The number of radical prostatectomy operations has increased worldwide as a result of the advances in the early diagnosis of prostatic carcinoma in recent years. Despite the advances in laparoscopic, robotic, and open radical prostatectomy techniques, postprostatectomy erectile dysfunction (PPED) already appears as one of the most important complications affecting patient’s quality of life after radical prostatectomy. The ratio of PPED after bilateral nerve-sparing radical prostatectomy has been reported between 14% and 61% in the literature [
Oxidative injury (OI) is a complex phenomenon that causes destruction in both local and remote tissues [
The protective effects of trimetazidine (1-(2, 3, 4-trimethoxybenzyl)piperazine dihydrochloride) (TMZ) in OI have been shown in many studies. It showed antioxidant effects by partial inhibition of fatty acid oxidation, reduced ionic imbalance which occurred during OI, and prevented membrane damage due to oxidative stress. Additionally, it also has been shown that TMZ reduced intracellular acidosis, protected ATP synthesis, and limited inflammatory process and formation of ROS [
In this study, we aimed to compare the effects of TMZ and sildenafil on the OI parameters in the cavernosal tissues of rats with bilateral cavernosal nerve injury and to evaluate the fibrotic changes in these tissues.
After the approval of the study design by the local ethical committee, a total of 32 male Sprague-Dawley rats were randomly divided into 4 groups. Group 1 (
Homogenization procedure of the penile tissues was performed for 2 min at 13,000 rpm with the homogenizer (IKA Ultra-Turrax t 25 Basic, Germany) in five volumes of ice-cold Tris-HCl buffer (50 mM, pH 7.4) containing 0.50 mL/L Triton x-100. Subsequently, determinations were carried out on the prepared homogenate, supernatant, and extracted samples using commercial chemicals produced by Sigma (St. Louis, USA). In compliance with the description of the procedure in previous studies, the protein measurements were executed in the samples.
The method of Sun et al. was used in the determination of SOD activity [
The level of the thiobarbituric acid-reactive substance was determined by using the method which is based on reaction with thiobarbituric acid (TBA) at 90 to 100°C [
The tissue PC content was determined by using a spectrophotometer (Cintra 10 E, Austria), which measured the quantity of the reaction of carbonyl group with 2, 4-dinitrophenylhydrazine to form 2, 4-dinitrophenylhydrazone [
The penectomy materials were fixed in 10% formalin solution, subsequently washed, and stored in 70% alcohol at 4°C until paraffin-embedded tissue sectioning (5
Biochemical and histopathological parameters among groups were compared with Kruskal Wallis analysis of variance. For multiple comparisons, Bonferroni adjusted Mann-Whitney
The tissue SOD, MDA, and PC analysis results of all the groups were presented in Table
Tissue SOD, MDA, and PC levels of the groups.
Control |
BCI |
BCI + TMZ |
BCI + sildenafil |
| |
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SOD (U/mg protein) |
|
|
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|
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MDA (nmol/g wet tissue) |
|
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|
|
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PC (nmol/mL tissue) |
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|
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Data were presented as mean ± standard deviation.
aThere was statistically significant difference from other groups
SOD: superoxide dismutase.
MDA: malondialdehyde.
PC: protein carbonyl.
BCI: bilateral cavernosal nerve injury.
TMZ: trimetazidine.
Histopathological distribution of tissue collagen densities was presented in Table
Distribution of cavernosal collagen density in the groups.
Degree of collagen density | ||||
---|---|---|---|---|
1+ |
2+ |
3+ |
4+ | |
Group 1 | 5 | 3 | 0 | 0 |
Group 2 | 0 | 2 | 2 | 4 |
Group 3 | 2 | 4 | 2 | 0 |
Group 4 | 2 | 6 | 0 | 0 |
1+: lowest collagen density.
2+: mild collagen density.
3+: moderate collagen density.
4+: highest collagen density.
Histological view of collagen density in the cavernosal tissues stained with Masson’s trichrome (×400).
Despite the different nerve-sparing techniques, erectile dysfunction after nerve-sparing radical prostatectomy has not been determined, yet. Many theories have been proposed about the formation of ED after nerve-sparing radical prostatectomy. The stretching of nerve, direct neural injury, pelvic fibrosis, and nerve entrapment due to surgery may play role in the etiopathogenesis of PPED. Due to cavernosal nerve damage, a pathophysiological process occurs in cavernosal tissue and, as a result of this process, smooth muscle/collagen ratio changes in favour of collagen. Eventually, fibrosis formation occurs in cavernosal tissue [
The relationship between oxygen concentration and cavernosal fibrosis has also been shown in several studies. Moreland et al. showed that TGF-b1 increased collagen synthesis in human corpus cavernosal smooth muscle cells in culture which was induced by hypoxia [
The development of ED after nerve-sparing radical prostatectomy due to oxidative damage has been shown in numerous studies in the literature [
Recent studies have reported that long-term use of PDE5 inhibitors showed effectiveness among patients who had complaints of ED after radical prostatectomy [
The protective effect of TMZ on OI also has previously been shown in many investigations in other tissues [
In our study, we found that, in TMZ- and sildenafil-treated groups, SOD, MDA, and PC levels which were the indicators of OI were significantly improved compared with BCI group. Histopathologically, collagen density in TMZ- and sildenafil-treated groups was reduced in comparison to BCI group, as well.
Although this is an experimental preclinical study, the results of this study should be supported with more comprehensive and detailed further clinical studies. Nowadays, PDE5 inhibitors are being used in penile rehabilitation of PPED but, in the light of these future clinical studies, it may be speculated that the addition of TMZ to this treatment protocol will help in reducing the regeneration time of injured cavernosal nerves and PPED rates.
As a result of our study, BCI created oxidative stress in rat penile tissue. Consequently, cavernosal tissue collagen densities were increased due to oxidative injury induced by BCI and this may lead to development of fibrosis in the cavernosal tissues. But the use of TMZ and sildenafil decreased oxidative damage and reduced fibrotic process in rat penile tissues due to cavernosal nerve injury.
The authors declared that there is no conflict of interests.