Benserazide is neuroprotective and improves functional recovery after experimental ischemic stroke by altering the immune response

Stroke is a leading cause of permanent disability worldwide. Despite intensive research over the last decades, key anti-inflammatory strategies that have proven beneficial in pre-clinical animal models have often failed in translation. The importance of neutrophils as pro- and anti-inflammatory peri...

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Published in:	Scientific reports Vol. 14; no. 1; pp. 17949 - 14
Main Authors:	Keuters, Meike Hedwig, Keksa-Goldsteine, Velta, Rõlova, Taisia, Jaronen, Merja, Kettunen, Pinja, Halkoluoto, Aurora, Goldsteins, Gundars, Koistinaho, Jari, Dhungana, Hiramani
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 02-08-2024 Nature Publishing Group Nature Portfolio
Subjects:	692/308/2778 692/420/256/2516 692/699/375/1370/534 Animal models Animals Aromatic-L-amino-acid decarboxylase Benserazide Benserazide - pharmacology Cell culture Chemokines Clinical trials Disease Models, Animal Drug development Functional improvement Human iPS neuronal cells Humanities and Social Sciences Humans Immune response Inflammation Ischemia Ischemic stroke Ischemic Stroke - drug therapy Ischemic Stroke - immunology Ischemic Stroke - metabolism Leukocytes (neutrophilic) Levodopa Macrophages Macrophages - drug effects Macrophages - immunology Macrophages - metabolism Male Mice Mice, Inbred C57BL Microglia Microglia - drug effects Microglia - metabolism multidisciplinary NETosis Neurodegenerative diseases Neuroinflammation Neurons - drug effects Neurons - metabolism Neuroprotection Neuroprotective Agents - pharmacology Neuroprotective Agents - therapeutic use Neutrophils Neutrophils - drug effects Neutrophils - immunology Neutrophils - metabolism Parenchyma Parkinson's disease Phenotypes Reactive oxygen species Recovery of function Recovery of Function - drug effects Science Science (multidisciplinary) Stroke Benserazide Neuroinflammation NETosis Ischemic stroke Functional improvement Human iPS neuronal cells
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Summary:	Stroke is a leading cause of permanent disability worldwide. Despite intensive research over the last decades, key anti-inflammatory strategies that have proven beneficial in pre-clinical animal models have often failed in translation. The importance of neutrophils as pro- and anti-inflammatory peripheral immune cells has often been overlooked in ischemic stroke. However, neutrophils rapidly infiltrate into the brain parenchyma after stroke and secrete an array of pro-inflammatory factors including reactive oxygen species, proteases, cytokines, and chemokines exacerbating damage. In this study, we demonstrate the neuroprotective and anti-inflammatory effect of benserazide, a clinically used DOPA decarboxylase inhibitor, using both in vitro models of inflammation and in vivo mouse models of focal cerebral ischemia. Benserazide significantly attenuated PMA-induced NETosis in isolated human neutrophils. Furthermore, benserazide was able to protect both SH-SY5Y and iPSC-derived human cortical neurons when challenged with activated neutrophils demonstrating the clinical relevance of this study. Additional in vitro data suggest the ability of benserazide to polarize macrophages towards M2-phenotypes following LPS stimulation. Neuroprotective effects of benserazide are further demonstrated by in vivo studies where peripheral administration of benserazide significantly attenuated neutrophil infiltration into the brain, altered microglia/macrophage phenotypes, and improved the behavioral outcome post-stroke. Overall, our data suggest that benserazide could serve as a drug candidate for the treatment of ischemic stroke. The importance of our results for future clinical trials is further underlined as benserazide has been approved by the European Medicines Agency as a safe and effective treatment in Parkinson’s disease when combined with levodopa.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-024-68986-4