Melatonin postconditioning combined with sitagliptin exerts full cardioprotection in diabetic hearts of aged rats through an AMPK-dependent mechanism

Abstract

The presence of multiple comorbidities in patients facing myocardial ischemia-reperfusion (IR) injury is the main obstacle for cardioprotection. This study investigated the effect of melatonin postconditioning combined with sitagliptin pretreatment on cardioprotection in diabetic aged rats by evaluating oxidative stress, apoptosis and involvement of the AMPK/SIRT1 pathway. The type-2 highfat/ streptozotocin experimental model in aged Sprague-Dawley rats (n=78) was used. The animals underwent left coronary occlusion for 30 min, followed by 3 h reperfusion. Diabetic rats were pretreated with sitagliptin (20 mg/kg, i.p.) and received melatonin (10 mg/kg, i.p.) early in reperfusion. Myocardial infarct size, histological changes, oxidative markers, mitochondrial reactive oxygen species (mitoROS) and expression of proteins regulating apoptosis and AMPK/SIRT1 activity were measured. The infarct sizesparing effect of the combination of melatonin plus sitagliptin was greater than that observed in individual treatments (P<0.01). Combination therapy significantly reduced IR-induced elevation of 8-isoprostane, mitoROS and proapoptotic proteins Bax and cleaved caspase-3, and increased IR-induced downregulation of mitochondrial superoxide-dismutase, glutathione, anti-apoptotic protein Bcl2, phosphorylated AMPK and SIRT1 (P<0.01, P<0.001). Inhibition of AMPK via compound-C completely reversed combinationinduced cardioprotection. Thus, improving cardiac antioxidative and antiapoptotic responses via upregulation of AMPK/SIRT1 activity may represent a central mechanism through which melatonin plus sitagliptin attenuate myocardial IR injury in diabetic-aged rats.

Co-administration of exercise training and melatonin on the function of diabetic heart tissue: a systematic review and meta-analysis of rodent models

“… Male Sprague Dawley rats 22 ± 2 (months) 300–325 (g) T2DM T2DM (a high-fat diet (62% calories obtained from fat)/ diet + 35 mg/kg of STZ by intraperitoneal + Melatonin (10 mg/kg) + Sitagliptin (20 mg/kg, i.p.) for 4 weeks N = 42 7 groups (6 rats each) 1—control group received only thoracotomy without LAD ligation; 2—IR groups; 3—IR + Melatonin group; 4—IR + Sitagliptin group; 5—IR + Melatonin + Sitagliptin group; 6—IR + CC group; 7—IR + CC + Melatonin + Sitagliptin group 2 weeks 10 weeks Improving antioxidative and antiapoptotic responses Up-regulation of AMPK/SIRT1 activity via melatonin [ 100 ] Male C57BL/6 J mice 8 weeks – T1DM T1DM 50 mg/kg (STZ) by intraperitoneal for 5 consecutive days + intraperitoneal injections of 10 mg/kg/d melatonin for 10 weeks 4 groups 1—normal glucose; 2—high glucose; 3—Mannitol; 4—melatonin 2 weeks 12 weeks after the first injection of STZ amelioration of high glucose-induced CMECs injury by melatonin Treatment of apoptosis and increased AMPK/SIRT1 signaling axis activity by melatonin in CMEC [ 101 ] Adult male Wister rats 8 weeks 170–200 (g) T2DM T2DM nicotinamide (100 mg/kg, ip) 20 min before STZ (55 mg/kg) + melatonin (10 mg/kg) by stomach tube daily for 15 days between 10:0 and 11:00 am N = 20 4 groups (5 rats each) 1—control group received standard diet 2—melatonin treated group 3—diabetic group 4—group receiving melatonin for 15 days after the induction of diabetes 3 days 15 days post diabetic induction of STZ Protective effects of melatonin against hyperglycemia, anti-lipid, antioxidant, anti-inflammatory and anti-apoptotic MLT improves serum glucose levels, HbA1-c, lipid profile, insulin levels and insulin resistance, glutathione and IL-10 and Bcl-2 levels and prevents the increase of pro-inflammatory cytokines and the expression of Bax, caspase-3 and P53 [ 9 ] …”

Sitagliptin Modulates Oxidative, Nitrative and Halogenative Stress and Inflammatory Response in Rat Model of Hepatic Ischemia-Reperfusion

“…Dipeptidyl peptidase-4 inhibitors are among the drugs studied for their potential use for new therapeutic purposes, a strategy referred to as drug repurposing or repositioning [ 9 ]. Recently, a large body of evidence has accumulated showing sitagliptin effectiveness in lessening tissue damage during intestinal [ 24 , 32 ], cardiac [ 23 , 33 ], cerebral [ 30 ], testicular [ 31 ] and renal [ 28 , 29 ] ischemia-reperfusion insult. Likewise, sitagliptin has reduced the histopathological signs of injury and decreased the serum activities of ALT and AST in animal models of hepatic IR [ 21 , 22 , 25 , 26 ], acting via mechanisms employing its anti-inflammatory and antioxidative properties.…”

“…Several experimental studies have demonstrated pleiotropic properties, including the antioxidative, anti-inflammatory and antiapoptotic action of sitagliptin [ 18 , 19 ], a well-tolerated DPP-4 inhibitor with moderate side effects [ 20 ]. Accordingly, we [ 21 , 22 ], as well as others [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ], have shown that sitagliptin alleviates injury caused by IR procedure. However, the molecular background has not been fully elucidated.…”