PMID- 32647341 OWN - NLM STAT- MEDLINE DCOM- 20210909 LR - 20240226 IS - 1745-7254 (Electronic) IS - 1671-4083 (Print) IS - 1671-4083 (Linking) VI - 42 IP - 3 DP - 2021 Mar TI - Zonisamide, an antiepileptic drug, alleviates diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress. PG - 393-403 LID - 10.1038/s41401-020-0461-z [doi] AB - Endoplasmic reticulum stress (ER stress) plays a key role in the development of cardiac hypertrophy and diabetic cardiomyopathy (DCM). Zonisamide (ZNS) was originally developed as an antiepileptic drug. Studies have shown that ZNS suppresses ER stress-induced neuronal cell damage in the experimental models of Parkinson's disease. Herein, we investigated whether ZNS improved DCM by attenuating ER stress-induced apoptosis. C57BL/6J mice were fed with high-fat diet (HFD) and intraperitoneally injected with low-dose streptozotocin (STZ) to induce type 2 diabetes mellitus (T2DM), and then treated with ZNS (40 mg.kg(-1).d(-1), i.g.) for 16 weeks. We showed that ZNS administration slightly ameliorated the blood glucose levels, but significantly alleviated diabetes-induced cardiac dysfunction and hypertrophy. Furthermore, ZNS administration significantly inhibited the Bax and caspase-3 activity, upregulated Bcl-2 activity, and decreased the proportion of TUNEL-positive cells in heart tissues. We analyzed the hallmarks of ER stress in heart tissues, and revealed that ZNS administration significantly decreased the protein levels of GRP78, XBP-1s, ATF6, PERK, ATF4, and CHOP, and elevated Hrd1 protein. In high glucose (HG)-treated primary cardiomyocytes, application of ZNS (3 muM) significantly alleviated HG-induced cardiomyocyte hypertrophy and apoptosis. ZNS application also suppressed activated ER stress in HG-treated cardiomyocytes. Moreover, preapplication of the specific ER stress inducer tunicamycin (10 ng/mL) eliminated the protective effects of ZNS against HG-induced cardiac hypertrophy and ER stress-mediated apoptosis. Our findings suggest that ZNS improves the cardiac diastolic function in diabetic mice and prevents T2DM-induced cardiac hypertrophy by attenuating ER stress-mediated apoptosis. FAU - Tian, Jia-Hui AU - Tian JH AD - Department of Pharmacology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. FAU - Wu, Qian AU - Wu Q AD - Department of Pharmacology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. FAU - He, Yong-Xiang AU - He YX AD - Department of Pharmacology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. FAU - Shen, Qi-Ying AU - Shen QY AD - Department of Pharmacology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. FAU - Rekep, Mubarak AU - Rekep M AD - Department of Pharmacology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. FAU - Zhang, Gui-Ping AU - Zhang GP AD - Department of Pharmacology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. FAU - Luo, Jian-Dong AU - Luo JD AD - Department of Pharmacology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. FAU - Xue, Qin AU - Xue Q AD - Department of Pharmacology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. xueqin1980@hotmail.com. FAU - Liu, Ying-Hua AU - Liu YH AD - Department of Pharmacology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. liuyinghua@gzhmu.edu.cn. LA - eng PT - Journal Article DEP - 20200709 PL - United States TA - Acta Pharmacol Sin JT - Acta pharmacologica Sinica JID - 100956087 RN - 0 (Anticonvulsants) RN - 0 (Blood Glucose) RN - 0 (Endoplasmic Reticulum Chaperone BiP) RN - 0 (Hspa5 protein, mouse) RN - 459384H98V (Zonisamide) SB - IM MH - Animals MH - Anticonvulsants/*therapeutic use MH - Apoptosis/drug effects MH - Blood Glucose/metabolism MH - Body Weight/drug effects MH - Cardiomegaly/blood/etiology/prevention & control MH - Diabetes Mellitus, Type 2/blood/complications/*drug therapy MH - Diabetic Cardiomyopathies/blood/*drug therapy/etiology MH - Diet, High-Fat MH - Endoplasmic Reticulum Chaperone BiP MH - Endoplasmic Reticulum Stress/*drug effects MH - Heart/drug effects MH - Male MH - Mice, Inbred C57BL MH - Myocytes, Cardiac/drug effects MH - Zonisamide/*therapeutic use MH - Mice PMC - PMC8026994 OTO - NOTNLM OT - apoptosis OT - diabetic cardiomyopathy OT - endoplasmic reticulum stress OT - zonisamide COIS- The authors declare no competing interests. EDAT- 2020/07/11 06:00 MHDA- 2021/09/10 06:00 PMCR- 2022/03/01 CRDT- 2020/07/11 06:00 PHST- 2019/10/16 00:00 [received] PHST- 2020/06/11 00:00 [accepted] PHST- 2020/07/11 06:00 [pubmed] PHST- 2021/09/10 06:00 [medline] PHST- 2020/07/11 06:00 [entrez] PHST- 2022/03/01 00:00 [pmc-release] AID - 10.1038/s41401-020-0461-z [pii] AID - 461 [pii] AID - 10.1038/s41401-020-0461-z [doi] PST - ppublish SO - Acta Pharmacol Sin. 2021 Mar;42(3):393-403. doi: 10.1038/s41401-020-0461-z. Epub 2020 Jul 9.