Protective Effect Of Tacrolimus Research Articles

Tacrolimus Up-regulates Expression of TGFβ Receptor Type II via ERK, Providing Protection Against Intestinal Epithelial Injury.

Transforming growth factor β (TGFβ) signaling plays a key role in modulating intestinal epithelial cell (IEC) homeostasis. The present study aimed to investigate the direct effect of tacrolimus on TGFβ signaling in IECs. The protective effects of tacrolimus, with or without anti-TGFβ antibody, in dextran sulfate sodium (DSS)-induced colitis were evaluated. Tacrolimus ameliorated IEC apoptosis-mediated mucosal destruction despite anti-TGFβ treatment. TGFβ receptor type II (TGFβ-RII), phosphor-SMAD family members 2/3, and phosphor-extracellular signal-regulated kinase (ERK) expression in IECs was enhanced in tacrolimus-treated mice, and these positive effects were maintained despite anti-TGFβ treatment. Moreover, tacrolimus induced TGFβ-RII up-regulation through ERK activation. Our data indicate that tacrolimus directly activated TGFβ-SMAD signaling via the ERK pathway in IECs, thereby providing protection against apoptosis-mediated intestinal epithelial injury.

P-299 Protective Effect of Tacrolimus on DSS-induced Colitis via Direct Activation of TGF-β–Smad Signaling Pathway in Intestinal Epitherial Cells

P-299 Protective Effect of Tacrolimus on DSS-induced Colitis via Direct Activation of TGF-β–Smad Signaling Pathway in Intestinal Epitherial Cells

The protective effects of tacrolimus on rat uteri exposed to ischemia-reperfusion injury: a biochemical and histopathologic evaluation

To evaluate the effects of the immunosuppressant tacrolimus as an antioxidant and analyze the histopathologic changes in rat uteri exposed to experimental ischemia-reperfusion (I/R) injury. Experimental study. Experimental surgery laboratory in a university. Twenty-eight female rats exposed to experimentally induced uterine I/R injury. Group I: control group; group II: uterine I/R injury-induced group; group III: pre-ischemia tacrolimus group; group IV: post-ischemia tacrolimus group. Uterine tissue malondialdehyde (MDA) level as a marker of lipid peroxidation and glutathione (GSH) level and superoxide dismutase (SOD) and catalase (CAT) activities as markers of tissue antioxidant capacity; histopathologic examination of all uterine rat tissue. Following aortic I/R injury, MDA levels were significantly increased whereas GSH levels and CAT and SOD activities were found to be decreased compared with control animals. MDA levels were found to recover prominently after the administration of tacrolimus in both groups III and IV. Administration of tacrolimus improved uterine GSH levels and CAT activity in the tacrolimus-treated groups. Our results indicate that tacrolimus reduces oxidative damage in rat uteri exposed to I/R injury induced by distal abdominal aortic occlusion. Histologic evaluation reveals that tacrolimus attenuates the inflammatory response and protects the tissue damage induced by I/R injury.

Protective effect of tacrolimus postconditioning on oxidative stress injury provoked by spinal cord ischemia-reperfusion in rats

To investigate whether protective effect of tacrolimus postconditioning on rats' spinal cord ischemia-reperfusion injury is mediated by up-regulation of activity of endogenous antioxidant enzymes and down-regulation of production of oxygen free radicals. Ninety male Sprague-Dawley rats were randomly divided into ischemia-reperfusion (IR) group, tacrolimus postconditioning (TP) group and sham operation (SO) group. The model of spinal cord ischemia was prepared by means of catheterization through femoral artery and balloon dilatation. IR group underwent reperfusion 20 min after spinal cord ischemia. TP group experienced a single injection of tacrolimus (0.5 mg/kg) through the left common carotid artery at the onset of reperfusion. SO group received femoral artery catheterization only. Fluoro spectro photometry was employed to detect the level of reactive oxygen species (ROS) in injured spinal cord segment at 15 minutes after reperfusion. The content of malondialdehyde (MDA) and activity of antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-PX) were determined at 15 minutes, 1, 6, and 24 hours after reperfusion respectively. BBB scale was conducted to evaluate hindlimb motor function at 14 days after reperfusion. The level of ROS in TP group was significantly lower than that in IR group at 15 minutes after reperfusion. The activity of SOD was significantly higher in TP group than in IR group at all observational time points, while the activities of CAT and GSH-PX were significantly higher in TP group than in IR group at 1 and 6 hours after reperfusion. The content of MDA in TP group was significantly less than that in IR group at all observational time points. The motor function score of TP group was significantly superior to that of IR group at 14 days after reperfusion. Tacrolimus post conditioning can improve activity of endogenous antioxidant enzymes, decrease production of oxygen free radicals, suppress lipid peroxidation, and thereby promote functional recovery after spinal cord ischemia-reperfusion injury in rats.

Protective effects of Tacrolimus, a calcineurin inhibitor, in experimental periodontitis in rats

Objective Periodontitis is a well-appreciated example of leukocyte-mediated bone loss and inflammation with pathogenic features similar to those observed in other inflammatory diseases, such as arthritis. Since Tacrolimus, is an immunomodulatory drug used for the treatment of some cases of arthritis, we hypothesized that it may modulate periodontal disease. Design Using a murine model of ligature-induced periodontal disease, we assessed the effects of daily administrations of Tacrolimus (1 mg/kg body weight) on bone loss, enzymatic (myeloperoxidase) analysis, differential white blood cells counts, airpouch exudate and cytokine expression for 5–30 days. Results Radiographic, enzymatic (myeloperoxidase) and histological analysis revealed that Tacrolimus reduced the severity of periodontitis. More specifically, Tacrolimus suppressed the expression of serum interleukin (IL-1β), tumour necrosis factor (TNF-α), IL-6, airpouch exudate PGE 2 and leukocytosis usually observed after the induction of periodontitis. Tacrolimus treatment in periodontitis-induced rats conferred protection against the inflammation-induced tissue and bone loss associated with periodontitis, through a mechanism involving IL-1β, TNF-α and IL-6. Conclusions The effects of Tacrolimus on periodontal disease pathogenesis may provide clues to a novel approach to host modulation therapy in destructive periodontal disease.

Warm ischemia-reperfusion injury is decreased by tacrolimus in steatotic rat liver

Ischemia-reperfusion (I-R) injury is poorly tolerated by fatty livers, most probably secondary to reduced cellular adenosine triphosphate (ATP) levels. We investigated the effectiveness of tacrolimus pretreatment on fatty liver I-R injury in obese Zucker rats. Tacrolimus (0.3 mg/kg, intravenously) was injected 24 hours before a 75-minute ischemic period and rats were sacrificed 6 hours later. Tacrolimus modified the response to I-R observed in obese Zucker rats, when compared to nontreated obese rats: a significant reduction in hepatocyte necrosis was associated with a significant increase in hepatocyte apoptosis. In addition, cell necrosis and apoptosis were significantly and inversely correlated in lean nontreated and treated obese Zucker rats following I-R. Tacrolimus also significantly increased the hepatic ATP levels, reduced in nontreated obese rats, toward values found in lean Zucker rat livers. This protective effect of tacrolimus was further confirmed in vivo by a significantly improved survival following pretreatment with tacrolimus, 24 hours prior to ischemia. In conclusion, in obese Zucker rat livers, tacrolimus pretreatment reversed the I-R injury toward the one found in lean Zucker rats. The correlations between ATP levels and the opposite changes in necrosis and apoptotic pathways strongly suggest a cause-effect relationship between tacrolimus and changes in ATP levels.

Calcineurin Inhibitors as Neuroprotectants

Tacrolimus (FK506) and cyclosporin (cyclosporin-A) are potent immunosuppressants which are presently in clinical use for the treatment of allograft rejection. Recent studies suggest that tacrolimus and cyclosporin may also be of therapeutic benefit for the treatment of neurodegenerative disorders, in particular those associated with acute brain ischaemia. At immunosuppressive doses, tacrolimus is a powerful neuroprotectant in many experimental models of cerebral ischaemia: reducing infarct volume and improving neurological outcome. In rat focal ischaemia models neuroprotection can be elicited by a single injection of tacrolimus given up to 72 hours before or up to 2 hours after the insult. A similar postocclusion window of efficacy has been reported in the gerbil forebrain ischaemia model. These neuroprotective properties are also shared by cyclosporin, although the poor penetration of cyclosporin across the blood-brain barrier necessitates the use of high doses (20 mg/kg) of this drug to achieve neuroprotection. The observation that sirolimus (rapamycin) is not neuroprotective in models of focal cerebral ischaemia, but can effectively inhibit the neuroprotective effects of tacrolimus, supports the view that the protective effects of tacrolimus are mediated via the inhibition of calcineurin.