الفهرس 
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Abstract
In the present study, CP administration significantly decreased PPAR-γ expression, which was in line with previous studies where CP suppress PPAR-γ expression by induced liver injury in rats (El-Sheikh and Rifaai, 2014; Alqahtani and Mahmoud, 2016). On the other hand, IRB caused an increase in PPAR-γ expression, and we supposed that up-regulation of PPAR-γ in the testis by IRB-pretreated rats caused suppression of ROS production and NF-κB, NLRP3 expression, and their subsequent downstream molecules caspase-1, and IL-18. This finding is supported by previous studies (Remels et al., 2009; Hong et al., 2015), where the PPAR-γ agonist pioglitazone significantly inhibited NALP3 inflammasome and IL‑1β induced by crystals of monosodium urate in HK-2 epithelial cells in renal tubes . The current research is the first to reveal the testicular protective role of IRB in rats with CP-induced testicular lesions. The present study extends beyond previous reports on testicular effects of other ARBs such as telmisartan and candesartan (Fouada et al., 2015; Sherif and Sarhan, 2019). This study provides new mechanistic insights into IRB’s testicular protective role. A modulatory effect of ARBs, specifically IRB, on NLRP3/caspase-1/IL-18 and PPAR-γ signalling are reported as contributing mechanisms to its potential testicular protection for the first time. One of the most common causes of male infertility is testicular damage. It occurs as a result of some diseases such as varicocele, as well as exposure to some toxic substances and the use of some drugs. Oxidative stress has been implicated as a major mechanism in testicular toxicity through the generation of oxidant radicals which can cause direct damage to cellular macromolecules such as DNA, proteins and lipids, leading to cellular damage and disturbances of redox-regulated cellular processes. In addition, the disruption of spermatogenesis can be caused by increased oxidative stress in the testis, which can activate linked downstream processes such as apoptosis and pyrosis. The current study was carried out to evaluate the potential protective effects of irbesartan on cyclophosphamide-induced testicular toxicity in rats. Furthermore, the underlying mechanisms that may be involved in its potential effects were investigated. In order to achieve these goals, testicular damage was experimentally induced in rats by intraperitoneal administration of cyclophosphamide for seven days. Adult male albino rats were used and divided into four groups (10 rats in each group). I ( Normal control): Rats were given 0.5 mL of 0.5 % CMC orally daily for 15 days. II ( IRB): Rats were given 0.5 mL of IRB (100 mg/kg/day) orally for 15 days. III ( CP): Rats were given 0.5 mL of 0.5 % CMC orally daily for 8 days, then CP (100 mg/kg/day) was given by intraperitoneal (I.P.) injection on day 9 of the experiment for seven successive days. ( IRB + CP): Rats were given 0.5 mL of IRB (100 mg/kg/day) orally for 8 days prior to CP, and on day nine, IRB was given parallel to CP (100 mg/kg/day, I.P.) for additional seven days. Twenty-four hours following the end of the treatment regimen, blood, epididymis and testis samples were collected for assessment of the following parameters: Biochemical parameters: - Serum testosterone concentration. - Epididymal sperm count. - Epididymal sperm viability. - Testicular lipid peroxides contents (measured as MDA). - Testicular reduced glutathione contents. - Testicular superoxide dismutase enzyme activity. - Testicular PPAR-γ mRNA expression. - Testicular caspase-1 contents. - Testicular IL-18 contents. Histopathological and immunohistochemical parameters: - Histopathological examination of testicular sections by H&E staining and Masson’s trichrome for assessment of testicular fibrosis. - Immunohistochemical determination of inflammation markers (NLRP3 and NF-κB), apoptotic and anti-apoptotic markers (Bax, Bcl-2 and caspase-3) in testicular sections. The effect of cyclophosphamide (100 mg/kg, I.P.) on the assessed parameters compared to normal control rats can be summarized as follows: ❖ Significant decrease in serum testosterone concentration. ❖ Significant decrease in epididymal sperm count. ❖ Significant decrease in epididymal sperm viability. ❖ Significant increase in testicular lipid peroxides contents (measured as MDA). ❖ Significant decrease in testicular GSH contents. ❖ Significant decrease in testicular SOD enzyme activity. ❖ Significant decrease in testicular PPAR-γ mRNA expression. ❖ Significant increase in testicular caspase-1 contents. ❖ Significant increase in testicular IL-18 contents. ❖ Histopathological examination revealed a significant degree of testicular deterioration associated with spermatogenic cell vacuolization, necrosis, and a total loss of spermatogenesis. ❖ Masson’s trichrome staining showed marked thickening of the tunica albuginea capsule associated with separating their fibers. ❖ Immunohistochemical examination showed strong positive immunostaining for Bax and caspase-3, NF-κB and NLRP3. ❖ Immunohistochemical examination showed light positive immunostaining for Bcl-2. The effect of prophylactic treatment with irbesartan (100 mg/kg, P.O.) on assessed parameters compared to cyclophosphamide intoxicated rats can be summarized as follows: ❖ Significant increase in serum testosterone concentration. ❖ Significant increase in epididymal sperm count. ❖ Significant increase in epididymal sperm viability. ❖ Significant decrease in testicular lipid peroxides contents (measured as MDA). ❖ Significant increase in testicular GSH contents. ❖ Significant increase in testicular SOD enzyme activity. ❖ Significant increase in testicular PPAR-γ mRNA expression. ❖ Significant decrease in testicular caspase-1 contents. ❖ Significant decrease in testicular IL-18 contents. ❖ Histopathological examination revealed mild alterations within the spermatogenic cells. A few show nuclear pyknosis with free sperm within the seminiferous tubules lumen. ❖ Masson’s trichrome staining showed mild cleavage of the collagen fibers. ❖ Immunohistochemical examination showed strong positive immunostaining for Bcl-2. ❖ Immunohistochemical examination showed moderate positive immunostaining for Bax and caspase-3, NF-κB, and NLRP3.