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The Effects of Trimetazidine and Sildenafil on Bilateral Cavernosal Nerve Injury Induced Oxidative Damage and Cavernosal Fibrosis in Rats

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The Effects of Trimetazidine and Sildenafil on Bilateral Cavernosal Nerve Injury Induced Oxidative Damage and Cavernosal Fibrosis in Rats Hindawi Publishing Corporation e Scientific World Journal Volume 2014, Article ID 970363, 6 pages http://dx.doi.org/10.1155/2014/970363 Research Article The Effects of Trimetazidine and Sildenafil on Bilateral Cavernosal Nerve Injury Induced Oxidative Damage and Cavernosal Fibrosis in Rats Dogan Atilgan,1 Bekir S. Parlaktas,1 Nihat Uluocak,1 Fikret Erdemir,1 Fatma Markoc,2 Oguzhan Saylan,3 and Unal Erkorkmaz4 1 Department of Urology, Medical Faculty, Gaziosmanpasa University, 60100 Tokat, Turkey 2 Department of Pathology, Medical Faculty, Gaziosmanpasa University, 60100 Tokat, Turkey 3 Department of Biochemistry, Medical Faculty, Gaziosmanpasa University, 60100 Tokat, Turkey 4 Department of Biostatistics, Medical Faculty, Gaziosmanpasa University, 60100 Tokat, Turkey Correspondence should be addressed to Dogan Atilgan; [email protected] Received 3 January 2014; Accepted 6 March 2014; Published 18 March 2014 Academic Editors: K. M. Azadzoi and A. Komiya Copyright © 2014 Dogan Atilgan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Aim. The aim of this study was to compare the effects of sildenafil and trimetazidine on bilateral cavernosal nerve injury-induced oxidative damage and fibrotic changes in cavernosal tissue in rat model. Material and Methods. A total of 32 male Sprague-Dawley rats were randomly divided into 4 groups; each group consist 8 rats (control, BCI, BCI + TMZ, and BCI + sildenafil groups). Tissue superoxide dismutase (SOD), malondialdehyde (MDA), and protein carbonyl (PC) levels were determined biochemically and distribution of cavernosal fibrosis density among groups was performed histopathologically. Results. Tissue SOD levels in BCI group were significantly lower than the control group ( < 0.05). Tissue MDA and PC levels in BCI group were significantly higher than the control group ( < 0.05). TMZ and sildenafil administration significantly increased tissue SOD levels ( < 0.05)and reducedtissueMDAandPClevels( < 0.05). Histologically, the degree of cavernosal fibrosis and collagen density was higher in BCI group in comparison to control, TMZ-treated, and sildenafil-treated groups. Conclusion.BCIcausedoxidativedamageand increased cavernosal fibrosis in rat penis. TMZ and sildenafil treatment decreased oxidative damage and reduced the degree of fibrosis in penile tissue due to BCI. 1. Introduction A number of therapeutic interventions have been proposed to prevent PPED. One of these methods is long-term use of The number of radical prostatectomy operations has in- PDE5 inhibitors. In previous studies, it has been shown that creased worldwide as a result of the advances in the early PDE5 inhibitors reduced the formation of cavernosal fibrosis diagnosis of prostatic carcinoma in recent years. Despite the effectively, which led to prevention of PPED [4–7]. advances in laparoscopic, robotic, and open radical prosta- Oxidative injury (OI) is a complex phenomenon that tectomy techniques, postprostatectomy erectile dysfunction causes destruction in both local and remote tissues [8]. The (PPED) already appears as one of the most important compli- OI develops when there is excessive production of reactive cations affecting patient’s quality of life after radical prostate- oxygen species (ROS) and/or free radicals, which exceeds ctomy. The ratio of PPED after bilateral nerve-sparing radical the natural antioxidant defence mechanisms in the body. The prostatectomy has been reported between 14% and 61% in oxidative stress can produce important destructive effects the literature [1–3]. According to the related reports, the in tissues by causing alterations in the cell membranes, cavernosal nerve damage appears to be the most important leading to irreversible cellular damage. Eventually, OI causes factor in the development of ED after radical prostatectomy. increase in tissue levels of malondialdehyde (MDA) and 2 The Scientific World Journal protein carbonyl (PC), which are the end products of lipid and extracted samples using commercial chemicals produced peroxidation and protein oxidation, respectively [9]. by Sigma (St. Louis, USA). In compliance with the description The protective effects of trimetazidine (1-(2, 3, 4-trime- of the procedure in previous studies, the protein measure- thoxybenzyl)piperazine dihydrochloride) (TMZ) in OI have mentswereexecutedinthesamples. been shown in many studies. It showed antioxidant effects by partial inhibition of fatty acid oxidation, reduced ionic 2.2.1. Determination of Tissue Superoxide Dismutase (SOD) imbalance which occurred during OI, and prevented mem- Activity. The method of Sun et al. was used in the deter- brane damage due to oxidative stress. Additionally, it also mination of SOD activity [17]. The inhibition of nitroblue has been shown that TMZ reduced intracellular acidosis, tetrazolium (NBT) reduction by xanthine-xanthine oxidase protected ATP synthesis, and limited inflammatory process system as a superoxide generator was the basic principle of the and formation of ROS [10–15]. Neuroprotective effects of method. After adding 1.0 mL of ethanol-chloroform mixture TMZontheperipheralnervedamagewerealsoreportedin (5/3, v/v) to the same volume of sample and centrifugation, the literature [16]. the activity of SOD was assessed in the ethanol phase of In this study, we aimed to compare the effects of TMZ and the supernatant. The amount causing 50% inhibition in the sildenafil on the OI parameters in the cavernosal tissues of NBT reduction rate was accepted as one unit of SOD and rats with bilateral cavernosal nerve injury and to evaluate the the activity of SOD was presented as U/mg protein for penile fibrotic changes in these tissues. tissue. 2. Materials and Method 2.2.2. Determination of Malondialdehyde (MDA) Level. The level of the thiobarbituric acid-reactive substance was deter- minedbyusingthemethodwhichisbasedonreactionwith 2.1. Experimental Design. After the approval of the study ∘ design by the local ethical committee, a total of 32 male thiobarbituric acid (TBA) at 90 to 100 C[18]. In this TBA test Sprague-Dawley rats were randomly divided into 4 groups. reaction, MDA and TBA enter into a reaction producing a =8 pink pigment which is absorbed maximally at 532 nm. The Group 1 ( ) was the control group; only penectomy was ∘ performed in this group. In Group 2 (=8), bilateral cav- reaction was performed at 90 C for a period of 15 min in a ernosal nerve injury was constituted and penectomies were pH = 2-3 media. After mixing the sample with two volumes of performed (BCI group). In Group 3 (=8), trimetazidine cold 10% (w/v) trichloroacetic acid to precipitate the protein, (TMZ) was given orally (5 mg/kg/day) for one week before this precipitated protein was pelleted by centrifugation. After BCI execution and continued 21 days after the operation (BCI the reaction of an aliquot of the supernatant with an equal + TMZ group). In Group 4 (=8), sildenafil was given volume of 0.67% (w7V) TBA for about 10 min in boiling orally (5 mg/kg/day) for one week before BCI execution and water, it was cooled and the absorbance was evaluated at continued 21 days after the operation (BCI + sildenafil group). 532 nm. The penile tissue MDA levels were presented as The penile tissues of the rats were analysed immunohisto- nmol/g wet tissue and graded according to the standard chemically and tissue oxidative damage parameters such as graphicswhichwereformedbymeasurementswiththe superoxide dismutase (SOD), malondialdehyde (MDA), and standardsolution(1,1,3,3-tetramethoxypropane). protein carbonyl (PC) levels were determined. In histopatho- logical examination, the intensity of cavernosal fibrosis was 2.2.3. Determination of Tissue Protein Carbonyl (PC). The tis- graded and distribution among groups was performed. sue PC content was determined by using a spectrophotometer (Cintra 10 E, Austria), which measured the quantity of the The Creation of Bilateral Cavernosal Nerve Injury (BCI). reaction of carbonyl group with 2, 4-dinitrophenylhydrazine Under xylazine anaesthesia (10 mg/kg i.p.), the rats were fixed to form 2, 4-dinitrophenylhydrazone [19]. to the table in supine position and the area was exposed via suprapubic median incision. The cavernosal nerves were 2.3. Histopathological Examination. The penectomy materi- identified at the posterolateral region of the prostate bilat- als were fixed in 10% formalin solution, subsequently washed, ∘ erally. In consistence with the previous studies, the nerves andstoredin70%alcoholat4C until paraffin-embedded were clamped for about 2 seconds to create neural injury. tissue sectioning (5 m) process. The corpora cavernosal This procedure was applied to the rats in Groups 2, 3, and 4. tissueswerestainedwithMasson’strichrome.Thecollagen On the 28th day of the total experimental time and 21st day density in the connective tissue of cavernosal tissue was of BCI execution, penectomies of the rats were performed. evaluated and graded on scales ranging from 1+, lowest Penile tissues were sent to laboratory for biochemical and density collagen, to 4+, highest density collagen ratios under histopathological examination in formaldehyde solution. light microscopy (×400). 2.2. Biochemical Analyses. Homogenization procedure of the 2.4. Statistical Analysis. Biochemical and histopathological penile tissues was performed for 2 min at 13,000 rpm with the parameters among groups were compared with
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