Immunophilins mediate the neuroprotective effects of FK506 in focal cerebral ischaemia

Sharkey, John; Butcher, Steven P.

doi:10.1038/371336a0

Cited by 440 publications

(222 citation statements)

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“…The immunosuppressive actions of FK506 and CsA involve the inactivation of NFAT (nuclear factor of activated T cells) via the inhibition of calcineurin. FK506 was first shown by Sharkey and Butcher (1994) to be a powerful neuroprotective agent in an in vivo model of focal cerebral ischemia when administered up to 60 minutes after occlusion. The minimum effective neuroprotective doses of FK506 and CsA are comparable with the immunosuppressant doses in humans, however, suggesting that a broad immunosuppressive effect predisposing to infection may complicate the clinical use of these drugs as a treatment for stroke (Bochelen et al, 1999;Brecht et al, 2003Brecht et al, , 2009Li et al, 2006;Sharkey et al, 1996;Uchino et al, 1998;Vachon et al, 2002;Yoshimoto and Siesjo, 1999).…”

Section: Fk506 and Cyclosporin Amentioning

confidence: 99%

Importance of T Lymphocytes in Brain Injury, Immunodeficiency, and Recovery after Cerebral Ischemia

Brait

Arumugam

Drummond

et al. 2012

J Cereb Blood Flow Metab

185

129

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Following an ischemic stroke, T lymphocytes become activated, infiltrate the brain, and appear to release cytokines and reactive oxygen species to contribute to early inflammation and brain injury. However, some subsets of T lymphocytes may be beneficial even in the early stages after a stroke, and recent evidence suggests that T lymphocytes can also contribute to the repair and regeneration of the brain at later stages. In the hours to days after stroke, T-lymphocyte numbers are then reduced in the blood and in secondary lymphoid organs as part of a 'stroke-induced immunodeficiency syndrome,' which is mediated by hyperactivity of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, resulting in increased risk of infectious complications. Whether or not poststroke T-lymphocyte activation occurs via an antigenindependent process, as opposed to a classical antigen-dependent process, is still controversial. Although considerable recent progress has been made, a better understanding of the roles of the different T-lymphocyte subpopulations and their temporal profile of damage versus repair will help to clarify whether T-lymphocyte targeting may be a viable poststroke therapy for clinical use.

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Section: Fk506 and Cyclosporin Amentioning

confidence: 99%

Importance of T Lymphocytes in Brain Injury, Immunodeficiency, and Recovery after Cerebral Ischemia

Brait

Arumugam

Drummond

et al. 2012

J Cereb Blood Flow Metab

185

129

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“…Over the past decade, there has been growing interest to understand the role of immunophilin, or neuroimmunophilins, in the nervous system (13,14). FKBP12 and FKBP52 are up-regulated in regenerating neurons suggesting they may play a protective or regenerative role following injury (15).…”

Section: Fkbp52mentioning

confidence: 99%

“…FKBP52 has been implicated in the cardiotrophic effect of cardiotrophin-1 (10) and in regulating the efficiency of adenoassociated virus type 2-mediated transgene expression (11). The Drosophila homolog of FKBP52, dFKBP59, regulates calcium channel activity in photoreceptor cells (12).Over the past decade, there has been growing interest to understand the role of immunophilin, or neuroimmunophilins, in the nervous system (13,14). FKBP12 and FKBP52 are up-regulated in regenerating neurons suggesting they may play a protective or regenerative role following injury (15).…”

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confidence: 99%

A Novel Role for the Immunophilin FKBP52 in Copper Transport

Sanokawa-Akakura

Dai

Akakura

et al. 2004

Journal of Biological Chemistry

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FK506-binding protein 52 (FKBP52) is an immunophilin that possesses peptidylprolyl cis/trans-isomerase(PPIase) activity and is a component of a subclass of steroid hormone receptor complexes. Several recent studies indicate that immunophilins can regulate neuronal survival and nerve regeneration although the molecular mechanisms are poorly understood. To investigate the function of FKBP52 in the nervous system, we employed a yeast two-hybrid strategy using the PPIase domain (domain I) as bait to screen a neonatal rat dorsal root ganglia cDNA expression library. We identified an interaction between FKBP52 domain I and Atox1, a copper-binding metallochaperone. Atox1 interacts with Menkes disease protein and Wilson disease protein (WD) and functions in copper efflux. The interaction between FKBP52 and Atox1 was observed in both glutathione S-transferase pull-down experiments and when proteins were ectopically expressed in human embryonic kidney (HEK) 293T cells and was sensitive to FK506. Interestingly, the FKBP52/Atox1 interaction was enhanced when HEK 293T cells were cultured in copper-supplemented medium and decreased in the presence of the copper chelator, bathocuproine disulfate, suggesting that the interaction is regulated in part by intracellular copper. Overexpression of FKBP52 increased rapid copper efflux in 64 Cu-loaded cells, as did the overexpression of WD transporter. Taken together, our present findings suggest that FKBP52 is a component of the copper efflux machinery, and in so, may also promote neuroprotection from copper toxicity. FKBP521 is a high molecular weight FK506-binding immunophilin first identified as a component of steroid hormone receptor heterocomplexes (1). Analysis of mRNA and protein levels has demonstrated that FKBP52 is widely expressed in mammalian tissues but particularly abundant in the nervous system (2, 3). Structurally, FKBP52 contains an N-terminal peptidylprolyl cis-trans-isomerase (PPIase) domain (domain I), a FKBP-like pseudo domain (domain II), three tetratricopeptide repeat (TPR) domains (domain III) that mediate proteinprotein interactions with HSP90, and a C-terminal domain calmodulin-binding site (domain IV) (4, 5).FKBP52 has been shown to play important roles in a diverse number of intracellular processes, but much research has focused on its involvement in steroid hormone regulation. FKBP52 regulates the maturation of steroid hormone receptor complexes through interactions between its TPR domain and HSP90 chaperones, which act as scaffolds for receptor assembly and are thought to enhance the affinity of estrogen receptor and the glucocorticoid receptor toward their ligands (1, 6). The PPIase domain of FKBP52 facilitates translocation of the activated steroid receptors to the nucleus by binding to cytoplasmic dynein (7). FKBP52 serves as a transcriptional regulator by repressing the activity of interferon regulatory factor-4 in immune cells (8) and heat-shock factor-1 in HeLa cells (9). FKBP52 has been implicated in the cardiotrophic effect of cardiotrophin-1 (10...

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“…10 Although the cellular mechanism underlying this neuroprotective effect also remains uncertain, pharmacological data have confirmed the importance of immunophilin binding and suggested a role for calcineurin. FK506 mediates its activity through binding to an immunophilin (FKBP).…”

Section: Discussionmentioning

confidence: 99%

FK506-induced intractable leukoencephalopathy following allogeneic bone marrow transplantation

Misawa

Takeuchi

Hibi

et al. 2000

Bone Marrow Transplant

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Summary:FK506-related leukoencephalopathy has been reported to be reversible and readily treated by discontinuation or reduction of FK506. We describe two pediatric cases of FK506-related leukoencephalopathy following allogeneic bone marrow transplantation, which could not be readily controlled. These cases show that FK506-related leukoencephalopathy is not always reversible, and patients may develop epilepsy. Bone Marrow Transplantation (2000) 25, 331-334. Keywords: FK506; leukoencephalopathy; bone marrow transplantation FK506 (tacrolimus) is an immunosuppressive drug, and more potent than cyclosporine (CsA). However, the clinical usefulness of FK506 is limited by its severe adverse effects including neurotoxicity. FK506-related leukoencephalopathy has been reported to be reversible and readily treated by discontinuation or reduction of FK506. [1][2][3][4][5][6][7] The signs and symptoms are usually resolved within 1 to 2 weeks with discontinuation of the drug or even reduction of its dose. We describe two pediatric cases of FK506-related leukoencephalopathy following allogeneic bone marrow transplantation, which could not readily be controlled. Case reports Case 1A 15-year-old girl was diagnosed as having chronic myelogenous leukemia in August 1993. She underwent allogeneic bone marrow transplantation (BMT) in March 1996, with marrow from an unrelated HLA-matched donor, following conditioning with cyclophosphamide and total body irradiation. Prophylaxis for graft-versus-host disease (GVHD) consisted of CsA and short-term methotrexate Correspondence: Dr A Misawa, Department of Pediatrics, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan Received 4 June 1999; accepted 14 October 1999 (MTX). On day 19, she developed acute GVHD grade II. FK506 was substituted for CsA, because GVHD was uncontrollable in spite of high-dose methylprednisolone (mPSL). GVHD symptoms were resolved in a few days and FK506 was discontinued on day 114. However, FK506 and mPSL were readministered because of recurrent GVHD. She recovered gradually and FK506 was tapered off in January 1997. Five months after FK506 discontinuation, she developed chronic GVHD. FK506 and prednisolone were readministered.In October 1997, she complained of severe headache, and developed generalized tonic-clonic convulsions, confusion, and left hemiparesis 3 months after FK506 readministration ( Figure 1a). She was afebrile. Her blood pressure was 142/90 mmHg. The pupillary reflexes and fundi were unremarkable. Platelets had decreased to 73 × 10 9 /l and the hemoglobin level was 14.0 g/dl. No red blood cell fragmentation was observed in a peripheral smear. The reticulocyte level was not increased (2.6%). She exhibited normal renal function. The serum concentrations of lactate dehydrogenase and bilirubin had increased to 744 IU/l (upper normal, 243 IU/l) and 1.92 mg/dl. The level of von Willebrand factor (vWF) was high (336%, NR 50-150%). The whole blood FK506 level was 5.6 ng/ml. The cerebrospinal fluid (CSF) conta...

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Immunophilins mediate the neuroprotective effects of FK506 in focal cerebral ischaemia

Cited by 440 publications

References 26 publications

Importance of T Lymphocytes in Brain Injury, Immunodeficiency, and Recovery after Cerebral Ischemia

Importance of T Lymphocytes in Brain Injury, Immunodeficiency, and Recovery after Cerebral Ischemia

A Novel Role for the Immunophilin FKBP52 in Copper Transport

FK506-induced intractable leukoencephalopathy following allogeneic bone marrow transplantation

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