FK506 and Cyclosporin A Enhance the Survival of Cultured and Grafted Rat Embryonic Dopamine Neurons

Castilho, Roger F.; Hansson, Oskar; Brundin, Patrik

doi:10.1006/exnr.2000.7405

Cited by 44 publications

(23 citation statements)

References 42 publications

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“…FK506 also prevented calcineurin-mediated dephosphorylation of nitric oxide synthase, leading to neuroprotection (Dawson et al, 1993;Nishino et al, 1996). In addition, FK506 was shown to increase the survival of grafted embryonic dopamine neurons (Castilho et al, 2000). However, the precise mechanisms of neuroprotection evoked by FK506 are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

FK506 prevents mitochondrial-dependent apoptotic cell death induced by 3-nitropropionic acid in rat primary cortical cultures

Almeida

Domingues

Rodrigues

et al. 2004

Neurobiology of Disease

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The mitochondrial toxin 3-nitropropionic acid (3-NP) has been largely used to study neurodegenerative disorders in which bioenergetic defects are implicated. In the present study, we analyzed the molecular pathways involved in FK506 neuroprotection against cell death induced by 3-NP, using cultured cortical neurons. 3-NP induced cytochrome c release and increased caspases -2, -3, -8, and -9-like activities, although, calpain activity was not significantly affected. FK506 decreased cytochrome c release and caspase-3-like activity induced by 3-NP, without changing the activities of other caspases. FK-506 also decreased the number of apoptotic neurons, determined by Hoechst. Under these conditions, FK506 alone significantly reduced calcineurin activity by about 50%. Our results also showed a decrease in mitochondrial Bax and an increase in mitochondrial Bcl-2 levels upon exposure to FK506 and 3-NP. However, no significant changes occurred in total Bcl-2 and Bax levels. Altogether, the results suggest that FK506 neuroprotection against 3-NP-induced apoptosis is associated with the redistribution of Bcl-2 and Bax in the mitochondrial membrane. D

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Section: Introductionmentioning

confidence: 99%

FK506 prevents mitochondrial-dependent apoptotic cell death induced by 3-nitropropionic acid in rat primary cortical cultures

Almeida

Domingues

Rodrigues

et al. 2004

Neurobiology of Disease

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“…planted with ventral mesencephalic (VM) cells and exhibited significant clinical improvements had been MATERIALS AND METHODS subjected to short-term immunosuppression (19,33,43). Subjects Cyclosporin A (CsA) is the most common immunosuppressant and in recent years has been suggested as a All procedures adhered to NIH guidelines for using neuroprotective agent (4,15,20,27,44,70). Because of this animals in research.…”

Section: Introductionmentioning

confidence: 99%

Intracerebral Xenotransplantation of GFP Mouse Bone Marrow Stromal Cells in Intact and Stroke Rat Brain: Graft Survival and Immunologic Response

et al. 2004

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The present study characterized survival and immunologic response of bone marrow stromal cells (BMSCs) following transplantation into intact and stroke brains. In the first study, intrastriatal transplantation of BMSC (60,000 in 3 µl) or vehicle was performed in normal adult Sprague-Dawley male rats that subsequently received daily cyclosporin A (CsA, 10 mg/kg, IP in 3 ml) or vehicle (olive oil, similar volume) starting on day of surgery up to 3 days posttransplantation. Animals were euthanized at 3 or 30 days posttransplantation and brains were processed either for green fluorescent protein (GFP) microscopy or flow cytometry (FACS). Both GFP epifluorescence and FACS scanning revealed GFP+ BMSCs in both groups of transplanted rats with or without CsA, although significantly increased (1.6-to 3-fold more) survival of GFP+ BMSCs was observed in the immunosuppressed animals. Further histologic examination revealed widespread dispersal of BMSCs away from the graft core accompanied by many long outgrowth processes in non-CsA-transplanted animals, whereas a very dense graft core, with cells expressing only sporadic short outgrowth processes, was observed in CsA-transplanted animals. There were no detectable GFP+ BMSCs in nontransplanted rats that received CsA or vehicle. Immunologic response via FACS analysis revealed a decreased presence of cytotoxic cells, characterized by near complete absence of CD8+ cells, and lack of activation depicted by low CD69 expression in CsA-treated transplanted animals. In contrast, elevated levels of CD8+ cells and increased activation of CD69 expression were observed in transplanted animals that received vehicle alone. CD4+ helper cells were almost nondetectable in transplanted rats that received CsA, but also only minimally elevated in transplanted rats that received vehicle. Nontransplanted rats that received either CsA or vehicle displayed very minimal detectable levels of all three lymphocyte markers. In the second study, a new set of male Sprague-Dawley rats initially received bilateral stereotaxic intrastriatal transplantation of BMSCs and 3 days after were subjected to unilateral transient occlusion of middle cerebral artery. The animals were allowed to survive for 3 days after stroke without CsA immunosuppression. Epifluorescence microscopy revealed significantly higher (5-fold more) survival of transplanted GFP+ BMSCs in the stroke striatum compared with the intact striatum. The majority of the grafts remained within the original dorsal striatal transplant site, characterized by no obvious migration in intact striatum, but with long-distance migration along the ischemic penumbra in the stroke striatum. Moreover, FACS scanning analyses revealed low levels of immunologic response of grafted BMSCs in both stroke and intact striata. These results, taken together, suggest that xenotransplantation of mouse BMSCs into adult rats is feasible. Immunosuppression therapy can enhance xenograft survival and reduce graft-induced immunologic response; however, in the acute phase posttranspl...

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“…In studies of traumatic spinal cord injury, pretreatment of animals with FK506 blocked Bad dephosphorylation and prevented the activation of caspase-3-mediated apoptosis [5]. The ability of CsA or FK506 to produce neuronal protection is attributed partially to inhibition of calcineurin [31,32]. However, CsA also interacts with mitochondrial cyclophilin D to prevent mitochondrial permeability transition, a critical step in mitochondria-mediated apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Calcineurin-mediated Bad translocation regulates cyanide-induced neuronal apoptosis

Shou

Prabhakaran

et al. 2004

Biochemical Journal

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In cyanide-induced apoptosis, an increase in cytosolic free Ca 2+ and generation of reactive oxygen species are initiation stimuli for apoptotic cell death. Previous studies have shown that cyanidestimulated translocation of Bax (Bcl-associated X protein) to mitochondria is linked with release of cytochrome c and subsequent activation of a caspase cascade [Shou, Li, Prabhakaran, Borowitz and Isom (2003) Toxicol. Sci. 75, 99-107]. In the present study, the relationship of the cyanide-induced increase in cytosolic free Ca 2+ to activation of Bad (Bcl-2/Bcl-X L -antagonist, causing cell death) was determined in cortical cells. Bad is a Ca 2+ -sensitive pro-apoptotic Bcl-2 protein, which on activation translocates from cytosol to mitochondria to initiate cytochrome c release. In cultured primary cortical cells, cyanide produced a concentration-and time-dependent translocation of Bad from cytosol to mitochondria. Translocation occurred early in the apoptotic response, since mitochondrial Bad was detected within 1 h of cyanide treatment. Mitochondrial levels of the protein continued to increase up to 12 h post-cyanide exposure. Concurrent with Bad translocation, a Ca 2+ -sensitive increase in cellular calcineurin activity was observed. Increased cytosolic Ca 2+ and calcineurin activation stimulated Bad translocation since BAPTA [bis-(o-aminophenoxy)ethane-N,N,N ,N -tetra-acetic acid], an intracellular Ca 2+ chelator, and cyclosporin A, a calcineurin inhibitor, significantly reduced translocation. BAPTA also blocked release of cytochrome c from mitochondria as well as apoptosis. Furthermore, treatment of cells with the calcineurin inhibitors cyclosporin A or FK506 blocked the apoptotic response, linking calcineurin activation and the subsequent translocation of Bad to cell death. These observations show that by inducing a rapid increase in cytosolic free Ca 2+ , cyanide can partially initiate the apoptotic cascade through a calcineurin-mediated translocation of Bad to mitochondria.

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FK506 and Cyclosporin A Enhance the Survival of Cultured and Grafted Rat Embryonic Dopamine Neurons

Cited by 44 publications

References 42 publications

FK506 prevents mitochondrial-dependent apoptotic cell death induced by 3-nitropropionic acid in rat primary cortical cultures

FK506 prevents mitochondrial-dependent apoptotic cell death induced by 3-nitropropionic acid in rat primary cortical cultures

Intracerebral Xenotransplantation of GFP Mouse Bone Marrow Stromal Cells in Intact and Stroke Rat Brain: Graft Survival and Immunologic Response

Calcineurin-mediated Bad translocation regulates cyanide-induced neuronal apoptosis

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