Topiramate modulates post-infarction inflammation primarily by targeting monocytes or macrophages.

Aims Monocytes/macrophages response plays a key role in post-infarction inflammation that contributes greatly to postinfarction ventricular remodelling and cardiac rupture. Therapeutic targeting of the GABA(A) receptor, which is enriched in monocytes/macrophages but not expressed in the myocardium, may be possible after myocardial infarction (MI). Methods and results After MI was induced by ligation of the coronary artery, C57BL/6 mice were intraperitoneally administered with 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 MI, when monocytes/macrophages dominated, in contrast with bicuculline, topiramate treatment significantly reduced Ly-6C(high) monocyte numbers by regulating splenic monocytopoiesis and promoted foetal derived macrophages preservation and conversion of M1 to M2 or Ly-6C(high) to Ly-6C(low) macrophage phenotype in the infarcted heart, though GABAAergic drugs failed to affect M1/M2 or Ly-6C(high)/Ly-6C(low) macrophage polarization directly. Accordingly, proinflammatory activities mediated by M1 or Ly-6C(high) macrophages were decreased and reparative processes mediated by M2 or Ly-6C(low) macrophages were augmented. As a result, post-infarction ventricular remodelling was attenuated, as reflected by reduced infarct size and increased collagen density within infarcts. Echocardiographic 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 MI therapy in the future.