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Topiramate modulates post-infarction inflammation primarily by targeting monocytes or macrophages.
- Source :
-
Cardiovascular Research . 4/1/2017, Vol. 113 Issue 5, p475-487. 13p. - Publication Year :
- 2017
-
Abstract
- Aims: Monocytes/macrophages response plays a key role in postinfarction inflammation that contributes greatly to postinfarction ventricular remodelling and cardiac rupture. Therapeutic targeting of the GABAa receptor, which is enriched in monocytes/macrophages but not expressed in the myocardium, may be possible after myocardial infarction (Ml). Methods and results:After Ml was induced by ligation of the coronary artery, C57BL/6 mice were intraperitoneally administered with and results one specific agonist or antagonist of the GABAA receptor (topiramate or bicuculline), in the setting of presence or depletion of monocytes/macrophages. Our data showed that within the first 2 weeks after Ml, when monocytes/macrophages dominated, in contrast with bicuculline, topiramate treatment significantly reduced Ly-6Chigh monocyte numbers by regulating splenic monocytopoiesis and promoted foetal derived macrophages preservation and conversion of M1 to M2 or Ly-6Chigh to Ly-6Clow macrophage phenotype in the infarcted heart, though GABAAergic drugs failed to affect M1/M2 or Ly-6Chigh/Ly-6Clow macrophage polarization directly. Accordingly, proinflammatory activities mediated by M1 or Ly-6Chigh macrophages were decreased and reparative processes mediated by M2 or Ly-6Clow macrophages were augmented. As a result, post-infarction ventricular remodelling was attenuated, as reflected by reduced infarct size and increased collagen density within infarcts. Echocardiography indices, mortality and rupture rates were reduced. After depletion of monocytes/macrophages by clodronate liposomes, GABAAergic drugs exhibited no effect on cardiac dysfunction and surrogate clinical outcomes. Conclusion: Control of the GABAA receptor activity in monocytes/macrophages can potently modulate post-infarction inflammation. Topiramate emerges as a promising drug, which may be feasible to translate for Ml therapy in the future. [ABSTRACT FROM AUTHOR]
- Subjects :
- *MYOCARDIAL infarction
*TOPIRAMATE
*MONOCYTES
*MACROPHAGES
*COLLAGEN
Subjects
Details
- Language :
- English
- ISSN :
- 00086363
- Volume :
- 113
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- Cardiovascular Research
- Publication Type :
- Academic Journal
- Accession number :
- 122395629
- Full Text :
- https://doi.org/10.1093/cvr/cvx027