for editorial assistance.

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