Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology and Toxicology

Bromocriptine (BC), a sympatholytic D2 receptor agonist, is an old drug used clinically for over 30 years to treat patients with PD and prolactinomas. Nevertheless, the new quick-release formulation of BC (bromocriptine-QR; Cycloset) was approved by the FDA in May 2009, as a novel therapeutic option in T2DM. However, the precise mechanisms are not completely unveiled. Hence, the objective of the current study is to clarify the potential molecular pathways of the insulin sensitizing effect of BC in the skeletal muscle of diabetic rats, a core peripheral organ in I/R/diabetes, and to evaluate its possible interaction with sitagliptin (SG) as an add-on therapy. The latter was chosen as the standard antidiabetic drug used herein. Here, the experimental model impersonates unhealthy dietary habit and T2DM was adopted, in which rats were fed high caloric diet of fat and fructose for 6 weeks followed by a single sub-diabetogenic dose of streptozotocin (STZ) (35 mg/kg; HF/Fr/STZ). Diabetic rats were treated with BC, SG at two dose levels (SG10 and SG20) and combination of BC+SG10 for 2 weeks.Several parameters have been settled to appraise the possible mechanisms of the tested drugs. Besides the glucose homeostasis and lipid profile-related parameters and GLP-1, the inflammatory pathway (leptin-IL-6/JAK2/p-STAT3/SOCS3), the insulin signaling cue (p-IR/p-AKT/GLUT4), and the PPAR-Þ/adiponectin trajectory in the soleus skeletal muscle of diabetic rat were gauged. Moreover, Nrf-2 and PARP-1 were assessed in the soleus skeletal muscle to measure the antioxidant capacity of tested drugs

Issued also as CD