| 1. |
- Maciel, EN, et al.
(författare)
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Cyclosporin A and Bcl-2 do not inhibit quinolinic acid-induced striatal excitotoxicity in rodents
- 2003
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Ingår i: Experimental Neurology. - 0014-4886. ; 183:2, s. 430-437
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial permeability transition (MPT) is a nonselective inner membrane permeabilization that contributes to neuronal cell death under circumstances such as brain trauma, ischemia, and hypoglycemia. Here we study the participation of MPT and the Bcl-2-sensitive apoptotic cell death pathway in glutamate receptor-mediated excitotoxicity. Intrastriatal infusions of the N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid caused massive striatal neurodegeneration in both rats and mice. Interestingly, transgenic mice overexpressing human Bcl-2 and rats systemically treated with cyclosporin A did not exhibit reduced sensitivity to quinolinic acid-induced striatal toxicity. Both Bcl-2 and cyclosporin A are inhibitors of MPT; in addition Bcl-2 also inhibits apoptotic stimuli-mediated release of mitochondrial apoptogenic factors. Isolated brain mitochondria from cyclosporin A-treated rats showed resistance to Ca2+-induced dissipation of the membrane potential, indicating protection against MPT. We conclude that quinolinic acid-mediated striatal excitotoxicity is not dependent on MPT and Bcl-2-sensitive apoptotic cell death pathways. (C) 2003 Elsevier Science (USA). All rights reserved.
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| 2. |
- Castilho, Roger F, et al.
(författare)
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FK506 and cyclosporin A enhance the survival of cultured and grafted rat embryonic dopamine neurons
- 2000
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 164:1, s. 94-101
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Tidskriftsartikel (refereegranskat)abstract
- We examined the effects of the immunophilin ligands and calcineurin inhibitors FK506 and cyclosporin A on the survival of rat embryonic dopamine (tyrosine hydroxylase (TH)-immunoreactive) neurons. The protective effects of FK506 and cyclosporin A were first studied in dissociated mesencephalic cell cultures subjected to serum deprivation. Significant increases in both the total number of surviving mesencephalic cells and the number of surviving TH-immunoreactive neurons were observed when FK506 or cyclosporin A was present following withdrawal of serum from the culture medium. In a second series of experiments, FK506 increased the survival of dopamine neurons when added only to a hibernation medium in which donor tissue pieces were stored for 7 days prior to preparation of the cultures. In a third set of experiments, we investigated the effects of FK506 and cyclosporin A on the survival of grafted rat embryonic dopamine neurons. When FK506 or cyclosporin A was present during tissue preparation and in the final mesencephalic cell suspension used for grafting, the survival of TH-immunoreactive neurons implanted in the striatum increased to around 185% of control values. In contrast, treatment of graft recipient rats, but not the graft suspension itself, with immunosuppressive doses of FK506 or cyclosporin A did not augment the survival of grafted TH-immunoreactive neurons. We conclude that administration of FK506 during storage of embryonic mesencephalic tissue and FK506 or cyclosporin A during preparation of nigral cell suspensions used for grafting can increase the survival of grafted embryonic dopamine neurons.
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| 3. |
- Emgård-Mattson, Mia, et al.
(författare)
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Patterns of cell death and dopaminergic neuron survival in intrastriatal nigral grafts
- 1999
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 160:1, s. 88-279
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies indicate that 80-95% of grafted dopamine neurons die following implantation of embryonic ventral mesencephalic tissue into the striatum. It is believed that the majority die within the first 1-3 weeks after surgery. The aim of this study was to study when and where the implanted neurons die, using the novel fluorescent stain Fluoro-Jade. Fluoro-Jade has recently been shown to stain cell bodies, dendrites, axons, and terminals of degenerating neurons. We transplanted dissociated ventral mesencephalic tissue from embryonic day 14 rat embryos into intact adult rat striatum. After perfusion and sectioning of the implanted rat brains, the number and distribution of Fluoro-Jade and tyrosine hydroxylase-positive neurons were evaluated at 6, 10, 14, and 42 days posttransplantation. Intensely Fluoro-Jade stained neurons were numerous in the grafts at 6 and 10 days after graft surgery; appeared in reduced numbers at 14 days; and had disappeared by the 42-day time point. The number of surviving tyrosine hydroxylase-positive, dopaminergic neurons in the grafts did not change between 6 and 42 days and the low survival rate confirmed that over 90% of these neurons had died during the first week. Assessment of the distribution of neurons positive for Fluoro-Jade or tyrosine hydroxylase revealed higher numbers of neurons stained for these markers located at the periphery than the center of the grafts, and this pattern did not change over time. This study indicates that transplanted neurons continue to die up to 14 days after grafting. Since the majority of transplanted tyrosine hydroxylase-positive neurons most probably die before 6 days after transplantation, neuroprotective strategies should primarily focus on the transplantation procedure and the first week after implantation.
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| 4. |
- Hansson, Oskar, et al.
(författare)
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Additive effects of caspase inhibitor and lazaroid on the survival of transplanted rat and human embryonic dopamine neurons
- 2000
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 164:1, s. 102-111
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Tidskriftsartikel (refereegranskat)abstract
- Major practical constraints on neural grafting in Parkinson's disease are the shortage of human donor tissue and the great loss of dopamine neurons during the grafting procedure. The vast majority of implanted embryonic dopamine neurons are believed to die within a few days of transplantation surgery, at least in part through apoptosis. We have previously found that survival of nigral grafts in rodents can be significantly augmented by pretreatment with the caspase inhibitor Ac-YVAD-cmk or by lazaroids (lipid peroxidation inhibitors). We now report that pretreatment with the caspase inhibitor Ac-DEVD-cmk, but not z-VAD-fmk, results in a significantly improved survival of transplanted dopamine neurons of similar magnitude to that achieved in this study using Ac-YVAD-cmk (both 220-230% of control). In addition, we found that treatment of the graft tissue with tirilazad mesylate (a lazaroid allowed for clinical use) almost doubled the survival of grafted dopamine neurons. When Ac-YVAD-cmk and tirilazad mesylate treatments were combined, the number of surviving dopamine neurons increased significantly further to 280% of control. Importantly, the same combination of neuroprotectants enhanced the survival of human dopamine neurons xenotransplanted to immunosuppressed rats (to 240% of control). In conclusion, these results suggest that combining treatments that counteract oxidative stress and caspase activation is a valuable strategy to enhance nigral graft survival that should be considered for clinical application.
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