Abstract
Glibenclamide (GLB), most widely used in the treatment of type II diabetes mellitus, inhibits K+ATP channel in pancreatic-β cells and releases insulin, while thioacetamide (TAA) is a well-known hepatotoxicant and most recommended for the induction of acute and chronic liver disease. The purpose of this study was to evaluate the hepatoprotective potential of GLB against TAA-induced hepatic damage in Wistar rats. TAA (200 mg/kg, ip, twice weekly) and GLB (1.25, 2.5, and 5 mg/kg/day, po) were administered for 6 consecutive weeks. Different biochemical, DNA damage, histopathological, TEM, immunohistochemical, and western blotting parameters were evaluated. GLB treatment has no effects on the TAA-induced significant decrease in body and liver weights. TAA treatment significantly increased liver index and treatment with GLB has no effect the same. TAA treatment altered the liver morphology, whereas treatment with GLB normalized the alteration in morphology. Further, significant increase in oxidative stress, apoptosis, and DNA damage was found in TAA-treated animals and GLB treatment significantly reduced these effects. TAA-induced plasma transaminases and serum ALP levels were significantly restored by GLB. Furthermore, histopathological findings showed the presence of lymphocyte infiltration, collagen deposition, bridging fibrosis, degeneration of portal triad, and necrosis in TAA-treated animals and GLB intervention significantly reduced the same. TEM images revealed that GLB significantly normalized the hepatic stellate cell morphology as well as restored the number of lipid droplets. GLB treatment significantly downregulated the expressions of TGF-β1, α-SMA, NLRP3, ASC, caspase-1, and IL-1β, and upregulated MMP-2 and catalase against TAA-induced liver damage. The outcomes of the present study confirmed that GLB ameliorated the liver damage induced by TAA.
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Abbreviations
- ALP:
-
Alkaline phosphatase
- ALT:
-
Alanine transaminase
- ASC:
-
Apoptosis-associated speck-like protein containing a caspase-recruiting domain
- AST:
-
Aspartate transaminase
- ATP:
-
Adenosine triphosphate
- CYP2E1:
-
Cytochrome P450 2E1
- DAB:
-
3,3′-Diaminobenzidine
- DMSO:
-
Dimethyl sulfoxide
- ECM:
-
Extracellular matrix
- GLB:
-
Glibenclamide
- HSC:
-
Hepatic stellate cell
- IL:
-
Interleukin
- IL-1β:
-
Interleukin-1 beta
- ip:
-
Intraperitoneal
- MT:
-
Masson’s trichrome
- MMP-2:
-
Matrix metalloproteinase-2
- NLRP3:
-
NACHT, LRR, and PYD domains-containing protein 3
- TMO:
-
Tail moment olive
- PAS:
-
Periodic acid-Schiff base
- po:
-
Per os (oral administration)
- PSR:
-
Picro Sirius Red
- PSRF:
-
PSR with fast green FCF
- SOD:
-
Superoxide dismutase
- T2DM:
-
Type II diabetes mellitus
- TAA:
-
Thioacetamide
- TEM:
-
Transmission electron microscopy
- TGF-β1:
-
Transforming growth factor beta1
- TL:
-
Tail length
- TM:
-
Tail moment
- TUNEL:
-
Terminal deoxynucleotidyl transferase dUTP nick end labeling assay
- US-FDA:
-
United States Food and Drug Administration
- WHO:
-
World Health Organization
- α-SMA:
-
Alpha-smooth muscle actin
- γ-GT:
-
γ-Glutamyl transferase
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Acknowledgements
We wish to acknowledge the financial assistance received from National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, India, for carrying out the above experimentation. The authors would like to acknowledge Mr. Vinod Kumar for TEM image analysis. We are also grateful to Dr. Sabbir Khan, Dr. Krishna Prahlad Maremanda, and Dr. Venkateswara Rao Amara for their timely advice and technical support.
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DKD conceived, conducted the experiments, analyzed the data, and wrote the manuscript. GBJ conceived the idea, reviewed the manuscript, and administered the project. Finally, both the authors have read and approved the manuscript.
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The experimental protocol was approved by the Institutional Animal Ethics Committee (IAEC) against approval number IAEC/16/54.
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Dwivedi, D.K., Jena, G.B. Glibenclamide protects against thioacetamide-induced hepatic damage in Wistar rat: investigation on NLRP3, MMP-2, and stellate cell activation. Naunyn-Schmiedeberg's Arch Pharmacol 391, 1257–1274 (2018). https://doi.org/10.1007/s00210-018-1540-2
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DOI: https://doi.org/10.1007/s00210-018-1540-2