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    An Experimental Insight Into the Role of Agomelatine in Renal Ischemia/Reperfusion Injury
    (Wiley, 2024) Aykora, Damla; Bahar, Mehmet Refik; Tanbek, Kevser; Ozturk, Dilara Altay; Karaca, Elif; Sandal, Suleyman; Tekin, Suat
    Acute kidney injury (AKI) is one of the leading causes of chronic kidney disease and accounts for 50%-75% of mortality following renal pathologies or organ transplantation. Ischemia-reperfusion injury (IRI) involves an interrupted blood supply to organs and the kidney; IRI exacerbates AKI development. Owing to several pharmacological treatment methods, AKI still has a poor prognosis, and novel therapeutic options are needed. Agomelatine (AGM) is a melatonin receptor agonist (MT1 and MT2) with increased bioavailability and lipophilicity. In this study, we aimed to investigate the antioxidant and anti-inflammatory effects of AGM in experimental renal IRI via long-term and short-term applications. Sixty male Sprague-Dawley rats were randomly divided into six groups (n = 10): the control, I/R, AGM20S, AGM40S, AGM20L, and AGM40L groups. Following the establishment of the renal IRI model, the rats received agomelatine at 20 and 40 mg/kg orally, and agomelatine solvent (hydroxyethylcellulose) was used as a vehicle. At the end of the experiment, blood samples and renal tissues were harvested for histopathological and biochemical analysis. Urea, creatinine, tumor necrosis factor (TNF-alpha), and interleukin-1 beta (IL-1 beta) levels were measured in blood serum samples. Malondialdehyde (MDA) levels and increased superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSHPx), and total glutathione (GSH) levels were measured in renal tissue supernatants. Our biochemical results indicated that AGM reduced creatinine, TNF-alpha, IL-1 beta, and malondialdehyde levels and increased SOD, CAT, GSHPx, and total GSH levels. Agolematine reduced infiltration, intratubular hemorrhage, and intratubular cast formation histopathologically. Our results suggest that AGM could be a potential therapeutic adjuvant agent for ischemia-reperfusion injury in the kidney and several other organs.
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    Protective effects of buloxibutid and empagliflozin on hypertension-induced cardiac and vascular injury in rats
    (Springer, 2026) Ozhan, Onural; Colak, Mehmet; Karaca, Elif; Dogru, Feyzi; Kucukakcali, Zeynep; Acet, Ahmet; Parlakpinar, Hakan
    This study aims to see the individual and combined effects of Angiotensin II type 2 (AT2) receptor agonist buloxibutid (also known as Compound 21 or C21) and sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin (EMPA) on effects of hypertension (HT), which is common today, on the heart, and vascular tissue. Male rats of the Sprague Dawley were divided into 5 groups: Control (C) group, HT group, HT + C21 group, HT + EMPA group and HT + C21 + EMPA group. After the protocol was completed, hemodynamic measurements were taken and heart and aorta tissues were evaluated biochemically, histopatologically and immunohistochemically. When the mean blood pressure (BP) values were compared, the mean BP of the HT group increased significantly compared to the C group (p < 0.05). Superoxide dismutase, glutathione and glutathione peroxidase activities in the heart, glutathione and catalase activities in the descending aorta were significantly higher in all treated groups compared to the HT group (p < 0.05). In the HT + C21 + EMPA group, histopathological damage score in hematoxylin-eosin (HE) stained heart sections compared to the HT group showed a decrease in tissue damage but cell infiltration was still observed. When HE staining method was applied, it was determined that the thoracic aorta sections in group C had normal histologic structure. In the HT group, dilatation in some parts and irregularities in elastic lamellae were observed. It was observed that the treated groups were similar to group C. When considering the individual and combined effects of C21 and EMPA, positive results on heart and vascular tissue were observed by hemodynamic, biochemical and histopathological analyses.
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    Renoprotective effects of compound 21 and empagliflozin in L-Name-induced hypertensive rats
    (Bmc, 2025) Ozhan, Onural; Colak, Mehmet; Karaca, Elif; Dogru, Feyzi; Kucukakcali, Zeynep; Acet, Ahmet; Parlakpinar, Hakan
    Background This study investigated the renoprotective effects of compound 21 (C21) and empagliflozin (EMPA) individually and in combination in an N omega-Nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rat model. The objective of this study was to evaluate their impact on oxidative stress (OS), biochemical markers, and histopathological changes in renal tissues. Methods Male Sprague-Dawley rats were divided into five groups: control, hypertension (HT), HT + C21, HT + EMPA, and HT + C21 + EMPA. Hypertension was induced by intraperitoneal L-NAME administration. Biochemical analyses of kidney tissue and histopathological evaluations were conducted to assess the treatment effects. Results Both C21 and EMPA significantly reduced the levels of OS markers, such as malondialdehyde, while increasing the levels of antioxidants, such as total antioxidants and glutathione. Compared with the individual treatments, the combination of C21 and EMPA exhibited superior efficacy in mitigating OS by significantly increasing superoxide dismutase and glutathione peroxidase activities. Furthermore, these treatments alleviated histopathological damage, including glomerular collapse, tubular degeneration, and interstitial inflammation, which were prominent in the HT group. The combined therapy group presented nearly normal histological structures in kidney tissues, with reduced inflammation and cellular damage. Urinary biochemical markers also reflected improved renal function in the treated groups, particularly in the combined therapy group. These findings indicate that the synergistic effects of C21 and EMPA enhance their protective impact on renal tissues. Conclusion C21 and EMPA demonstrated significant renoprotective effects in this HT model by reducing OS, enhancing antioxidant defenses, and mitigating renal tissue damage. Their combined administration offered synergistic benefits, highlighting their potential as a therapeutic strategy for hypertension-induced renal injury. Further research is warranted to validate these findings in clinical settings.