Zonisamide, an antiepileptic drug, alleviates diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress

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...

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Bibliographic Details
Published in:Acta pharmacologica Sinica 2021-03, Vol.42 (3), p.393-403
Main Authors: Tian, Jia-Hui, Wu, Qian, He, Yong-Xiang, Shen, Qi-Ying, Rekep, Mubarak, Zhang, Gui-Ping, Luo, Jian-Dong, Xue, Qin, Liu, Ying-Hua
Format: Article
Language:English
Subjects:
Animals
Anticonvulsants - therapeutic use
Antiepileptic agents
Apoptosis
Apoptosis - drug effects
Bax protein
Bcl-2 protein
Blood Glucose - metabolism
Body Weight - drug effects
Cardiomegaly - blood
Cardiomegaly - etiology
Cardiomegaly - prevention & control
Cardiomyocytes
Cardiomyopathy
Caspase-3
Diabetes
Diabetes mellitus (non-insulin dependent)
Diabetes Mellitus, Type 2 - blood
Diabetes Mellitus, Type 2 - complications
Diabetes Mellitus, Type 2 - drug therapy
Diabetic Cardiomyopathies - blood
Diabetic Cardiomyopathies - drug therapy
Diabetic Cardiomyopathies - etiology
Diet, High-Fat
Dosage
Endoplasmic reticulum
Endoplasmic Reticulum Chaperone BiP
Endoplasmic Reticulum Stress - drug effects
Heart - drug effects
High fat diet
Hypertrophy
Male
Mice
Mice, Inbred C57BL
Movement disorders
Myocytes, Cardiac - drug effects
Neurodegenerative diseases
Parkinson's disease
Streptozocin
Tunicamycin
Zonisamide
Zonisamide - therapeutic use
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Summary: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 ·d , 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 μM) 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.
ISSN:1671-4083
1745-7254
DOI:10.1038/s41401-020-0461-z