Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology
Reduction of diabetes-induced oxidative stress by phosphodiesterase inhibitors in rats
Introduction
Free radicals are continually produced in the body as a result of normal metabolic processes and interaction with environmental stimuli. Oxidative stress results from an imbalance between radical-generating and radical-scavenging systems, i.e. increased free radical production or reduced activity of antioxidant defenses or both. Oxidative stress is currently suggested as the mechanism underlying diabetes and diabetic complications (Halliwell and Gutteridge, 1989). Enhanced oxidative stress and changes in antioxidant capacity, observed in both clinical and experimental diabetes mellitus are thought to be the etiology of chronic diabetic complications (Baynes, 1991). Many of the complications of diabetes including retinopathy and atherosclerotic vascular disease, the leading cause of mortality in diabetes have been linked to oxidative stress and antioxidants (i.e. vitamin E, C,...) have been considered as treatments (Ceriello, 2000, Cunningham, 1998, Reaven et al., 1995, Strain, 1991, Young et al., 1991).
The phosphodiesterases (PDEs) are a superfamily of enzymes which catalyse the hydrolysis of the cyclic nucleotides cAMP and cGMP to their corresponding inactive 5-monophosphate counterparts. The cyclic nucleotides play a prominent role in the regulation of important cellular functions and PDE inhibition can therefore elicit a variety of effects (Dal-Piaz and Giovannoni, 2000). At present at least 11 different families of PDE isoenzymes are known. Some of them are characterized by substrate specificity (cAMP or cGMP), different kinetic properties and different tissue distribution. The xanthine analogue theophylline has been used as a cAMP-PDEI in the treatment of asthma for more than 60 years. Milrinone is a non-selective PDEI which increase both cAMP and cGMP levels and is used in cardiovascular diseases as an inotropic agent. Sildenafil is a selective cGMP-PDEI inhibitor used in the treatment of sexual dysfunctions (Souness et al., 2000). There are experimental evidences that increasing intracellular cAMP and cGMP by use of PDEI like theophylline and sildenafil prevent from induction of oxidative stress in salivary glands (Abdollahi et al., 2003a, Abdollahi et al., 2003b). There are also good evidences on anti lipid-peroxidation properties of either cAMP or cGMP analogs in rat neural (Keller et al., 1998), renal cells (Kohda and Gemba, 2001), lung (Sciuto et al., 1997, Zhang et al., 1999), and sperm function (Zhang et al., 1998). The relationship with endothelium dysfunction in diabetes patients and low cGMP levels has been also reported (Aydin et al., 2001).
This study was undertaken because to our knowledge there were no published reports on the effects of PDEIs on streptozotocin-induced diabetes mellitus in rats.
Section snippets
Chemicals
Hydrogen peroxide, sodium sulfate, Triton X-100, 2,4,6-tripyridyl-s-triazine (TPTZ), 2-thiobarbituric acid (TBA), trichloroacetic acid (TCA), Tris base, phosphate buffer, n-butanol from Merck (Germany), and glucose oxidase, peroxidase, o-dianisidine–HCl, 1,1,3,3-tetraethoxypropan, and streptozotocin from Sigma-Aldrich (USA) were used in this study.
Animals
Male Wistar rats (Rattus norvegicus; from Animal House of Faculty of Pharmacy, TUMS) weighing 185–230 g were used in this study. The animals were
Results
Plasma glucose of control animals was 5.1 ± 0.1 which reached 21.8 ± 0.8 mmol/L in STZ-induced diabetes at the end of the study period. Plasma glucose level was not affected by PDEI treatment. The mean TAC and TBARS in control animals were 163 ± 14.67 and 1.45 ± 0.13 μmol/L, respectively, reaching 88 ± 7.92 and 2.33 ± 0.21 μmol/L respectively in diabetic rats (P < 0.01) (Fig. 1). Treatment of diabetic rats with milrinone (1.55 ± 0.14 μmol/L), sildenafil (1.75 ± 0.16 μmol/L), and theophylline (1.82 ± 0.16 μmol/L)
Discussion
Data of this study provide a good indication of the presence of oxidative stress in blood of diabetic rats which is well supported by previous reports and suggests that free radicals play a crucial role in the STZ-induced diabetes (Maritim et al., 2003, Anwar and Meki, 2003). Reduced antioxidant levels as a result of increased free radical production in experimental diabetes have been reported by many authors (Grankvist et al., 1981, Saxena et al., 1993, Giugliano et al., 1995). Damasceno et
Acknowledgment
This study was supported by a grant from TUMS. This study will be presented at 7th European Association Congress of Clinical Pharmacology and Therapeutics, 2005, Poland.
References (51)
- et al.
Protection by nitric oxide of morphine-induced inhibition of rat submandibular gland function
Pharmacol. Res.
(2002) - et al.
Interaction of cadmium with nitric oxide in rat submandibulary gland function
Pharmacol. Res.
(2000) - et al.
Increasing intracellular cAMP and cGMP inhibits cadmium-induced oxidative stress in rat submandibular saliva
Comp. Biochem. Physiol., C
(2003) - et al.
Leukocyte lipid peroxidation, superoxide dismutase, glutathione peroxidase and serum and leukocyte vitamin C concentrations of patients with type II diabetes mellitus
Clin. Chim. Acta
(1996) - et al.
Antioxidant role of mulberry (Morus indica L. cv. Anantha) leaves in streptozotocin-diabetic rats
Clin. Chim. Acta
(2003) - et al.
Cyclic GMP-dependent protein kinase regulates the expression of thioredoxin and thioredoxin peroxidase-1 during hormesis in response to oxidative stress-induced apoptosis
J. Biol. Chem.
(2003) - et al.
Oxidative stress in streptozotocin-induced diabetic rats: effects of garlic oil and melatonin
Comp. Biochem. Physiol., A
(2003) - et al.
Oxidative stress and nitric oxide related parameters in type II diabetes mellitus: effects of glycemic control
Clin. Biochem.
(2001) - et al.
Antioxidant status, lipid peroxidation and nitric oxide end products in patients of type 2 diabetes mellitus with nephropathy
Clin. Biochem.
(2003) Oxidative stress and glycemic regulation
Metabolism
(2000)
Phosphodiesterase 4 inhibitors, structurally unrelated to rolipram, as promising agents for the treatment of asthma and other pathologies
Eur. J. Med. Chem.
Oxidative stress and diabetes in pregnant rats
Anim. Reprod. Sci.
Diabetes mellitus hypertension, cardiovascular disease: which role for oxidative stress?
Metabolism
Dipyridamole enhances interleukin-1 beta-stimulated nitric oxide production by cultured rat vascular smooth muscle cells
Eur. J. Pharmacol.
Characterization of low dose streptozotocin-induced progressive diabetes in mice
Environ. Toxicol. Pharmacol.
Modulation by cyclic AMP and phorbol myristate acetate of cephaloridine-induced injury in rat renal cortical slices
Jpn. J. Pharmacol.
Lipid oxidation products in cell signaling
Free Radic. Biol. Med.
Effects of alpha-lipoic acid on biomarkers of oxidative stress in streptozotocin-induced diabetic rats
J. Nutr. Biochem
Coordinated control of endothelial nitric-oxide synthase phosphorylation by protein kinase C and the cAMP-dependent protein kinase
J. Biol. Chem.
Effect of combination therapy with dipyridamole and quinapril in diabetic nephropathy
Diabetes Res. Clin. Pract.
Cyclic AMP mediates endothelial protection by nitric oxide
Biochem. Biophys. Res. Commun.
Nitric oxide protects endothelial cells from tumor necrosis factor-alpha-mediated cytotoxicity: possible involvement of cyclic GMP
FEBS Lett.
The nitric oxide donor SIN-1 protects endothelial cells from tumor necrosis factor-alpha-mediated cytotoxicity: possible role for cyclic GMP and heme oxygenase
J. Mol. Cell. Cardiol.
Impaired antioxidant status in diabetic rat liver
Biochem. Pharm.
Immunosuppressive and anti-inflammatory effects of cyclic AMP phosphodiesterase (PDE) type 4 inhibitors
Immunopharmacology
Cited by (138)
An assessment of the nutraceutical potential of Juglans regia L. leaf powder in diabetic rats
2017, Food and Chemical ToxicologyCitation Excerpt :Studies have shown evidence of derangement in the oxidant-antioxidant balance due to hyperglycaemia-induced decrease in the activity of free radical scavenging enzymes and increase free radicals formation (Giacco and Brownlee, 2010; Fiorentino et al., 2013). In this study diabetes mellitus was associated with decrease in activities of SOD, CAT and GPX which is consistent with the literature data (Usman et al., 2016; Milani et al., 2005) and indicative of increased oxidative stress. Twice daily administration of J. regia L. however, resulted in a dose related reversal of oxidative stress.
Diabetes mellitus: A health syndrome
2023, Therapeutic Mushrooms for Diabetes Mellitus: Current Evidences and Future ScopeFunction of sildenafil on diseases other than urogenital system: An umbrella review
2023, Frontiers in Pharmacology