Repurposing the mucolytic agent ambroxol for treatment of sub-acute and chronic ischaemic stroke

Author:

Patzwaldt Kristin1,Berezhnoy Georgy1,Ionescu Tudor1,Schramm Linda1,Wang Yi2,Owczorz Miriam1,Calderón Eduardo3,Poli Sven2,Serna Higuita Lina M4,Gonzalez-Menendez Irene56,Quintanilla-Martinez Leticia56,Herfert Kristina1,Pichler Bernd16,Trautwein Christoph1,Castaneda-Vega Salvador13ORCID

Affiliation:

1. Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tuebingen , Tuebingen 72076 , Germany

2. Hertie Institute for Clinical Brain Research, Department for Neurology, University Hospital Tuebingen , Tuebingen 72076 , Germany

3. Department of Nuclear Medicine and Clinical Molecular Imaging, University Hospital Tuebingen , Tuebingen 72076 , Germany

4. Institute for Clinical Epidemiology and Applied Biostatistics, University Hospital Tuebingen , Tuebingen 72076 , Germany

5. Institute of Pathology and Neuropathology, Comprehensive Cancer Center, Eberhard Karls University , Tuebingen 72076 , Germany

6. Cluster of Excellence iFIT (EXC 2180) ‘Image-Guided and Functionally Instructed Tumor Therapies’, Eberhard Karls University Tuebingen , Tuebingen 72076 , Germany

Abstract

AbstractAmbroxol is a well-known mucolytic expectorant, which has gained much attention in amyotrophic lateral sclerosis, Parkinson’s and Gaucher’s disease. A specific focus has been placed on ambroxol’s glucocerebrosidase-stimulating activity, on grounds that the point mutation of the gba1 gene, which codes for this enzyme, is a risk factor for developing Parkinson’s disease. However, ambroxol has been attributed other characteristics, such as the potent inhibition of sodium channels, modification of calcium homeostasis, anti-inflammatory effects and modifications of oxygen radical scavengers. We hypothesized that ambroxol could have a direct impact on neuronal rescue if administered directly after ischaemic stroke induction. We longitudinally evaluated 53 rats using magnetic resonance imaging to examine stroke volume, oedema, white matter integrity, resting state functional MRI and behaviour for 1 month after ischemic stroke onset. For closer mechanistic insights, we evaluated tissue metabolomics of different brain regions in a subgroup of animals using ex vivo nuclear magnetic resonance spectroscopy.Ambroxol-treated animals presented reduced stroke volumes, reduced cytotoxic oedema, reduced white matter degeneration, reduced necrosis, improved behavioural outcomes and complex changes in functional brain connectivity. Nuclear magnetic resonance spectroscopy tissue metabolomic data at 24 h post-stroke proposes several metabolites that are capable of minimizing post-ischaemic damage and that presented prominent shifts during ambroxol treatment in comparison to controls. Taking everything together, we propose that ambroxol catalyzes recovery in energy metabolism, cellular homeostasis, membrane repair mechanisms and redox balance. One week of ambroxol administration following stroke onset reduced ischaemic stroke severity and improved functional outcome in the subacute phase followed by reduced necrosis in the chronic stroke phase.

Funder

Clinician-Scientist Programme of the Faculty of Medicine

University of Tuebingen

Werner Siemens Stiftung

Bruker Biospin

Publisher

Oxford University Press (OUP)

Subject

Neurology,Cellular and Molecular Neuroscience,Biological Psychiatry,Psychiatry and Mental health

Cited by 4 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3