الفهرس 
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Abstract
Phenobarbital (PB) is one of the most commonly used antiepileptic drugs worldwide. This drug has been used since the early twentieth century. PB is one of the sedative-hypnotic agents which belong to the barbiturates class of drugs. Furthermore, PB offers a wide array of clinical uses that usually include anti-seizure management. The half-life of PB makes it possible to take just one dose each day (Suddock and Cain, 2021). It has been reported that PB is associated with cognitive deficits and several adverse effects (Lewis and Adams, 2022). Hepatic hypertrophy induced by PB is mediated by a moderate increase in hepatocyte DNA synthesis and dramatic enlargement of individual hepatocytes (Eze et al., 2009). Traditional medicine includes herbal medicine as a subset. Herbal medicine focuses on using herbs or herbal treatments to control ailments, in contrast to traditional medicine, which uses techniques like spiritism and soothsaying to address healthcare issues (WHO, 2013). Cranberry (CB) is a medicinal plant of the family Ericaceae genus and Vaccinium red fruits edible color evergreen leaves, oval, appear small flowers in the form of a bell (Azez and Hamza, 2020). CB is rich in sugars, but low in calories. They contain only small amounts of fat, but a high content of dietary fiber; organic acids, such as citric acid, malic acid, tartaric, oxalic and fumaric acid; certain minerals in trace amounts (Nile and Park, 2014; Tunde et al., 2018). CB intake led to significantly increased in the plasma antioxidant levels (Tunde et al., 2018). Vitamin C could be a very potent antioxidant occurring in significant amounts in fresh berries, which is an essential vitamin with powerful reducing properties and well known by its high antioxidant activity due to the neutralization of free radicals and other reactive oxygen species, formed via cell metabolism, which are associated with several forms of tissue damage and diseases (Koyuncu and Dilmacunal, 2010; Sona Skrovankova et al., 2015). The present study aimed to evaluate the protective effect of the co-treatment with CB and Vit-C on the hepatorenal and reproductive toxicities that were induced by phenobarbital in experimental rats. Fifty-six (56) male Wister rats were divided into 8 groups (n = 7) according to body weights to minimize the standard errors between groups into eight groups as follows: group 1: Rats were administrated with dist. H2O orally daily for 2 months and served as a negative control group. group 2: Rats were administrated with dist. H2O (300 μl) orally daily for a month (D-0 to D-29), and then administrated with 300 μl of CB (500 mg/kg) orally, daily for a month from D-30 to D-60. group 3: Rats were administrated with dist. H2O (300 μl) orally daily for a month (D-0 to D- 29), then administrated with Vit-C dose (27 mg/ kg) orally, daily for a month from D-30 to D-60. group 4: Rats were administrated with dist. H2O orally (300 μl) daily for a month from D-0 to D-30, and then administrated with CB as group 2 and Vit-C as group 3. group 5: Rats were administrated with dist. H2O orally daily for a month from D-0 to D- 29, and then administrated with PB (160 mg/kg) orally, daily for a month from D-30 to D-60. group 6: Rats were administrated with PB daily for a month from D-0 to D-29, and then were administered with CB as in group 2. group 7: Rats were administrated with PB daily for a month from D-0 to D-29, and then were administered with Vit-C as in group 3. group 8 : Rats were administrated with PB daily for a month from D-0 to D-29, and then were co-treated with CB as in group 2 and with Vit-C as in group 3. All groups of rat were weighted at the beginning of the experiment (I.B.wt) and at the end of the experiment (F.B.wt). The percentage of the change in the total body weight (% B.wt) was evaluated. Sers samples were collected from each rat from all groups for biochemical analyses. Sections from each lobe of liver, testis and kidney of all rats were collected and stored at -80 ºC for determination of the antioxidant/antioxidant biomarkers. Liver, kidney and testis tissues were fixed for histopathological and immunohistochemical investigations. The results showed that the groups of rat that were treated with CB or Vit-C did not show any significant differences in the percentage of b.wt changes when compared to the negative control group. PB-treated rats showed significant decrease in the % b.wt changes when compared to the control group. However, the group of PB-treated rats that were treated with either CB or Vit-C showed significant increase in the % b,wt changes when compared to the PB-injected rats alone. The PB-treated rats that were treated with a combination of CB and Vit-C showed significant increase in the % b.wt changes represented by 19% when compared to the PB-injected rats alone. The relative organ weights of the liver, kidney and testes did not change significantly except in the group of rats that were treated with PB. The results showed that there were no significant differences in the liver transaminases enzymes (ALT and AST) in the groups of rats that were treated with CB or with Vit-C, when compared to the negative control. As compared to PB-treated rats alone, the PB-treated group that had co-treatment with CB and Vit-C did show the most significant decrease in the liver transaminases activities accompanied with much more improvement in the total protein and albumin levels when compared to the group of rats that were injected with PB-alone. Rats that were treated with a combination of CB/Vit-C showed the highest improvement in kidney functions that evidenced by significant decrease in the levels of urea and creatinine when compared to PB-treated rats. The treatment of PB-injected rats with a combination of CB and Vit-C, however, led to a significant decrease in the total lipid and cholesterol levels more than treatment with CB or Vit-C alone when compared to the group of rats that were treated with PB-alone. Rats that injected with PB and treated with CB or/and Vit-C did show significant increase in the hepatic, renal and testicular SOD and CAT activities. In addition to a significant increase in the hepatic, renal and testicular GSH level with significant decrease in the hepatic, renal, and testicular MDA level when compared to PB-treated rats. The co-administration of CB and Vit-C resulted in a significant improved in sperm count, motility and vitality when compared with PB-treated rats. Examination of control liver sections showed normal structure with no histopathological changes, and a characteristic central vein and hepatocyte arrangement. Also, the liver of CB and Vit-C treated rats showed normal like structure of hepatic structure, normal central vein, and normal radiating hepatic strand with normal blood sinusoid and normal phagocytic Kupffer cells. Treatment with phenobarbital showing loss of cellular organization, hydropic deteriorated cells, changed lobular shape and nuclear degradation in some spots, disarrangement of normal hepatic cells, necrosis, and severe fatty degeneration were all visible. Treatment with CB after phenobarbital injection showed moderate congestion, and mild level of fatty deterioration. No necrotic areas were seen. Treatment with Vit-C after PB- injection showed moderate veins congestion and no fatty deterioration were seen. Some hepatic cells showed degree of degenerated hepatocyte. No pyknotic nuclei were seen. Treatment with combination of CB and Vit-C after phenobarbital injection showed improvement adequate, and the hepatic cords were properly positioned around the sinusoids. Hepatocytes and portal components appeared to be in acceptable condition. No Congestion and pyknotic nuclei were seen. The histology of control rat renal parenchyma was normal structure the appear as the cortex region. The renal cortex was packed with renal (Malpighian) corpuscles, glomerular capillaries, Bowman’s capsules, and urine space. The CB and Vit-C treated rat’s exhibits the cortex that contains glomeruli with normal Bowman’s space capsules, and normal appearance of mostly renal tubules. Furthermore, the histological changes in the kidney of PB-treated rat appeared in the form of some glomeruli were seen to be vacuolated, congestion, fractured, and Shrunken size inside Bowman’s capsules and irregular capsular space volume). CB and Vit-C/PB-treated rat had normal like structure of glomeruli with normal and standard size inside Bowman’s capsule. Congestion was noted to be moderate and pyknotic nuclei were visible. No luminal cast was seen. There was no evidence of lymphatic invasion. Examination of control testis sections showed normal structure with seminiferous tubules and interstitial tissue. Each tubule was lined with stratified epithelium (spermatogenic cells). Similarly, the testis of CB and Vit-C treated rats showed normal like structure of seminiferous tubules and interstitial tissue and healthy spermatogenic cells include spermatogonia, spermatocytes, spermatid, and spermatozoa. PB-treated rat indicated tissues had disorganized seminiferous tubules and a significant loss in the spermatogenic cell lineage. The set of seminiferous tubules with considerable damage to their architecture and basement membrane disruption, irregular and undulating membrane. CB/ PB-treated rats showed normal structure with seminiferous tubules and interstitial tissue. With moderate loss of germinal epithelium series Vit-C / PB-treated rats indicate appearance of testicular tissue; seminiferous tubules with complete spermatogenesis and entire germinal epithelial series, lumen with spermatozoa. The combination of CB and Vit-C after PB-treated rats showed improvement degree. Usual appearance of testicular tissue, seminiferous tubules with complete spermatogenesis, and entire germinal epithelial series. Multiple numbers of spermatozoa were present inside the lumen. Inter-tubular space appeared with normal width, and size contain considerable number of intact interstitial cells. In conclusion, the treatment with CB or Vit-C ameliorates the adverse effects on the liver, kidney, and testicular tissues that were induced by PB, however, the highest ameliorative effects on the liver, kidney, and testicular tissues were reported in the group of rats that were injected with PB- and were co-treated with CB/Vit-C.