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Chrysin, a natural flavone, possesses multiple biological activities, such as antioxidant, anti-inflammatory and anti-cancer. We evaluated whether chrysin had beneficial effects on the reduction of prostate weight in a rat model of benign prostatic hyperplasia (BPH). BPH is the most common benign tumor in men over 50 years of age. Many factors contribute to the pathogenesis of BPH particularly the imbalance between proliferation and apoptosis as well as oxidative stress.
A preliminary dose response study was conducted where rats were randomly divided into five groups of eight animals in each and treated for five consecutive days per week for two successive weeks as follows; the first group (control group) was given (2.5ml/kg) of mixture of DMSO and corn oil (1:9) which was used as a vehicle for chrysin through oral gavage and (1ml/kg) olive oil subcutaneously (S.C.). The second group was given chrysin vehicle and 3 mg/kg testosterone dissolved in olive oil S.C. to induce BPH. The third, the forth and the fifth groups were given an oral dose of chrysin (25mg/kg, 50mg/kg and 100mg/kg) respectively one hour before testosterone injection. Seventy two hours after the last testosterone injection, blood samples were collected from the retro-orbital plexus and allowed to clot. Serum was separated by centrifugation at 3000 g for 10 min and used for determination of prostatic-specific antigen (PSA). Then, rats were sacrificed and the prostates were collected, weighed and subjected to histopathological examination for the determination of the optimal dose of chrysin to be used for further mechanistic investigations. chrysin in the dose of 50 mg/kg has been shown to be the most effective in protecting against testosterone induced BPH.
A mechanistic study was carried out for 2 weeks where a group of rats was kept as a control. BPH was induced by administration of testosterone s.c.. Another group was administrated 3 mg /kg testosterone s.c. and 50 mg/kg chrysin orally. The last group received 50 mg/kg chrysin orally.
The following parameters were investigated:
1- Dose response study :
Prostate weight and prostate weight/body weight ratio
Histological examination by H&E staining.
2- Mechanistic study
Apoptosis and proliferation markers: P21, P53, Bax, Bcl-2, PCNA, caspase-3 and NF-κB.
Oxidative stress markers: reduced glutathione, catalase activity, lipid peroxides and SOD activity.
The findings of the present study can be summarized as follows:
1- chrysin, in the dose of 50 mg/kg, significantly inhibited testosterone-mediated increase in the prostate weight, prostate weight/body weight. This was further confirmed by histological examination as well as assessment of serum PSA level.
2- Testosterone triggered a significant decrease in mRNA level of P21, P53 and Bax while significantly increased that of Bcl-2 as compared to the control group. Concomitant treatment with chrysin significantly protected against the testosterone-driven decline in mRNA expression of P21, P53 and Bax and maintained them at near basal levels as seen in the control group. chrysin significantly decreased Bcl-2 mRNA level as compared to the testosterone-treated group. Interestingly, treatment of animals with chrysin along with testosterone afforded significant protection against testosterone induced decline in Bax/Bcl-2 ratio the most important contributing factor to the apoptotic signaling.
3- The expression of PCNA in the epithelial cells has been studied immunohistochemically as a marker of proliferation. There was a boost in the number of stained cells in testosterone-treated group while concomitant treatment with chrysin was able to minimize the number of PCNA stained cells.
4- Caspase-3 enzyme level was significantly decreased by 46.5% in testosterone-treated rats as compared with control rats while chrysin significantly attenuated testosterone-induced reduction in its level.
5- NF-κB, a heterodimer composed of p50 and p65 subunits, is known to block apoptotic pathway and enhance cell survival. The expression of the activated p65 subunit of NF-κB was detected immuno-histochemically. The group treated with chrysin showed no significant change in the expression of NF-κB compared to the control group. However, testosterone-alone treated group showed significant increase in NF-κB expression compared to that of the control group. Concomitant treatment of rats with chrysin ameliorated testosterone-induced expression of NF-κB to a level similar to that of the control group.
6- chrysin was effective in opposing testosterone-induced oxidative stress, which play an important role in BPH pathogenesis and in NF-κB activation. chrysin significantly decreased the level of MDA, enhanced that of GSH as well as catalase and SOD enzymatic activity to almost the control level.
7- Testosterone triggered a significant increase in mRNA level of IGF-1 and IGF-1R compared to the control group. Concomitant treatment with chrysin significantly protected against the testosterone-driven increase in their mRNA expression and maintained them at near basal levels as seen in the control group.