Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tacrolimus is a potent immunosuppressive agent and has been used in liver transplantation (LTx) for nearly a decade. More than 70% of children can be maintained on tacrolimus monotherapy, without steroids, by the end of 1 yr post-Tx. This freedom from steroids does not appear to change significantly in subsequent years. The use of steroids has obvious metabolic and cosmetic disadvantages, besides affecting linear growth in children. The present study identifies why some children still require steroid therapy after successful LTx. One hundred and sixty-six consecutive pediatric patients who had undergone primary LTx between October 1989 and December 1992, were included in this study. Follow-up ranged from 6 to 9 yr (mean 7.5 +/- 0.8 yr). One hundred and forty-one children were alive in November 1998 and these patients constituted the study group. Their current rate of prednisone use, reason for prednisone use, and prednisone dose were examined retrospectively. Of the 141 patients, 139 (98.5%) had stopped taking steroids at some time-point after LTx. Thirteen patients (9%) were off immunosuppression altogether (group I), 97 were undergoing tacrolimus monotherapy (group II), and the remaining 31 were receiving therapy with steroids and tacrolimus (group III). The mean prednisone dose at the last follow-up was 6.5 +/- 4.9 mg/day (median 5.0 mg/day). In group III, two children were never weaned off steroids because of inadequate follow-up (both lived outside the country), and the remaining 29 children completely stopped steroid therapy at some time-point after LTx; however, prednisone was re-introduced for clinically suspected or biopsy-proven rejection in 24. Seven children in group III had completely stopped immunosuppressive therapy either as part of an immunosuppression reduction protocol (n = 3) or for suspected or proven post-transplant lymphoproliferative disorder (PTLD) (n = 4). In eleven of the 18 children in group III, requirement of steroid for rejection was thought to be related, in part, to non-compliance. In three children in group III, steroids were re-introduced for renal dysfunction, and two of these patients subsequently received a kidney Tx. In one child with cerebral ischemia, steroids were used to reduce brain edema, and another child had features of auto-immune hepatitis. Hence, almost all children can be weaned off steroids when tacrolimus is used as primary immunosuppression after primary LTx. However, approximately 22% of children may need re-institution of steroids because of late acute rejection or renal dysfunction. The concomitant use of other non-steroidal immunosuppressive agents with tacrolimus may further reduce the dose and rate of steroid use.
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PMID:Reasons why some children receiving tacrolimus therapy require steroids more than 5 years post liver transplantation. 1132 46

Tacrolimus (FK506), a potent immunosuppressive drug, is effective in attenuating brain infarction after cerebral ischemia. However, there has been no report characterizing the neuroprotective action and therapeutic time window of tacrolimus systematically using different types of stroke models and extended observation periods. Therefore, we evaluated the neuroprotective effect of tacrolimus in three different animal models of cerebral ischemia: transient and permanent focal ischemia in rats and transient global ischemia in gerbils. Tacrolimus at doses higher than 0.1 mg/kg (i.v.) produced a statistically significant reduction in ischemic brain damage following permanent and transient focal ischemia in rats when administered immediately after the onset of ischemia. Tacrolimus (1 mg/kg, i.v.) demonstrated similar neuroprotective activity even after delayed administration (2 h after permanent or 1 h after transient focal ischemia). The neuroprotective effect of tacrolimus was still present 2 weeks after transient focal ischemia and 1 week after permanent focal ischemia. After transient global ischemia in gerbils, tacrolimus (1 mg/kg, i.v.) given immediately after reperfusion also produced long-lasting neuroprotective effects with a protective time-window of 1-2 h. Taken together, the results clearly indicate that tacrolimus exerts potent, long-term neuroprotective effects with a favorable therapeutic time-window, regardless of the model of cerebral ischemia. These results strengthen the notion that tacrolimus might be of clinical value for the treatment of acute stroke.
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PMID:Neuroprotective action of tacrolimus (FK506) in focal and global cerebral ischemia in rodents: dose dependency, therapeutic time window and long-term efficacy. 1259 Nov 30

While the immunosuppressant tacrolimus (FK506) is known to be neuroprotective following cerebral ischemia, the mechanisms underlying its neuroprotective properties are not fully understood. To determine the mode of action by which tacrolimus ameliorates neurodegeneration after transient focal ischemia, we therefore evaluated the effect of tacrolimus on DNA damage, release of cytochrome c, activation of microglia and infiltration of neutrophils following a 60-min occlusion of the middle cerebral artery (MCA) in rats. In this model, cortical brain damage gradually expanded until 24 h after reperfusion, whereas brain damage in the caudate putamen was fully developed within 5 h. Tacrolimus (1 mg/kg) administered immediately after MCA occlusion significantly reduced ischemic damage in the cerebral cortex, but not in the caudate putamen. Tacrolimus decreased both apoptotic and necrotic cell death at 24 h and reduced the number of cytochrome c immunoreactive cells at 8 h after reperfusion in the ischemic penumbra in the cerebral cortex. In contrast, tacrolimus did not show significant neuroprotection for necrotic cell death and reduction of cytochrome c immunoreactive cells in the caudate putamen. Tacrolimus also significantly decreased microglial activation at 8 h and inflammatory markers (cytokine-induced neutrophil chemoattractant and myeloperoxidase [MPO] activity) at 24 h after reperfusion in the ischemic cortex but not in the caudate putamen. These results collectively suggest that tacrolimus ameliorates the gradually expanded brain damage by inhibiting both apoptotic and necrotic cell death, as well as suppressing inflammatory reactions.
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PMID:Multiple modes of action of tacrolimus (FK506) for neuroprotective action on ischemic damage after transient focal cerebral ischemia in rats. 1521 98

We investigated the neuroprotective effect of tacrolimus (FK506) on the ischemic cell death with respect to cytochrome c translocation and DNA fragmentation, which are pivotal events in the necrotic and apoptotic signaling pathway, using permanent focal cerebral ischemia in rats. Immunohistochemically, cytochrome c was observed in the cytoplasm as early as 1 h after middle cerebral artery (MCA) occlusion in the infarcted hemisphere. Cytosolic release of cytochrome c after MCA occlusion was also confirmed by Western blot analysis and enzyme immunoassay. Terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL) showed DNA fragmentation evolving in the ipsilateral cortex and the caudate putamen after 3 and 6 h, respectively, following MCA occlusion. Tacrolimus (1 mg/kg, i.v.), administered immediately after MCA occlusion, significantly attenuated the release of cytochrome c in the ischemic region, the number of TUNEL-positive cells in the ischemic penumbra zone, and the size of cortical ischemic lesions. This study demonstrated that tacrolimus ameliorated the accumulation of cytochrome c in the cytosol and the increase of TUNEL-positive cells induced by cerebral ischemia, indicating that the neuroprotective action of tacrolimus on ischemic brain injury caused by permanent focal cerebral ischemia could partially be attributed to the attenuation of the activation of the apoptotic execution machinery.
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PMID:Neuroprotective effect of tacrolimus (FK506) on ischemic brain damage following permanent focal cerebral ischemia in the rat. 1533 15

Tacrolimus (FK506) has a neuroprotective action on cerebral infarction produced by cerebral ischemia, however, detailed mechanisms underlying this action have not been fully elucidated. We examined temporal profiles of survival-and death-related signals, Bad phosphorylation, release of cytochrome c (cyt.c), activation of caspase 3 and DNA fragmentation in the brain during and after middle cerebral artery occlusion (MCAo) in mice, and then examined the effect of tacrolimus on these signals. C57BL/6J mice were subjected to transient MCAo by intraluminal suture insertion for 60 min. Tacrolimus (1 mg/kg, i.p.) was administered immediately after MCAo. There were biphasic increases in the release of cyt.c in the ischemic core and penumbra; with the first increase toward the end of the occlusion period and the second increase 3-12 h after reperfusion. Tacrolimus significantly inhibited the increase of cytosolic cyt.c during ischemia and reperfusion. Phosphorylated Bad, Ser-136 (P-Bad(136)) and Ser-155 (P-Bad(155)) were detected 30 min after MCAo and after reperfusion in the ischemic cortex, respectively. Tacrolimus increased P-Bad(136) during ischemia and prolonged P-Bad(155) expression after reperfusion. Tacrolimus also decreased caspase-3 and terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling-positive cells, and reduced the size of infarct 24 h after reperfusion. Our study provided the first evidence that the neuroprotective action of tacrolimus involved inhibition of biphasic cyt.c release from mitochondria, possibly via up-regulation of Bad phosphorylation at different sites after focal cerebral ischemia and reperfusion.
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PMID:Tacrolimus (FK506) attenuates biphasic cytochrome c release and Bad phosphorylation following transient cerebral ischemia in mice. 1693 31

The aim of this study was to evaluate the effect of tacrolimus on recombinant tissue-plasminogen activator (rt-PA)-induced hemorrhagic transformation, and to characterize its suppressive action for hemorrhage. Thrombotic occlusion of the middle cerebral artery (MCA) was induced by photochemical reaction in spontaneously hypertensive rats, and hemorrhagic scores and brain damage were measured 24 h after MCA occlusion. Administration of rt-PA 3 h after MCA occlusion significantly worsened spontaneous hemorrhagic changes and tended to aggravate brain damage. Hematoma was observed in 7 of 15 rats treated with rt-PA, and 0 of 15 rats in the control group. Tacrolimus alone administered intravenously 3 h after MCA occlusion did not produce any hemorrhagic changes. The combined treatment of tacrolimus followed by rt-PA significantly decreased the incidence of hematoma and brain damage in comparison with that of the rt-PA treated group. Permeability of the blood-brain-barrier (BBB) detected by extravasations of Evans blue was investigated 6 h after MCA occlusion, as was the integrity of microvascular endothelial cells as determined by immunohistochemical assessment of the prevalence of platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31). Combined treatment of rt-PA with tacrolimus reduced the rt-PA-induced extravasation of Evans blue and preserved CD31-positive cells in the ischemic hemisphere. Thus, tacrolimus was able to reduce the rt-PA-induced hemorrhagic transformation, which might be due to the protective effects on cerebral microvascular endothelial cells after thrombotic cerebral ischemia during the acute phase of cerebral ischemia. In conclusion, the combination of rt-PA with tacrolimus may be useful for decreasing the risk of thrombolytic therapy.
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PMID:Tacrolimus (FK506) suppresses rt-PA-induced hemorrhagic transformation in a rat thrombotic ischemia stroke model. 1910 26

FK506 (Tacrolimus) has the potential to decrease cerebral ischemia-reperfusion injury. However, the clinical trial of FK506 as a neuroprotectant failed due to adverse side effects. This present study aimed to conduct the selective delivery of FK506 to damaged regions, while at the same time reducing the dosage of FK506, by using a liposomal drug delivery system. First, the cytoprotective effect of polyethylene glycol-modified liposomes encapsulating FK506 (FK506-liposomes) on neuron-like pheochromocytoma PC12 cells was examined. FK506-liposomes protected these cells from H2O2-induced toxicity in a dose-dependent manner. Next, we investigated the usefulness of FK506-liposomes in transient middle cerebral artery occlusion (t-MCAO) rats. FK506-liposomes accumulated in the brain parenchyma by passing through the disrupted blood-brain barrier at an early stage after reperfusion had been initiated. Histological analysis showed that FK506-liposomes strongly suppressed neutrophil invasion and apoptotic cell death, events that lead to a poor stroke outcome. Corresponding to these results, a single injection of FK506-liposomes at a low dosage significantly reduced cerebral cell death and ameliorated motor function deficits in t-MCAO rats. These results suggest that liposomalization of FK506 could reduce the administration dose by enhancing the therapeutic efficacy; hence, FK506-liposomes should be a promising neuroprotectant after cerebral stroke.
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PMID:Treatment of cerebral ischemia-reperfusion injury with PEGylated liposomes encapsulating FK506. 2324 12