Dr. Hany M. Abo-Haded

Size: px

Start display at page:

Download "Dr. Hany M. Abo-Haded"

Samson Ball
6 years ago
Views:

1 BY Dr. Hany M. Abo-Haded Pediatric Cardiology Unit, Mansoura Universty Children Hospital, Mansoura, Egypt Co-authors: Dina S El-Agamy and Mohamed A Elkablawy

Background Doxorubicin (DOX) is an anthracycline derivative that is used for treating a wide variety of human cancers. However, it has many adverse effects basically, cardiotoxicity.

2 Background Doxorubicin (DOX) is an anthracycline derivative that is used for treating a wide variety of human cancers. However, it has many adverse effects basically, cardiotoxicity. DOX Induce Pro-apoptotic activation of NF-κB (in endothelial cells & cardiomyocytes) production proinflammatory cytokines {TNF-α and NO} : severe damage to the plasma membrane, loss of myofibrils, dilation of the sarcoplasmic reticulum and myocyte necrosis.

Background cont. Glucagon-like peptide-1 (GLP-1) is the most important incretin hormone, secreted by the entero-endocrine L- cells of the intestinal mucosa.

3 Background cont. Glucagon-like peptide-1 (GLP-1) is the most important incretin hormone, secreted by the entero-endocrine L- cells of the intestinal mucosa. It stimulates insulin secretion in response to nutrients ingestion. However, GLP-1 has very short half-life (2 to 3 min) due to rapid degradation by Dipeptidyl Peptidase 4 (DPP4). DPP4 inhibitors (Sitagliptin) : Potent Anti-diabetic effects, by increasing GLP-1 levels in the blood and extend its action, INSULIN serum level. -Therapeutic potential for different diseases such as tissue inflammation, diabetic nephropathy, and CVS disorders (as hypertension, cardiac ischemia and atherosclerosis). - It was found that it decreases the cardiac infarct size following induction of myocardial ischemia in rats.

4 Aim of the Study The aim of this study is to investigate the potential effects of sitagliptin on DOX-induced Cardiotoxicity and to explore the underlying mechanisms.

6 Materials and Methods Experimental design 32 Wistar male rats were randomly assigned to 4 groups: Group (1): Control group, rats were administered physiological saline orally for 10 days. Group (2): DOX group, rats received physiological saline orally for 10 days and then DOX (20 mg/kg, i.p) on day ten. Group (3): Sitagliptin (10 mg/kg) for 10 days + DOX (20 mg/kg, i.p) on day ten. Group(4): Sitagliptin (20 mg/kg) + DOX (20 mg/kg, i.p) on day ten.

7 Materials and Methods cont. Electrocardiography(ECG). Assessment of serum cardiotoxicity markers: CK-MB, LDH Assessment of histopathological cardiac damage. (Histopath Exam) Measurements of oxidative stress markers and assessment of antioxidant status: MDA, SOD, GSH. Immunohistochemical examinations: NF-κB Estimation of inflammatory cytokines: TNF-α, NO

9 Electrocardiography(ECG) Effects of doxorubicin with/without sitagliptin pretreatment on ECG parameters

10 Assessment of serum cardiotoxicity markers Effects of doxorubicin (DOX) with/without sitagliptin (Sita) pre-treatment on serum cardiotoxicity markers: A) CK-MB: creatine kinase-mb B) LDH: lactate dehydrogenase.

11 Assessment of histopathological cardiac damage (A) Control group: Normal heart architecture was observed (B) DOX group: showed disruption of cardiac muscle architecture, loss of muscle striation, hydropic degeneration, apoptosis and focal necrosis. Cardiac myocytes show focal apoptosis and signs of necrosis (pyknosis, kariorrhexis and karyolysis) with inflammatory cellular infiltrate (C, D) Sitagliptin + DOX groups: less cardiac lesions.

12 Measurements of oxidative stress markers and assessment of antioxidant status. Effects of doxorubicin (DOX) with/without sitagliptin (Sita) pretreatment on cardiac oxidative stress markers. A) MDA: malon dialdehyde, B) SOD: superoxide dismutase, C) GSH: reduced glutathione.

Immunohistochemical examinations Effects of doxorubicin (DOX) with/without sitagliptin pretreatment on the expression of nuclear factor kappa B (NF-κB) by immunohistochemical staining.

13 Immunohistochemical examinations Effects of doxorubicin (DOX) with/without sitagliptin pretreatment on the expression of nuclear factor kappa B (NF-κB) by immunohistochemical staining. (A) Control group with mild light brown cytoplasmic immunostaining (B) DOX group, showing intense brown cytoplasmic immunostaining of NF-κB (C, D) Sitagliptin + DOX groups, showing a marked decrease in the cytoplasmic expression of NF-κB in a dose dependent manner of sitagliptin.

14 Estimation of inflammatory cytokines Effects of doxorubicin (DOX) with/without sitagliptin (Sita) pretreatment on inflammatory cytokines in cardiac tissue. A) TNF-α B) Nitric oxide

16 In conclusion, the current study demonstrates for the first time the Cardioprotective effects of Sitagliptin against DOX-induced Cardiotoxicity. This effect may be mediated through potent antioxidative, anti-inflammatory and anti-apoptotic activities of sitagliptin. Thus, it is reasonable to presume that sitagliptin may be beneficial in patients on DOX-Chemotherapy. Further clinical studies are needed to prove that effect.

MOLECULAR MEDICINE REPORTS 11: , 2015

MOLECULAR MEDICINE REPORTS 11: 527-532, 2015 Oxysophoridine attenuates the injury caused by acute myocardial infarction in rats through anti oxidative, anti inflammatory and anti apoptotic pathways CONG