Alteration of Energy Metabolism and Antioxidative Processing in the Hippocampus of Rats Reared in Long-Term Environmental Enrichment

Environmental enrichment (EE) is a typical experimental method that promotes levels of novelty and complexity that enhance experience-dependent neuroplasticity and cognitive behavior function in laboratory animals. Early EE is associated with resilience in the face of later-life challenges. Since increased synaptic activity enhances endogenous neuronal antioxidant defenses, we hypothesized that long-term EE beginning at an early stage may alter the levels of oxidative stress. We investigated global protein expression and oxidative stress in hippocampal proteins from rats nurtured for a 6-month EE beginning in the prenatal period. The analysis of protein expression was carried out using 2-dimensional gel electrophoresis with matrix-associated laser desorption ionization time-of-flight mass spectrometry. Proteins with altered expression were involved in energy metabolism (phosphoglycerate mutase 1, α-enolase isoform 1, adenylate kinase 1, and triose phosphate isomerase) and antioxidant enzymes (superoxide dismutase 1, glutathione S-transferase ω type 1, peroxiredoxin 5, DJ-1, and glial maturation factor β). Using Western blot assays, some of the proteins with altered expression and NADPH oxidase 2 were confirmed to be decreased. Further confirmation was demonstrated with attenuated expression of 7,8-dihydro-8-oxo-deoxyguanine, a DNA oxidative stress marker, in the hippocampus of EE group rats. Our data demonstrate that a long-term EE program beginning in the prenatal and early postnatal phase of development modulates energy metabolism and reduced oxidant stress possibly through enhanced synaptic activity. We provide evidence that EE can be developed as a tool to protect the brain from oxidative stress-induced injury.

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Hypermetabolism of glutathione, glutamate and ornithine via redox imbalance in methylglyoxal-induced peritoneal injury rats

The Journal of Biochemistry ◽

10.1093/jb/mvz077 ◽

2019 ◽

Author(s):

Ichiro Hirahara ◽

Eiji Kusano ◽

Denan Jin ◽

Shinji Takai

Keyword(s):

Oxidative Stress ◽

Intraperitoneal Administration ◽

Methionine Sulfoxide ◽

Mesenchymal Cell ◽

Oxidative Stress Marker ◽

Peritoneal Fibrosis ◽

Metabolome Analysis ◽

Glycation End Products ◽

Excessive Proliferation

Abstract Peritoneal dialysis (PD) is a blood purification treatment for patients with reduced renal function. However, the peritoneum is exposed to oxidative stress during PD and long-term PD results in peritoneal damage, leading to the termination of PD. Methylglyoxal (MGO) contained in commercial PD fluids is a source of strong oxidative stress. The aim of this study was to clarify the mechanism of MGO-induced peritoneal injury using metabolome analysis in rats. We prepared peritoneal fibrosis rats by intraperitoneal administration of PD fluids containing MGO for 21 days. As a result, MGO-induced excessive proliferation of mesenchymal cells with an accumulation of advanced glycation end-products (AGEs) at the surface of the thickened peritoneum in rats. The effluent levels of methionine sulfoxide, an oxidative stress marker and glutathione peroxidase activity were increased in the MGO-treated rats. The levels of glutathione, glutamate, aspartate, ornithine and AGEs were also increased in these rats. MGO upregulated the gene expression of transporters and enzymes related to the metabolism of glutathione, glutamate and ornithine in the peritoneum. These results suggest that MGO may induce peritoneal injury with mesenchymal cell proliferation via increased redox metabolism, directly or through the formation of AGEs during PD.

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Effects of ovariectomy on antioxidant defence systems in the right ventricle of female rats with pulmonary arterial hypertension induced by monocrotaline

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2016-0445 ◽

2018 ◽

Vol 96 (3) ◽

pp. 295-303 ◽

Cited By ~ 2

Author(s):

Rafaela Siqueira ◽

Rafael Colombo ◽

Adriana Conzatti ◽

Alexandre Luz de Castro ◽

Cristina Campos Carraro ◽

...

Keyword(s):

Oxidative Stress ◽

Pulmonary Arterial Hypertension ◽

Right Ventricle ◽

Protein Expression ◽

Arterial Hypertension ◽

Female Rats ◽

Antioxidant Defenses ◽

Thioredoxin 1 ◽

Pulmonary Arterial ◽

The Right

The aim of this study was to evaluate the impact of ovariectomy on oxidative stress in the right ventricle (RV) of female rats with pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). Rats were divided into 4 groups (n = 6 per group): sham (S), sham + MCT (SM), ovariectomized (O), and ovariectomized + MCT (OM). MCT (60 mg·kg−1 i.p.) was injected 1 week after ovariectomy or sham surgery. Three weeks later, echocardiographic analysis and RV catheterisation were performed. RV morphometric, biochemical, and protein expression analysis through Western blotting were done. MCT promoted a slight increase in pulmonary artery pressure, without differences between the SM and OM groups, but did not induce RV hypertrophy. RV hydrogen peroxide increased in the MCT groups, but SOD, CAT, and GPx activities were also enhanced. Non-classical antioxidant defenses diminished in ovariectomized groups, probably due to a decrease in the nuclear factor Nrf2. Hemoxygenase-1 and thioredoxin-1 protein expression was increased in the OM group compared with SM, being accompanied by an elevation in the estrogen receptor β (ER-β). Hemoxygenase-1 and thioredoxin-1 may be involved in the modulation of oxidative stress in the OM group, and this could be responsible for attenuation of PAH and RV remodeling.

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Salivary Gland Extract from Aedes aegypti Improves Survival in Murine Polymicrobial Sepsis through Oxidative Mechanisms

Cells ◽

10.3390/cells7110182 ◽

2018 ◽

Vol 7 (11) ◽

pp. 182 ◽

Cited By ~ 3

Author(s):

Rafaelli de Souza Gomes ◽

Kely Navegantes-Lima ◽

Valter Monteiro ◽

Ana de Brito Oliveira ◽

Dávila Rodrigues ◽

...

Keyword(s):

Oxidative Stress ◽

Salivary Gland ◽

Aedes Aegypti ◽

Bacterial Load ◽

Polymicrobial Sepsis ◽

Antioxidant Defenses ◽

Oxidative Stress Marker ◽

Trolox Equivalent Antioxidant Capacity ◽

Salivary Gland Extract ◽

Gland Extract

Sepsis is a systemic disease with life-threatening potential and is characterized by a dysregulated immune response from the host to an infection. The organic dysfunction in sepsis is associated with the production of inflammatory cascades and oxidative stress. Previous studies showed that Aedes aegypti saliva has anti-inflammatory, immunomodulatory, and antioxidant properties. Considering inflammation and the role of oxidative stress in sepsis, we investigated the effect of pretreatment with salivary gland extract (SGE) from Ae. aegypti in the induction of inflammatory and oxidative processes in a murine cecum ligation and puncture (CLP) model. Here, we evaluated animal survival for 16 days, as well as bacterial load, leukocyte migration, and oxidative parameters. We found that the SGE pretreatment improved the survival of septic mice, reduced bacterial load and neutrophil influx, and increased nitric oxide (NO) production in the peritoneal cavity. With regard to oxidative status, SGE increased antioxidant defenses as measured by Trolox equivalent antioxidant capacity (TEAC) and glutathione (GSH), while reducing levels of the oxidative stress marker malondialdehyde (MDA). Altogether, these data suggest that SGE plays a protective role in septic animals, contributing to oxidative and inflammatory balance during sepsis. Therefore, Ae. aegypti SGE is a potential source for new therapeutic molecule(s) in polymicrobial sepsis, and this effect seems to be mediated by the control of inflammation and oxidative damage.

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Hepatic Postnatal Developmental Expression of Trace Mineral Associated Antioxidant Enzymes

Current Developments in Nutrition ◽

10.1093/cdn/nzaa054_149 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1077-1077

Author(s):

Laura Sherlock ◽

Kara Sjostrom ◽

Nancy Krebs ◽

Clyde Wright ◽

Eva Nozik-Grayck

Keyword(s):

Oxidative Stress ◽

Antioxidant Enzymes ◽

Protein Expression ◽

Developmental Regulation ◽

Immune Surveillance ◽

Developmental Expression ◽

Antioxidant Defenses ◽

Trace Mineral ◽

Mrna And Protein Expression ◽

Neonatal Liver

Abstract Objectives Oxidative stress is central to the etiology of many diseases of prematurity. Lower antioxidant defenses render premature infants vulnerable to oxidative damage secondary to infection and oxygen therapy. Antioxidant enzymes (AOE) increase perinatally in the blood and lungs. Many AOE require a micronutrient such as selenium (Se) or zinc (Zn) to function at maximum efficacy. These trace elements are low in neonates compared to adults. The liver is an important immune surveillance organ where antioxidant defense is critical for host response. It also plays a major role in micronutrient processing. However, the developmental regulation and expression of AOE in the liver is incompletely described. We hypothesized the neonatal liver would have decreased trace mineral associated AOE. Methods C57BL/6mice were sacrificed at P0, P7, P21 and 8–12 weeks. mRNA and protein expression of key AOE (SOD1, SOD2, SOD3, Gpx1, Gpx4, Msrb1, TrxR1) and factors for Se processing (Sephs2/Sps2, Scly, Pstk) were measured by qPCR and Western blot. Results Hepatic mRNA for selenoenzymes Gpx1 and Msrb1 were developmentally regulated, low at P0 and increased by adult (P < 0.05, n = 5–6). Gpx1 protein increased 7–8-fold and Msrb1 protein increased 6-fold from P0 to adult (P < 0.0001, n = 4). Gene expression of Zn related SOD1 and Mn SOD2 increased postnatally, low at P0 and increased in adult (P < 0.01 n = 5–6). Protein expression for each increased 1.5 and 3-fold from P0 to adult respectively (P < 0.001, n = 4) The mRNA and protein expression for Gpx4, TrxR1 and SOD3 remained constant postnatally. As the greatest increase was observed in selenoenzymes, factors for Se processing were evaluated. Sephs2, Scly and Pstk mRNA increased from P0 compared to P21 and adult mice (P < 0.05, n = 4–6). Protein expression for Pstk and Scly was highest at P21 and protein for Sps2 increased postnatally (P < 0.01, n = 4). Conclusions The liver experiences a postnatal increase in essential trace mineral associated AOE. Additionally, the hepatic machinery for Se processing is low in neonatal mice. We speculate that the neonatal liver is vulnerable to oxidative stress secondary to low AOE defense. We also speculate states that decreased neonatal micronutrient status may further impair the hepatic redox state. Funding Sources CCTSI Child Maternal Health Mentored Grant (L.S).

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Excitotoxic Insults Lead to Peroxiredoxin Hyperoxidation

Oxidative Medicine and Cellular Longevity ◽

10.4161/oxim.2.2.8300 ◽

2009 ◽

Vol 2 (2) ◽

pp. 110-113 ◽

Cited By ~ 6

Author(s):

Frédéric Léveillé ◽

Francesc X. Soriano ◽

Sofia Papadia ◽

Giles E. Hardingham

Keyword(s):

Oxidative Stress ◽

Nmda Receptor ◽

Response Curve ◽

Synaptic Activity ◽

Receptor Activity ◽

Antioxidant Defenses ◽

Enzymatic System ◽

System A ◽

Highly Sensitive ◽

Toxic Concentrations

Post-mitotic neurons must have strong antioxidant defenses to survive the lifespan of the organism. We recently showed that neuronal antioxidant defenses are boosted by synaptic activity. Elevated synaptic activity, acting via the N-methyl-D-aspartate (NMDA) receptor, enhances thioredoxin activity, facilitates the reduction of hyperoxidized peroxiredoxins, and promotes resistance to oxidative stress. In contrast, blockade of spontaneous synaptic NMDA receptor activity renders neurons highly sensitive to hyperoxidation of peroxiredoxins by oxidative insults. These NMDA receptor-dependent effects are mediated in part by a coordinated program of gene expression changes centered on the thioredoxin-peroxiredoxin system, a thiol-based enzymatic system which is an important reducer of oxidative stressors such as hydroperoxides. We show here that while too little glutamatergic activity can render neurons vulnerable to peroxiredoxin hyperoxidation, so can too much. Exposure of neurons to toxic concentrations of glutamate, activating both synaptic and extrasynaptic NMDA receptors, acutely induces peroxiredoxin hyperoxidation. Thus, the effect of NMDA receptor activity on the activity of neuronal peroxiredoxins follows the classical U-shaped dose response curve.

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P0541KLOTHO IS INVOLVED IN EARLY AND LONG-TERM PROTECTION AGAINST RHABDOMYOLYSIS ASSOCIATED AKI

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0541 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Melania Guerrero Hue ◽

Cristina García Caballero ◽

Alfonso Rubio Navarro ◽

Juan Manuel Amaro Villalobos ◽

Raul Rodrigues Diez ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Renal Function ◽

Protein Expression ◽

Renal Fibrosis ◽

Tubular Cell ◽

Tubular Injury ◽

Tubular Cells ◽

Glycerol Injection

Abstract Background and Aims Rhabdomyolysis is characterized by the breakdown of the skeletal muscle and the subsequent myoglobin (Mb) release into the bloodstream. A common complication of this syndrome is acute renal injury (AKI). Once filtered by the kidney, Mb causes oxidative stress, inflammation and tubular cell death. There is no specific treatment for rhabdomyolysis-AKI, so it is crucial a better understanding of this syndrome to identify new therapeutic targets. Klotho is an anti-aging protein mostly expressed by the kidney. In addition to its functions in the regulation of mineral metabolism, Klotho protects from AKI-harmful effects. However, no previous studies analyzed the role of Klotho in rhabdomyolysis. Method We performed a pre-clinical model of rhabdomyolysis in C57BL/6J mice (male, 12 weeks old, n=30) by intramuscular injection of 10 ml/kg of 50% glycerol (≥99.5% m/v). Mice were sacrificed 3 and 6 hours or 1, 3, 7 and 30 days after glycerol administration. To evaluate to beneficial effect of Klotho in rhabdomyolysis, C57BL/6J mice were injected intraperitoneally with 0.1 mg/kg recombinant mouse Klotho (1819-KL, R&D Systems), or vehicle (PBS) 30 minutes before and 1, 3 and 5 days after glycerol injection. Blood, urine and renal samples were collected to analyze renal function, Klotho/FGF23 levels, oxidative stress, inflammation, fibrosis and cell death, all of them pathological processes affecting Klotho expression. In addition, we carried out studies in murine tubular cells (MCTs) to study the molecular mechanisms involved in Klotho regulation. Results Our results indicate that rhabdomyolysis induces an early decrease in Klotho renal mRNA and protein expression as well as Klotho serum levels. Klotho levels decreased in line with augmentation of creatinine concentration, kidney inflammation (CCL2 and IL-6 mRNA expression) and tubular injury marker NGAL. Moreover, patients with rhabdomyolysis-AKI also showed lower plasma Klotho levels and increased FGF23 plasma concentration than age-matched healthy individuals. Renal klotho protein expression remained reduced one month after rhabdomyolysis-induction, in line with long term renal fibrosis and pro-inflammatory macrophage accumulation (F4/80+ cells). Exogenous recombinant Klotho administration ameliorated renal function and reduced rhabdomyolysis-mediated tubular cell death oxidative stress (4-HNE staining) and tubular injury 24h after glycerol injection. In the same line, Klotho administration during AKI development reduced long term renal fibrosis and macrophage infiltration one month later. Antioxidant therapies with N-acetylcysteine (NAC) and sulforaphane, a potent Nuclear factor erythroid-2-related factor 2 (Nrf2) inducer, reduced Mb-mediated Klotho decrease in cultured tubular cells. Inhibition of TNF-α and IL-6 with infliximab and tocilizumab, respectively, also reverted Mb-mediated Klotho decrease. Inhibition of the inflammatory NFkB and p38 pathways also prevented Mb-mediated Klotho reduction. Conclusion Our findings are the first to demonstrate decreased renal and soluble Klotho levels not only in the early phases of rhabdomyolysis-induced AKI, but also when renal function was recovered, indicating that long-term consequences of AKI, such as inflammation and fibrosis, are also involved in Klotho downregulation. In addition, our results also indicate that Klotho administration may be a potential strategy to decrease rhabdomyolysis- long term negative effects.

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Gold nanoparticles alter parameters of oxidative stress and energy metabolism in organs of adult rats

Biochemistry and Cell Biology ◽

10.1139/bcb-2015-0030 ◽

2015 ◽

Vol 93 (6) ◽

pp. 548-557 ◽

Cited By ~ 21

Author(s):

Gabriela Kozuchovski Ferreira ◽

Eria Cardoso ◽

Francieli Silva Vuolo ◽

Monique Michels ◽

Elton Torres Zanoni ◽

...

Keyword(s):

Oxidative Stress ◽

Gold Nanoparticles ◽

Energy Metabolism ◽

Acute Administration ◽

Sod Activity ◽

Adult Rats ◽

Protein Levels ◽

Carbonyl Protein ◽

Term Administration

This study evaluated the parameters of oxidative stress and energy metabolism after the acute and long-term administration of gold nanoparticles (GNPs, 10 and 30 nm in diameter) in different organs of rats. Adult male Wistar rats received a single intraperitoneal injection or repeated injections (once daily for 28 days) of saline solution, GNPs-10 or GNPs-30. Twenty-four hours after the last administration, the animals were killed, and the liver, kidney, and heart were isolated for biochemical analysis. We demonstrated that acute administration of GNPs-30 increased the TBARS levels, and that GNPs-10 increased the carbonyl protein levels. The long-term administration of GNPs-10 increased the TBARS levels, and the carbonyl protein levels were increased by GNPs-30. Acute administration of GNPs-10 and GNPs-30 increased SOD activity. Long-term administration of GNPs-30 increased SOD activity. Acute administration of GNPs-10 decreased the activity of CAT, whereas long-term administration of GNP-10 and GNP-30 altered CAT activity randomly. Our results also demonstrated that acute GNPs-30 administration decreased energy metabolism, especially in the liver and heart. Long-term GNPs-10 administration increased energy metabolism in the liver and decreased energy metabolism in the kidney and heart, whereas long-term GNPs-30 administration increased energy metabolism in the heart. The results of our study are consistent with other studies conducted in our research group and reinforce the fact that GNPs can lead to oxidative damage, which is responsible for DNA damage and alterations in energy metabolism.

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E47 regulates hematopoietic stem cell proliferation and energetics but not myeloid lineage restriction

Blood ◽

10.1182/blood-2010-07-297689 ◽

2011 ◽

Vol 117 (13) ◽

pp. 3529-3538 ◽

Cited By ~ 18

Author(s):

Qi Yang ◽

Brandt Esplin ◽

Lisa Borghesi

Keyword(s):

Energy Metabolism ◽

Myeloid Differentiation ◽

Short Term ◽

Hematopoietic Stem ◽

Altered Expression ◽

Helix Loop Helix ◽

Multipotent Progenitors

Abstract The immune system is replenished by self-renewing hematopoietic stem cells (HSCs) that produce multipotent progenitors (MPPs) with little renewal capacity. E-proteins, the widely expressed basic helix-loop-helix transcription factors, contribute to HSC and MPP activity, but their specific functions remain undefined. Using quantitative in vivo and in vitro approaches, we show that E47 is dispensable for the short-term myeloid differentiation of HSCs but regulates their long-term capabilities. E47-deficient progenitors show competent myeloid production in short-term assays in vitro and in vivo. However, long-term myeloid and lymphoid differentiation is compromised because of a progressive loss of HSC self-renewal that is associated with diminished p21 expression and hyperproliferation. The activity of E47 is shown to be cell-intrinsic. Moreover, E47-deficient HSCs and MPPs have altered expression of genes associated with cellular energy metabolism, and the size of the MPP pool but not downstream lymphoid precursors in bone marrow or thymus is rescued in vivo by antioxidant. Together, these observations suggest a role for E47 in the tight control of HSC proliferation and energy metabolism, and demonstrate that E47 is not required for short-term myeloid differentiation.

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Thyroid redox imbalance in adult Wistar rats that were exposed to nicotine during breastfeeding

Scientific Reports ◽

10.1038/s41598-020-72725-w ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Rosiane Aparecida Miranda ◽

Egberto Gaspar de Moura ◽

Patrícia Novaes Soares ◽

Thamara Cherem Peixoto ◽

Bruna Pereira Lopes ◽

...

Keyword(s):

Oxidative Stress ◽

Thyroid Gland ◽

Protein Expression ◽

Wistar Rats ◽

Saline Control ◽

Nicotine Exposure ◽

Dependent Manner ◽

Altered Expression ◽

Redox Imbalance ◽

Thyroid Dysfunctions

Abstract Maternal nicotine exposure causes several consequences in offspring phenotype, such as obesity and thyroid dysfunctions. Nicotine exposure can increase oxidative stress levels, which could lead to thyroid dysfunction. However, the mechanism by which nicotine exposure during breastfeeding leads to thyroid gland dysfunction remains elusive. We aimed to investigate the long-term effects of maternal nicotine exposure on redox homeostasis in thyroid gland, besides other essential steps for thyroid hormone synthesis in rats from both sexes. Lactating Wistar rats were implanted with osmotic minipumps releasing nicotine (NIC, 6 mg/kg/day) or saline (control) from postnatal day 2 to 16. Offspring were analyzed at 180-day-old. NIC males showed lower plasma TSH, T3 and T4 while NIC females had higher T3 and T4. In thyroid, NIC males had higher sodium-iodide symporter protein expression, whereas NIC females had higher thyroid-stimulating hormone receptor (TSHr) and thyroperoxidase (TPO) protein expression. TPO activity was lower in NIC males. Hydrogen peroxide generation was decreased in NIC males. Activities of superoxide dismutase, catalase and glutathione peroxidase were compromised in NIC animals from both sexes. 4-Hydroxynonenal was higher only in NIC females, while thiol was not affected in NIC animals from both sexes. NIC offspring also had altered expression of sex steroid receptors in thyroid gland. Both sexes showed similar thyroid morphology, with lower follicle and colloid size. Thyroid from female offspring exposed to nicotine during breastfeeding developed oxidative stress, while the male gland seemed to be protected from redox damage. Thyroid dysfunctions seem to be associated with redox imbalance in a sex-dependent manner.

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Erectile dysfunction drugs altered the activities of antioxidant enzymes, oxidative stress and the protein expressions of some cytochrome P450 isozymes involved in the steroidogenesis of steroid hormones

PLoS ONE ◽

10.1371/journal.pone.0241509 ◽

2020 ◽

Vol 15 (11) ◽

pp. e0241509

Author(s):

Salah A. Sheweita ◽

Amal A. Meftah ◽

Mohamed S. Sheweita ◽

Mahmoud E. Balbaa

Keyword(s):

Oxidative Stress ◽

Antioxidant Enzymes ◽

Erectile Dysfunction ◽

Protein Expression ◽

Phosphodiesterase Inhibitors ◽

Hydroxysteroid Dehydrogenase ◽

Related Factors ◽

Protein Expressions ◽

Cytochrome P450 Isozymes

Objectives Infertility is a global health problem with about 15 percent of couples involved. About half of the cases of infertility are related to male-related factors. A major cause of infertility in men is oxidative stress, which refers to an imbalance between levels of reactive oxygen species (ROS) and antioxidants. Erectile dysfunction drugs (EDD), known as phosphodiesterase inhibitors (PDEIs), have been used for the treatment of ED. It has been shown that oxidative stress plays an important role in the progression of erectile dysfunction. Oxidative stress can be alleviated or decreased by non-antioxidants and antioxidant enzymes. The present study was undertaken to determine if these compounds could have a role in the incidence of infertility, especially after long-term use. Therefore, the present study aims to investigate the effect of EDD on the activities of antioxidant enzymes, free radical levels as well as the protein expression of different cytochrome P450 isozymes involved in the steroidogenesis of different hormones. In addition, the activity of both 17β-hydroxysteroid dehydrogenase and 17-ketosteroid reductase were assayed. The architectures of both livers and testes cells were investigated under the influence of EDD. Methods A daily dose of Sildenafil (1.48 mg/kg), Tadalafil (0.285 mg/kg) and Vardenafil (0.285 mg/kg) were administered orally to male rabbits for 12 week. Western immunoblotting, ELISA, spectrophotometric and histopathological techniques were used in this study. Results The present study showed that Sildenafil, Vardenafil, and Tadalafil treatments significantly decreased the levels of glutathione and free radicals in both livers and testes of rabbits. Also, Vardenafil and Sildenafil induced the activity of superoxide dismutase and catalase whereas, glutathione S-transferase, glutathione reductase, and glutathione peroxidase activities inhibited in livers of rabbits. The protein expression of cytochrome P450 isozymes (CYP 11A1, 21A2, and 19C) which are involved in the steroidogenesis was markedly changed in both livers and testes of rabbits after their treatments for 12 weeks. After the treatment of rabbits with these medication, the protein expression of CYP11A1 was slightly down-regulated in both livers and testes except Sildenafil up-regulated such protein expression. In addition, the protein expressions of CYP11A1 and CYP 19C in both livers and testes were down-regulated after treatment of rabbits with Sildenafil, Vardenafil, and Tadalafil for 12 weeks. Also, these drugs inhibited the activity of both 17β-hydroxysteroid dehydrogenase and 17-ketosteroid reductase in testes of rabbits. Moreover, Sildenafil, Vardenafil, and Tadalafil-treated rabbits showed a decrease in spermatocytes and the number of sperms in the testes. Conclusions It is concluded that ED drugs induced the activities of both SOD and catalase which consequently decreased MDA level. Decrement in MDA levels and oxidative stress could therefore sustain the erection for a long period of time. On the other hand, it is not advised to use these drugs for a long-term since the protein expressions of CYP isozymes involved in steroidogenesis as well as the numbers of spermatocytes in testes were decreased.

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