الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Cisplatin (CIS) is deemed to be the “penicillin of cancer drugs” due to its universal, early and effective treatment for many cancers. It is highly effective in testicular cancer and is a central component of treatment regimens for several other malignancies. CIS produces cross-links, including the DNA cross-links that are presumably responsible for its potent antineoplastic effect.
Unfortunately, this success has been plagued with many unwanted dose-limiting side effects chiefly nephrotoxicity and testicular damage rendering a greater majority of young male patients sterile.
The testis is a well-known target organ for injury resulting from exposure to both chemotherapeutic and toxic environmental agents.
Investigating the potential hazardous effect of CIS on testis has been a point of interest in the recent research work, as it is well documented that, after injection of CIS, it passes to the testicular tissue causing decreased reproductive organ weights and degenerated spermatogenic cells.
It is obvious that CIS disrupts the redox balance of testicular tissue via an increase in lipid peroxidation, mitochondrial dysfunction and oxidative/nitrosative stress which result in inhibition of protein synthesis and DNA damage.
Consequently, anti-oxidants have been shown to protect non-malignant cells and organs against damage by CIS.
Melatonin is the main secretory product of the pineal gland in the brain. It participates in important physiological functions including the control of circadian rhythms and influencing the immune system. Also studies have documented its protective actions in various experimental models of oxidative stress due to its high efficacy as a free radical scavenger and indirect antioxidant.
Quercetin is one of the most abundant flavonoids in the human diet. It represents 60–75% of flavonoid intake, commonly present in most edible fruits and vegetables, it is known for its biological activities such as antioxidant, antiviral, anticancer, antimicrobial and anti-inflammatory activities. It can scavenge free radicals, inactivate ROS, preventing oxidation of membrane lipids, oxidative modification of proteins and DNA fragmentation.
The aim of the present study was to evaluate the biochemical and histological alterations that might occur in the seminiferous tubules of adult male albino rats following an administration of a single high dose of CIS. In addition, this study attempted to throw the light on the possible chemoprotective effects of melatonin and quercetin as antioxidants, when administered with CIS.
After approval of the Local Ethics Committee of the Faculty of Medicine, Alexandria University, The present study was carried out on fifty four adult male albino rats, each with an average weight of 150-200 gm. Rats were divided randomly into three groups as follows:
The control group (group I): was further subdivided into three equal sub groups, 8 animals each:
• Subgroup Ia (negative control): received isotonic saline IP at a single dose of 7 ml/kg.
• Subgroup Ib: received melatonin IP at a dose of 10mg/kg/day for five days.
• Subgroup Ic: received quercetin by orogastric tube at a dose of 50mg/kg/day for ten days.
The toxicity group (group II):10 rats each received cisplatin IP at a single dose of 7 mg/kg.
The chemo-protected group (group III) was further subdivided into two equal subgroups, 10 rats each:
• Subgroup IIIa: received the same dose of CIS as toxicity group followed immediately by melatonin IP at a dose of 10mg/kg/day for five days.
• Subgroup IIIb: received the same dose of CIS as toxicity group and followed immediately by oral quercetin at a dose of 50mg/kg/day for ten days.
Each group was sacrificed with ether anesthesia as scheduled, ten days after the beginning of experiment. Both testes of each sacrificed albino rat were dissected out carefully, weighed and used for biochemical and histological examination. Blood samples were collected to measure serum testosterone level.
CIS caused testicular toxicity as there was significant increase in testicular MDA levels, significant decreases in SOD activity and GSH levels in CIS-treated group compared with control group. Also CIS administration resulted in significant depletion of testosterone level, testicular and epididymal weight. Histological findings paralleled the biochemical results where CIS induced distorted seminiferous tubules (STs) with wide intertubular spaces, the STs were lined by relatively few germ cells with cytoplasmic vacuolation and deeply stained nuclei. Multinuclear giant cells were further revealed. Some STs showed dilated lumen free of sperms. In addition, many Leydig cells in the intertubular spaces exhibited deeply stained nuclei.
The findings of present work reinforce the significant role of ROS in the pathogenesis of CIS induced injury in the testis.
Melatonin and quercetin substantially alleviated the testis oxidative damage as shown by decreasing lipid peroxidation, increasing the levels of antioxidants (SOD, GSH), restoration of serum testosterone level and ameliorating the CIS’s effect on histological alterations and reproductive organ weights.
In addition to their protective effects, melatonin alone and quercetin alone were found to be safe at indicated doses and did not induce any histopathological or biochemical changes in the testis.
This study clearly indicates that CIS-treatment markedly impaired testicular function and combined treatment with melatonin or quercetin prevented much of the toxicity in rats with better results observed with quercetin.
Based on these results, melatonin and quercetin could be used as supplements for amelioration of toxic manifestations in CIS treated patients after further experimental and clinical trials.