Protective role of arjunolic acid in response to streptozotocin-induced type-I diabetes via the mitochondrial dependent and independent pathways.
Increasing evidences in both experimental and clinical studies suggest that oxidative stress is involved in the pathogenesis of diabetic tissue damage. Pancreatic beta-cell death is the cause of decreased insulin production in diabetes. Streptozotocin (STZ) is widely used to induce experimental diabetes due to its ability to selectively target and destroy insulin producing pancreatic beta-cells via the formation of both reactive oxygen species (ROS) and RNS (reactive nitrogen species). This study investigated the prophylactic role of arjunolic acid (AA) against STZ-induced diabetes in the pancreas tissue of the Swiss albino rats (as a working model). We observed that STZ administration (at a dose of 65mg/kg body weight, injected in the tail vain) caused increased production of both ROS and RNS in the pancreas tissue of experimental animals. Formation of these reactive intermediates decreased the intracellular antioxidant defense, increased the levels of lipid peroxidation, protein carbonylation, serum glucose and TNF-alpha. Investigating the signaling pathways, we found that STZ administration caused the activation of phospho-ERK1/2, phospho-p38, NF-kappaB and destruction of mitochondrial transmembrane potential, release of cytochrome c as well as activation of caspase 3 in the pancreas tissue keeping the levels of total ERK1/2 and p38 significantly unchanged. Treatment of animals with AA (at a dose of 20mg/kg body weight, orally) both prior and post to the STZ administration effectively reduced these adverse effects by inhibiting the excessive ROS and RNS formation as well as by down-regulating the activation of phospho-ERK1/2, phospho-p38, NF-kappaB and mitochondrial dependent signal transduction pathways leading to apoptotic cell death. Combining all, these results suggest that AA plays some beneficial roles against STZ-induced diabetes.
Manna
Prasenjit
P
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VIIM Calcutta 700054, West Bengal, India.
Sinha
Mahua
M
Sil
Parames C
PC
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D050050:Protein Carbonylation / Q000187:drug effects; D051381:Rats; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014315:Triterpenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000975:Antioxidants; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D016328:NF-kappa B; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; C061640:arjunolic acid; D045304:Cytochromes c; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3