Effects of timolol treatment on pancreatic antioxidant enzymes in streptozotocin-induced diabetic rats: an experimental and computational study

Abstract

Background: the study aimed to investigate whether timolol-treatment has a beneficial effect on pentose phosphate pathway enzyme activities such as glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGDH) enzyme activities and cAMP level in streptozotocin-induced diabetic rats in pancreatic tissues. Methods: diabetes was induced by streptozotocin (STZ) in 3-month old male Wistar rats. The diabetic rats were treated with timolol (5 mg/kg body weight, for 12 weeks) while the control group received saline. Enzyme activities were determined in pancreas tissue. To support our results, we performed in silico calculations, using Protein Data Bank structures. Results: timolol treatment of STZ-induced diabetic rats had no noteworthy effect on high blood-glucose levels. However, this treatment induced activities of G6PD and 6PGDH in diabetic rats. Timolol treatment significantly increased cAMP level in diabetic pancreatic tissue. We found that timolol cannot bind strongly to either G6PD or 6PGD, but there is a relatively higher binding affinity to adenylyl cyclase, responsible for cAMP production, serving as a regulatory signal via specific cAMP-binding proteins. Conclusions: our data point out that timolol treatment has beneficial effects on the antioxidant defence mechanism enzymes in the pancreas of STZ-induced diabetic rats. / Uvod: cilj istrazivanja je bio da se utvrdi da li tretman timololom ima pozitivan efekat na aktivnosti enzima pentoze fosfata, kao sto su aktivnosti glukoze-6-fosfat dehidrogenaze (G6PD), enzimske aktivnosti 6-fosfoglukonat dehidrogenaze i cAMP nivo u tkivu pankreasa kod pacova kojima je dijabetes izazvan streptozotocionom. Metode: dijabetes je izazvan streptozotocionom (STZ) kod tromesecnih muzjaka vistar pacova. Pacovi sa dijabetesom su tretirani timololom (5 mg/kg telesne tezine tokom 12 nedelja), dok je kontrolna grupa primila fizioloski rastvor. Enzimske aktivnosti su utvrivane u tkivu pankreasa. Da bismo potkrepili nase rezultate, sproveli smo in silico racunanja koristeci strukture Proteinske baze podataka. Rezultati: tretman timololom na pacovima kojima je dijabetes izazvan putem STZ-a nije imao znacajan uticaj na visoke nivoe glukoze u krvi. Medutim, kod takvih pacova ovaj tretman je indukovao aktivnosti G6PD i 6PGDH. Lecenje timololom znacajno je povecalo nivo cAMP-a u dijabeticnom tkivu pankreasa. Utvrdili smo da se timolol ne moze snazno vezati ni za G6PD, ni za 6PGD, ali da postoji relativno veci afinitet vezivanja za adenilil ciklazu, odgovornu za proizvodnju cAMP, koja sluzi kao regulatorni signal putem odredenih cAMP vezivnih proteina. Zakljucak: nasi podaci ukazuju da tretman timololom ima pozitivne efekte na antioksidantne enzime od brambenog sistema u pankreasu pacova sa dijebetesom izazvanim putem STZ-a.