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    Early administration of milrinone ameliorates lung and kidney injury during sepsis in juvenile rats
    (Wiley, 2022) Keskin, Halil; Tavacı, Taha; Halıcı, Hamza; Yüksel, Tuğba Nurcan; Özkaraca, Mustafa; Bilen, Arzu; Halıcı, Zekai
    Background A sepsis model was created, induced by cecal ligation and puncture (CLP), in juvenile rat groups. Milrinone (MIL), which is known to have a modulatory effect on pro-inflammatory cytokines, was administered to the designated rat groups in the early period before severe sepsis developed. The study was aimed at investigating the possible protective effects of milrinone on the lung and kidney tissues of rats in the late phase of sepsis. Methods The rat pups were divided into seven groups with six animals in each group: (1) healthy rats who received no drug; (2) CLP-S12 (sacrificed at hour 12); (3) CLP-S24 (sacrificed at hour 24); (4) CLP-MIL1-S12 (administered with 0.5 mg/kg milrinone at hour 1 and sacrificed at hour 12); (5) CLP-MIL1-S24 (administered with 0.5 mg/kg milrinone at hour 1 and sacrificed at hour 24): (6) CLP-MIL12-S24 (administered with 0.5 mg/kg milrinone at hour 12 and sacrificed at hour 24), (7) and CLP-MIL1,12-S24 (administered with 0.5 mg/kg milrinone at hours 1 and 12 and sacrificed at hour 24). Results Significant differences were found between the early and late administration of milrinone in terms of both molecular and histopathological results. The results showed that the tissues were significantly preserved in the groups in which milrinone had been started in the early period compared to the sepsis control groups and the groups in which milrinone had been started in the late period. Conclusions In addition to the positive inotropic effects of milrinone, its immunomodulatory properties that result in decreased cytokine storm can be beneficial during early period of sepsis.
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    Neuroprotective effect of roflumilast under cerebral ischaemia/reperfusion injury in juvenile rats through NLRP-mediated inflammatory response inhibition
    (Wiley, 2021) Keskin, Halil; Keskin, Filiz; Tavaci, Taha; Halıcı, Hamza; Yüksel, Tuğba Nurcan; Özkaraca, Mustafa; Halıcı, Zekai
    This study aims to investigate the protective effect of roflumilast, a phosphodiesterase (PDE)-4 enzyme inhibitor, and demonstrate its possible role in the development prevention of cerebral ischemia/reperfusion injury (CI/RI) after stroke induced by carotid artery ligation in juvenile rats. The rats were randomly divided into five groups: healthy group without any treatment, healthy group administered with 1 mg/kg roflumilast, CI group not administered with roflumilast, CI group administered with 0.5 mg/kg roflumilast, and CI group administered with 1 mg/kg roflumilast. In the CI groups, reperfusion was achieved 2h after ischemia induction; in the roflumilast groups, this drug was intraperitoneally administered immediately after reperfusion and at the 12(th) hour. At the end of 24h, the rats were sacrificed and their brain tissues removed for examination. The mRNA expressions obtained with real-time PCR of IL-1 beta, TNF-alpha, and NLRP3 significantly increased in the CI/RI-induced groups compared with the control group, and this increase was significantly lower in the groups administered with roflumilast compared with the CI/RI-induced groups. Moreover, ELISA revealed that both IL-1 beta and IL-6 brain levels were significantly higher in the CI/RI-induced groups than in the controls. This increase was significantly lower in the groups administered with roflumilast compared with the CI/RI-induced groups. Histopathological studies revealed that the values closest to those of the healthy group were obtained from the roflumilast groups. Nissl staining revealed that the Nissl bodies manifested normal density in the healthy and roflumilast-administered healthy groups, but were rare in the CI/RI-induced groups. Roflumilast treatment increased these decreased Nissl bodies with increasing doses. Observations indicated that the Nissl body density was close to the value in the healthy group in the CI/RI-induced group administered with 1 mg/kg roflumilast. Overall, roflumilast reduced cellular damage caused by CI/RI in juvenile rats, and this effect may be mediated by NLRP3.