Topiramate modulates post-infarction inflammation primarily by targeting monocytes or macrophages.
OBJECTIVE
Monocytes/macrophages response plays a key role in post-infarction inflammation that contributes greatly to post-infarction 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 (MI).


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-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, pro-inflammatory 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. 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.


CONCLUSIONS
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.
Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China.
Zhaohui
Z
Wang
Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China.
Shiyuan
S
Huang
Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China.
Yuling
Y
Sheng
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China.
Xu
X
Peng
Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China.
Hui
H
Liu
Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China.
Nan
N
Jin
Department of Emergency Surgery, the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, 26 Shengli Ave, Wuhan 430014, China.
Jun
J
Cai
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China.
Yanwen
Y
Shu
Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China.
Ting
T
Li
Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China.
Ping
P
Li
Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China.
Cheng
C
Fan
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China.
Xiaofan
X
Hu
Department of Geriatrics, LIYUAN Hospital, Tongji Medical College, Huazhong University of Science and Technology, 39 Yanhu Ave, Wuhan 430077, China.
Wenyong
W
Zhang
Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China.
Rui
R
Long
Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China.
Ya
Y
You
Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China.
Caihong
C
Huang
Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China.
Yi
Y
Song
Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China.
Chunhua
C
Xiang
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, China.
Jue
J
Wang
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China.
Yong
Y
Yang
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China.
Kun
K
Liu
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000950:Antigens, Ly / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology*; D006342:Heart Rupture, Post-Infarction / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009205:Myocarditis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D018079:Receptors, GABA / Q000187:drug effects* / Q000378:metabolism; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D000077236:Topiramate; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D000950:Antigens, Ly; D018755:GABA Agonists; C546241:Gabra1 protein, mouse; C546270:Gabrb3 protein, mouse; C526827:Ly6 protein, mouse; D018079:Receptors, GABA; D011963:Receptors, GABA-A; D000077236:Topiramate; D005632:Fructose; D003094:Collagen
GABAA receptor; Macrophage; Monocyte; Myocardial infarction; Topiramate