Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Decreased cerebral blood flow, hence decreased oxygen and glucose, leads to ischemic brain injury via complex pathophysiological events, including excitotoxicity, mitochondrial dysfunction, increased intracellular Ca2+, and reactive oxygen species (ROS) generation. Each of these could also contribute to cerebral edema, which is the primary cause of patient mortality after stroke. In vitro brain slices are widely used to study ischemia. Here we introduce a slice model to investigate ischemia-induced edema. Significant water gain was induced in coronal slices of rat brain by 5 min of oxygen and glucose deprivation (OGD) at 35 degrees C, with progressive edema formation after return to normoxic, normoglycemic medium. Edema increased with increasing injury severity, determined by OGD duration (5-30 min). Underlying factors were assessed using glutamate-receptor antagonists (AP5/CNQX), blockade of mitochondrial permeability transition [cyclosporin A (CsA) versus FK506], inhibition of Na+/Ca2+ exchange (KB-R7943), and ROS scavengers (ascorbate, Trolox, dimethylthiourea, Tempol). All agents except KB-R7943 and FK506 significantly attenuated edema when applied after OGD; KB-R7943 was effective when applied before OGD. Significantly, complete prevention of ischemia-induced edema was achieved with a cocktail of AP5/CNQX, CsA and Tempo applied after OGD, which demonstrates the involvement of multiple, additive mechanisms. The efficacy of this cocktail further shows the potential value of combination therapies for the treatment of cerebral ischemia.
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PMID:Brain edema induced by in vitro ischemia: causal factors and neuroprotection. 1278 60

FK506, a calcineurin inhibitor, shows potent neuroprotective effects in animal models such as those of stroke and neurodegenerative diseases. However, the mechanism underlying these neuroprotective effects is unclear. In this study, an in vitro model, in which FK506 protected the cells against cell death, was established and analyzed in detail by pharmacological experiments. Thapsigargin (TG), an inhibitor of endoplasmic reticulum calcium-ATPase, induced SH-SY5Y cell death. FK506 concentration-dependently protected the cells from this type of death. In contrast, FK506 did not suppress SH-SY5Y cell death caused by the following molecules: tunicamycin (TM), an inhibitor of N-linked glycosylation; etoposide (Eto), a topoisomerase II inhibitor; and staurosporine (STS), a phospholipid/calcium-dependent protein kinase inhibitor. Additionally, FK506 did not inhibit TG-induced cell death in either SK-N-MC or HeLa cell lines. FK506 completely inhibited caspase-3 activation and apoptosis caused by TG in a concentration-dependent manner, but not that caused by TM, Eto, and STS. TG did not activate caspase-3 in SK-N-MC cells, although it slightly activated caspase-3 in HeLa cells. FK506 did not change caspase-3 activity in either SK-N-MC or HeLa cell lines. Cyclosporin A, another calcineurin inhibitor, showed the same results as FK506 in this study, whereas rapamycin, an immunosuppressant not associated with calcineurin activity, did not have any effect in this context. Thus, the suppressive effects of FK506 on cell death are specific to SH-SY5Y cells treated with TG and are caused by the inhibition of calcineurin and subsequent suppression of caspase-3 activation. Therefore, an in vitro system using SH-SY5Y cells treated with TG could provide a model reflective of certain aspects of the neuroprotective activity of FK506.
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PMID:Detailed in vitro pharmacological analysis of FK506-induced neuroprotection. 1287 56

Tacrolimus (FK506), an immunosuppressive drug, is known to have potent neuroprotective activity and attenuate cerebral infarction in experimental models of stroke. Here we assess the neuroprotective efficacy of tacrolimus in a nonhuman primate model of stroke, photochemically induced thrombotic occlusion of the middle cerebral artery (MCA) in cynomolgus monkeys. In the first experiment, tacrolimus (0.01, 0.032, or 0.1 mg/kg) was intravenously administered immediately after MCA occlusion, and neurologic deficits and cerebral infarction volumes were assessed 24 hours after the ischemic insult. Tacrolimus dose-dependently reduced neurologic deficits and infarction volume in the cerebral cortex, with statistically significant amelioration of neurologic deficits at 0.032 and 0.1 mg/kg and significant reduction of infarction at 0.1 mg/kg. In the second experiment, the long-term efficacy of tacrolimus on neurologic deficits and cerebral infarction was assessed. Vehicle-treated monkeys exhibited persistent and severe deficits in motor and sensory function for up to 28 days. A single intravenous bolus injection of tacrolimus (0.1 or 0.2 mg/kg) produced long-lasting amelioration of neurologic deficits and significant reduction of infarction volume. In conclusion, we have provided compelling evidence that a single dose of tacrolimus not only reduces brain infarction but also ameliorates long-term neurologic deficits in a nonhuman primate model of stroke, strengthening the view that tacrolimus might be beneficial in treating stroke patients.
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PMID:Tacrolimus, a potential neuroprotective agent, ameliorates ischemic brain damage and neurologic deficits after focal cerebral ischemia in nonhuman primates. 1452 29

FK506 (tacrolimus), an immunosuppressant, reportedly reduces ischemic brain injury following transient middle cerebral artery occlusion (MCAO) in rats. The authors previously reported that the therapeutic window of FK506 in this model is more than 1 h, but less than 2 h. The aim of the present study is to determine whether mild hypothermia (35 degrees C) enhances the neuroprotective effects of FK506 and expands its therapeutic window. Sprague-Dawley rats were subjected to 2 h MCAO followed by 24 h reperfusion. Animals were randomly divided into four groups: (I) vehicle-treated normothermic group; (II) FK506-treated normothermic group; (III) vehicle-treated hypothermic group; (IV) FK506-treated hypothermic group. Animals received a single injection of FK506 (0.3 mg/kg) or vehicle intravenously at 2 h after ischemic induction. During ischemia, temporal muscle and rectal temperatures were maintained at 37 degrees C in the normothermic animals and at 35 degrees C in the hypothermic animals. Infarct volumes and neurological performance were evaluated at 24 h after reperfusion. The combination of FK506 and mild hypothermia significantly reduced infarct volume (cortex, -61%; striatum, -31%) and edema volume (cortex, -57%; striatum, -41%), while mild hypothermia or FK506 alone failed to improve ischemic brain damage. Furthermore, this combination also provided for the best functional outcome. These results demonstrate that the combination of FK506 and mild hypothermia significantly reduces ischemic brain damage following transient MCAO in rats, and expands the therapeutic window for FK506. This therapy may be a new approach for treatment of acute stroke.
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PMID:Mild hypothermia enhances the neuroprotective effects of FK506 and expands its therapeutic window following transient focal ischemia in rats. 1514 54

Recent advances in MRI technology and the development of effective neuroprotective agents has improved the outcome of stroke. In order to salvage tissue after an ischemic insult it is important to differentiate the core and penumbra area of the ischemic lesion. The penumbra surrounds the ischemic core, damage in this area is reversible if effective neuroprotective agents are given and reperfusion occurs. In this symposium detection of penumbra in an ischemic lesion using diffusion weighted imaging (DWI) and perfusion imaging (PI), diffusion-perfusion mismatch, and indications for thrombolytic therapy are discussed. If a hypoperfusion area is revealed with PI without a corresponding lesion indicated with DWI or when the DWI lesion is less than one third of the PI lesion, combined thrombolytic and neuroprotective therapies are recommended. In contrast, when both PI and DWI show an identical lesion, only neuroprotective therapy is advised. Additionally, newly developed neuroprotective agents, especially the combined effect of rt-PA and the immunosuppressant, FK506, on an embolic infarct model are discussed.
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PMID:[Advances in the diagnosis and treatment of cerebral ischemia during the acute phase]. 1515 94

Neuroimmunophilin ligands (NILs) are drugs derived from the immunosuppressant FK506 (tacrolimus) that have been shown to have variable efficacy in reversing neuronal degeneration and preventing cell death. In a wide range of animal models mimicking Parkinson's disease, dementia and even surgical nerve damage they induce re-sprouting, are neurotrophic or prevent nerve damage. The neurotrophic mechanism of action of these compounds is not known and may be dependent on the type of damage and genetic variability at the species or cellular level. Some evidence suggests that NILs may act through a family of proteins called FK506 binding proteins, some of which may regulate steroid hormone receptors. Other evidence suggests that NILs may protect neurons by upregulating the antioxidant glutathione and stimulating nerve regrowth by inducing the production of neurotrophic factors. Initial clinical trials have had mixed success. In one, patients with moderately severe Parkinson's disease showed no overall improvement in fine motor skills following 6 months of treatment by the neuroimmunophilin GPI 1485. But these patients did exhibit decreased loss of dopaminergic nerve terminals with a low dose of GPI 1485 and in fact some increase in dopaminergic terminals within 6 months of the higher dose of GPI 1485 drug treatment. As a result, a second phase II clinical trial using a patient population with less severe degeneration has been initiated concurrent with an investigation of GPI 1485 and other neuroprotective therapies funded by the National Institute of Neurological Disorders and Stroke. Another clinical trial ongoing at this time is exploring the use of a neuroimmunophilin ligand to prevent nerve degeneration and erectile dysfunction resulting from prostatectomy. In summary, neuroimmunophilins show promise to reverse some forms of neurodegeneration but exact factors that predict outcome have not been identified.
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PMID:Neuroimmunophilins: a novel drug therapy for the reversal of neurodegenerative disease? 1545 Mar 48

Immunophilin ligands, such as cyclosporin A and FK506, have neuroprotective effects in experimental stroke models, although the precise mechanism is unclear. Cyclophilin C-associated protein (CyCAP) is a natural cellular ligand for the immunophilin, cyclophilin C, and has a protective effect against endotoxins by downmodulating the proinflammatory response. Expressions of CyCAP and cyclophilin C mRNA in a rat middle cerebral artery (MCA) occlusion ischemia model were investigated by Northern blotting and in situ hybridization. Both CyCAP and cyclophilin C mRNAs were ubiquitously distributed in the neurons of the normal brain. Expression increased in neurons of the periinfarct zone up to 7 days after MCA occlusion. The neuronal distribution was confirmed by counterimmunostaining of NeuN. Both mRNAs were predominantly expressed in microglia of the ischemic core at 7 days, confirmed by immunostaining with the microglial marker, ED1. The quantification of CyCAP and cyclophilin C mRNAs at 7 days by Northern blot analysis showed the 8.5-fold increase (P<0.005, n=6) and 6.8-fold increase (P<0.005, n=6), respectively, in ischemic core compared with control. The coincidence of CyCAP and cyclophilin C expression in neurons and microglia suggests distinct roles in each cellular population. In particular, the early increase in penumbral neurons might be related to protection in periinfarct neurons.
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PMID:Cyclophilin C-associated protein and cyclophilin C mRNA are upregulated in penumbral neurons and microglia after focal cerebral ischemia. 1564 40

FK506 is a candidate drug for acute stroke. For such drugs, any decision to proceed to clinical trial should be based on a full and unbiased assessment of the animal data, and consideration should be given to the limitations of those data. Such an assessment should include not only the efficacy of a drug but also the in vivo characteristics and limits to that efficacy. Here we use systematic review and meta-analysis to assess the evidence for a protective effect of FK506 in animal models of stroke. In all, 29 studies were identified describing procedures involving 1759 animals. The point estimate for the effect of FK506 was a 31.3% (95% confidence interval 27.2% to 35.4%) improvement in outcome. Efficacy was higher with ketamine anaesthesia and temporary ischaemia and was lower in rats, in animals with comorbidities, and where outcome was measured as infarct size alone. Reported study quality was modest by clinical trial standards, and efficacy was lower in high-quality studies. These findings show a substantial efficacy for FK506 in experimental stroke, but raise concerns that our estimate of effect size might be too high because of factors such as study quality and possible publication bias.
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PMID:Systematic review and metaanalysis of the efficacy of FK506 in experimental stroke. 1570 98

Tacrolimus (FK506), an immunosuppressive drug, has been shown to exert a potent neuroprotective activity when administered immediately after occlusion of the middle cerebral artery (MCA) in a nonhuman primate model of stroke. Here, we assessed the neuroprotective efficacy of tacrolimus with delayed treatment using the same model and compared with that of recombinant tissue plasminogen activator (rt-PA). Ischemic insult was induced by photochemically induced thrombotic occlusion of MCA in cynomolgus monkeys, and tacrolimus (0.2 mg/kg) and/or rt-PA (1.0 mg/kg) was intravenously administered 2 h after MCA occlusion. In another experiment, tacrolimus (0.1 mg/kg) was administered 4 h after MCA occlusion. Neurological deficits were monitored for 28 days after the ischemic insult and cerebral infarct volumes were measured with brain slices. With drug administration 2 h after the ischemic insult, tacrolimus significantly reduced neurological deficits and infarct volumes in the cerebral cortex without affecting the recanalization pattern in the MCA, however, rt-PA did not significantly improve neurological deficits or infarct volumes, even though it increased the recanalization rate of the occluded MCA. Combined treatment with tacrolimus and rt-PA exerted additional protection. Administration of tacrolimus 4 h after the ischemic insult still showed significant amelioration of neurological deficits. These results suggested that tacrolimus had a wider therapeutic time window than rt-PA in the nonhuman primate stroke model.
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PMID:Therapeutic time window of tacrolimus (FK506) in a nonhuman primate stroke model: comparison with tissue plasminogen activator. 1716 59

Many practical therapies have been explored as clinical applications for ischemic cerebral infarction; however, most are still insufficient to treat acute stroke. We show here a potential combination therapy in a rat focal ischemic model to improve neurological symptoms as well as to reduce infarct volumes at the maximum level. We applied protein transduction technology using artificial anti-death Bcl-xl derivative with three amino acid-substitutions (Y22F, Q26N and R165K) (FNK) protein fused with a protein-transduction-domain peptide (PTD-FNK). When PTD-FNK was administrated 1 h after initiating ischemia followed by the administration of an immunosuppressant FK506 with a 30-min time lag, infarct volumes of the total brain and cortex were markedly reduced to 27% and 14%, respectively. This procedure not only reduced the infarct volume and edema, but also markedly improved neurological symptoms. The therapeutic effect continued for at least 1 week after ischemia. FK506 inhibited the transduction of PTD-FNK in vitro, which explains the requirement of a time lag for the administration of FK506. An additional in vitro experiment showed that PTD-FNK, when administered 30 min before FK506, gave the maximal protective effect by reducing the intracellular calcium concentration. We propose that this combination therapy would provide a synergistic protective effect by both drugs, reducing adverse the effects of FK506.
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PMID:Combination therapy with transductive anti-death FNK protein and FK506 ameliorates brain damage with focal transient ischemia in rat. 1836 25


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