Yi̇Lmaz, Mehmet; Suleyman, Bahadi̇R; Mammadov, Renad; Altuner, Durdu; Coban, Taha Abdulkadi̇R; Bulut, Seval; Coskun, Resi̇T; Suleyman, Hali̇S

The aim of the study was to investigate the effects of lacidipine, amlodipine, and benidipine on the analgesic activity and toxicity of tramadol. Rats (n = 6/each group) were divided into five groups as control (CG), tramadol (TRD), lacidipine+tramadol (LTRD), amlodipine+tramadol (ATRD), and benidipine+tramadol (BTRD). Tramadol was administered once at a dose of 50 mg/kg and lacidipine, amlodipin, benidipin were administered at a dose of 4 mg/kg orally, once a day for 10 days. After the animals were sacrificed, malondialdehyde (MDA) and total glutathione (tGSH) levels were measured in brain, heart, liver, and kidney tissues. Troponin I (Tp I), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and creatinine levels were determined in serum. Paw pain thresholds were measured one hour before and after drug administration. The analgesic effect of tramadol was increased the most by benidipine, while amlodipine and lacidipine increased it equally. Lacidipine failed to suppress MDA increase and tGSH decrease in brain tissue. Benidipine suppressed MDA increase and tGSH decrease in brain tissue better than amlodipine. All three drugs suppressed cardiac tissue oxidative stress and the release of TP I into the circulation. Lacidipine and amlodipine could not prevent tramadol-induced oxidative stress in liver and kidney tissues, whereas benidipine prevented excessive MDA increase and tGSH decrease. Benidipine significantly suppressed the increase of ALT, AST, BUN, and creatinine. Analgesic activity was 35.1% in TRD, 43.7% in LTRD, 50.4% in ATRD, and 67.5% in BTRD. Study results show that benidipine and tramadol co-treatment is better than co-treatment with lacidipine or amlodipine in achieving minimal toxic effects and maximum analgesia.

Alpkan, Abdullah; Çankaya, Murat

Trastuzumab is one of the most commonly used monoclonal antibodies in the treatment of breast cancer. It is effective because it binds to the HER2 receptor and inhibits the signaling pathways for proliferation and metastasis. However, intrinsic or acquired resistance resulting from the various signaling pathways of heterogeneous breast cancer reduces its efficacy. To increase its efficacy, it is combined with different agents in the treatment. In this study, the synergistic effect of the combination of trastuzumab and gambogic acid on the breast cell line MDA-MB -453 was investigated in vitro. At the end of 12-, 24-, 48-, and 72-h incubation, their antiproliferative effects were determined by the XTT method. Combination Index (CI) values of the study were calculated using CompuSyn.exe software. The highest synergistic effect was obtained with 12.5 µg/mL trastuzumab + 1.25 µM gambogic acid (CI-4) at the 72nd h. The activity of the antioxidant enzyme catalase (CAT) was also measured for the applications. We observed that a combination of trastuzumab and gambogic acid decreased CAT activity at 24, 48, and 72nd h. It was concluded that gambogic acid may be a good candidate for combination with other agents in targeted drug design.

Isik, Bahar; Ates, Irem; Suleyman, Bahadir; Mammadov, Renad; Bulut, Seval; Gulaboglu, Mine; Ozcicek, Adalet; Suleyman, Halis

The increase in cyclooxygenase-2 (COX-2) activity and the decrease in COX-1 activity were associated with increased intracellular calcium. Lacidipine, a calcium channel blocker, can protect gastric tissue from aspirin-induced damage while potentiating the analgesic and anti-inflammatory properties of aspirin. The aim of this study was to investigate the anti-inflammatory, analgesic, and gastric tissue effects of using lacidipine and aspirin in combination and separately. (LA). Twenty-four rats were randomly divided into CG (carrageenan control), LCG (carrageenan + lacidipine), ACG (carrageenan + aspirin), and LACG (carrageenan + LA) groups. Lacidipine 4 mg/kg, aspirin 100 mg/kg were given orally to the animals on an empty stomach. Carrageenan was injected into the hind paws of rats to induce inflammation and pain. Paw volumes were measured at 0, 1, and 4 hours after carrageenan administration, and paw pain thresholds were measured at 1 and 4 hours. After euthanasia (thiopental sodium, 50 mg/kg), paw and gastric tissues were excised and biochemically analyzed. Gastric tissues were also examined macroscopically. In the paw tissues of animals receiving lacidipine, malondialdehyde (MDA) was lower than in the CG and AG, while total glutathione (tGSH) was higher (p<0.05). Lacidipine inhibited COX-2, but not COX-1 isoenzyme. LA—lacidipine, and aspirin—inhibited inflammation and hyperalgesia at 1 and 4 hours, respectively. Lacidipine prevented aspirin-induced COX-1 inhibition and gastric ulcer formation. Lacidipine combined with aspirin may be beneficial for initiating its anti-inflammatory activity early, achieving a potent analgesic effect, and preventing aspirin-induced gastric injury.

Yilmaz, Canan T.U.Z.; Suleyman, Bahadir; Mammadov, Renad; Ozcicek, Adalet; Bulut, Seval; Yazici, Gulce N.A.Z.; Gulapoglu, Mine; Suleyman, Halis

Indomethacin is used in the treatment of ankylosing spondylitis, osteoarthritis, tendinitis, and other inflammations. However, it has been reported indomethacin has nephrotoxic, gastrotoxic, and hepatotoxic effects. The aim of this study is to investigate the effect of nimesulide on indomethacin-induced liver damage in rats biochemically and histopathologically. Experimental animals (21 rats) were divided into 3 groups: the healthy (HG) group receiving distilled water as a solvent, the 25 mg/kg indomethacin administered (IDO) group, and the 50 mg/kg nimesulide + 25 mg/kg indomethacin administered (NIDO) group. Malondialdehyde (MDA), total glutathione (GSH) levels and cyclooxygenase-1 (COX-1), cyclooxygenase (COX-2) enzyme activities were determined from liver tissues. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were also measured in serum. The data obtained in the IDO group were compared with the data obtained from the NIDO and MDA and decreased tGSH levels with indomethacin HG groups. Increased application in liver tissue approached the HG group with nimesulide application, and the difference was found to be insignificant. Nimesulide prevented the decrease in COX-1 and COX-2 levels observed with indomethacin administration. Again, the increase in ALT and AST levels, which increased with indomethacin administration, was prevented by nimesulide. As a result of the histopathological evaluation, it was observed that nimesulide reduced the damage caused by indomethacin. Nimesulide at 50 mg/kg prevented oxidative liver damage induced with indomethacin at 25 mg/kg. Our results suggest that nimesulide may be useful in the treatment of hepatotoxicity and COX-1 inhibition side effects without suppressing analgesic and anti-inflammatory activity due to indomethacin use.

Koc, Alparslan; Kuyrukluyildiz, Ufuk; Sayar, Ali Caner; Gazi, Mustafa; Süleyman, Bahadir; Mammadov, Renad; Akbaş, Nergis; Arslan, Remzi; Süleyman, Halis; Yavuzer, Bülent

Long-term treatment with tramadol is reported to be toxic to the kidneys. Research shows that tramadol reduces antioxidants and increases oxidants produced in renal tissue. We aimed to investigate the carvacrol effect on tramadol-induced renal injury in rats. The animals were divided into four groups: healthy (HG), individual tramadol (TR), individual carvacrol (CR), and tramadol + carvacrol (TC). Malondialdehyde (MDA), total glutathione (tGSH), glutathione peroxidase (GPO), superoxide dismutase (SOD), total oxidant status (TOS), total antioxidant status (TAS), blood urea nitrogen (BUN), and creatinine (Cr) were measured. Renal tissue was examined histopathologically. MDA, TOS, BUN, and Cr were significantly elevated in group TR and identified as low in group TC compared to group TR but higher than in the HG group. The tGSH, SOD, GPO, and TAS levels were low in group TR and higher in group TC than in group TR but lower than in the HG group. Histological examination of the TR group revealed diffuse necrosis and focal polymorphonuclear leukocytes (PMNLs) in the tubules. In the TC group, tubular atrophy and necrosis were minimal, and PMNL was rare. We observed that tramadol increases oxidants, decreases antioxidants, increases BUN and Cr, and examined whether the toxic effect on renal tissue regressed with carvacrol.

Ekinci, Bilge; Suleyman, Bahadir; Mammadov, Renad; Gezer, Arzu; Mendil, Ali Sefa; Akbas, Nergis; Bulut, Seval; Dal, Cagatay Nusret; Suleyman, Halis

Diabetic neuropathies are the most frequent complication of diabetes. While numerous metabolic pathways are disrupted in diabetic neuropathy, oxidative stress has been indicated as a significant reason for this condition. In this study, the effect of carvacrol, which has antioxidant effects, on experimental diabetic neuropathy and neuropathic pain was investigated. Alloxan was used to induce diabetes in the experiment. Diabetes was created by administering 120 mg/kg of alloxan intraperitoneally (i.p) once a day for 3 days. Rats with a blood glucose concentration above 250 mg/kg in the blood taken from the tail veins at the end of three days were considered diabetic. Rats were categorized under healthy control (HG), alloxan-induced hyperglycemia (AG), and alloxan-induced hyperglycemia + carvacrol-treated (ACG) groups. Carvacrol was i.p injected at 50 mg/kg dose to the ACG (n = 6) group of rats with hyperglycemia. The same volume of distilled water as the solvent was applied in the same way to AG (n = 6) and HG (n = 6) rat groups. This procedure was repeated once a day for three months. Carvacrol showed an anti-hyperglycemic effect in diabetic rats, a protective effect against lowering pain threshold, and analgesic activity in rat paws. Carvacrol prevented the oxidant/antioxidant balance from changing in favor of oxidants. The results supported that carvacrol is an agent against alloxan-induced peripheral diabetic neuropathic pain.

Gündoǧdu, Betül; Taş, Hakan Gökalp; Süleyman, Bahadir; Mamedov, Renad; Yüce, Neslihan; Kuyrukluyildiz, Ufuk; Süleyman, Halis

Lutein has an anti-inflammatory impact on tissues, according to recent research. The goal of our research was to see how lutein affected the biochemical and histological results of ischemia-reperfusion (I/R) intervention on rats' livers. A total of 18 rats were divided into a sham operation group (HG), a liver I/R (KIR) group, or lutein (1mg/kg)+liver I/R (LIR) groups. Biochemical measures and histological exams were done in all three groups after I/R intervention. MDA, NF-κB, TNF-α, IL-1, ALT, and AST levels were significantly higher (p < 0.001) in the KIR group compared to the HG and LIR groups, although tGSH was significantly lower (p < 0.001). The HG group was histopathologically normal. The KIR group had severe degeneration, necrosis, and inflammation in the portal area and parenchyma. The LIR group had mild inflammation in the portal area and parenchyma. The use of lutein might be an alternative treatment for liver damage caused by I/R responses during surgery.

Erhan, Ertugrul; Bayram, Rana; Suleyman, Bahadir; Kurt, Nezahat; Suleyman, Halis; Salcan, Ismail

One of the major side effects of dose-limiting cisplatin is ototoxicity, resulting in restricted clinical use. Cerebrolysin is a neuroprotective, neurotrophic and antioxidant drug derived from the brains of pigs. No studies have investigated the positive effects of Cerebrolysin on the damage to auditory nerves caused by cisplatin- induced oxidative stress. Eighteen rats were randomly divided into three groups of six: the Cerebrolysin and cisplatin group (CCG), the cisplatin group (CG) and the healthy group (HG). The CCG was administered 2.5 mL/kg of Cerebrolysin via subcutaneous injection daily, while the CG and HG were administered physiological saline solutions daily. Every other day, after receiving their dose of Cerebrolysin or physiological saline solution, the CCG and CG groups were administered 5 mg/kg of cisplatin via intraperitoneal injection (IP) every other day. The substances were administered for eight days. In acoustic nerve tissue, while the CCís oxidant parameters were significantly higher (p < 0.0001) than those of the CCG and HG groups, its antioxidant parameters were also significantly lower (p < 0.0001). Cerebrolysin antagonized the balance of oxidants and antioxidants in acoustic nerve tissue, resulting in higher concentrations of oxidants. The results suggested that Cerebrolysin may be useful in the treatment of cisplatin-induced oxidative acoustic nerve injury.

Coskun, Resit; Celik, Aziz Inan; Suleyman, Zeynep; Cimen, Ferda Keskin; Cankaya, Murat

The previous studies formed the role of oxidants and proinflammatory cytokines in the pathogenesis of acute psychological stress-related cardiac damage leading to mortality and other complications. The aim of the study is to examine the protective effect of rutin against stress-induced cardiac damage. In the literature, no studies have been found analyzing the effects of rutin in acute stress-related oxidative damage induced by immobilization method in rats. Rutin was administered orally to rutin + stress applied (RSG) group albino rats at a dose of 50 mg/kg. For healthy control (HG) and stress applied to control (SAG) groups, distilled water as a solvent was orally administered at the same volume (0.5 mL). One hour after rutin and distilled water applications, all animals except for HG brought into a supine position and their legs and arms were ligated and kept in the same position for 24 h. The oxidant, cytokine and cardiac biomarker levels in blood serum and heart tissues of SAG animals were found to be significantly higher and total glutathione was lower than RSG and HG groups. Histopathologically dilated congested blood vessels and myocardial destruction, hemorrhage, edema, and polymorphonuclear leukocyte infiltration were observed in the SAG heart tissues. On the other hand, the histological heart tissue results of the RSG group was found to be similar compared to the healthy tissue except for the slightly dilated congested blood vessel. These results indicate that the rutin may be useful in the treatment of stress-related oxidative cardiac damage.

Erhan, Ertugrul; Bayram, Rana; Cimen, Ferda Keskin; Altuner, Durdu; Seckin, Ender; Kurt, Nezahat; Suleyman, Halis

Ototoxicity of cisplatin is one of the major dose-limiting side effects. Cisplatin-dependent ototoxic-ity is known to be associated with reactive oxygen species. Protective effect of taxifolin, being a flavanone found in onions, milk thistle, French maritime, and Douglas fir bark, against cisplatin-associated ototoxicity will be examined in this study. There are no studies in the literature examining the protective effect of taxifolin against cisplatin-induced ototoxicity. 50 mg/kg taxifolin was orally administered to TXC group rats (n-6), and distilled water was orally administered as a solvent to CG (n-6) and HG (n-6) groups. One hour later, 5 mg/kg cisplatin was administered intraperitoneally (i.p) to TXC and CG groups. This procedure was repeated once a day for 7 days. At the end of this period, all animals were sacrificed by high-dose anesthesia (50 mg/kg thiopen-tal sodium) and biochemical and histopathological examinations were performed on the dissected cochlear tissue. Our biochemical test results showed that oxidant parameters were significantly increased whereas antiox-idant parameters were significantly decreased in the cisplatin group (CG) compared to taxifolin (TXC) and healthy (HG) groups (p < 0.0001 for both parameters). Histopathological results showed that severe cochlear vestibular membrane degeneration, dilated conjunctival blood vessels, edema and destruction developed in the cisplatin group. However, no pathological findings were found in the taxifolin-treated group except for mild degeneration and edema. This information suggests that taxifolin may be useful in the treatment of cisplatin-associated oxidative cochlear damage.