| 1. |
- Brundin, Patrik, et al.
(författare)
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Graft survival
- 1999
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Ingår i: Journal of Neurosurgery. - 0022-3085. ; 90:4, s. 804-805
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Tidskriftsartikel (refereegranskat)
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| 2. |
- 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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| 3. |
- Hansson, Oskar, et al.
(författare)
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Transgenic mice expressing a Huntington's disease mutation are resistant to quinolinic acid-induced striatal excitotoxicity
- 1999
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Ingår i: Proceedings of the National Academy of Sciences. - 1091-6490. ; 96:15, s. 8727-8732
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease (HD) is a hereditary neurodegenerative disorder presenting with chorea, dementia, and extensive striatal neuronal death. The mechanism through which the widely expressed mutant HD gene mediates a slowly progressing striatal neurotoxicity is unknown. Glutamate receptor-mediated excitotoxicity has been hypothesized to contribute to the pathogenesis of HD. Here we show that transgenic HD mice expressing exon 1 of a human HD gene with an expanded number of CAG repeats (line R6/1) are strongly protected from acute striatal excitotoxic lesions. Intrastriatal infusions of the N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid caused massive striatal neuronal death in wild-type mice, but no damage in transgenic HD littermates. The remarkable neuroprotection in transgenic HD mice occurred at a stage when they had not developed any neurological symptoms caused by the mutant HD gene. At this stage there was no change in the number of striatal neurons and astrocytes in untreated R6/1 mice, although the striatal volume was decreased by 17%. Moreover, transgenic HD mice had normal striatal levels of NMDA receptors, calbindin D28k (calcium buffer), superoxide dismutase activity (antioxidant enzyme), Bcl-2 (anti-apoptotic protein), heat shock protein 70 (stress-induced anti-apoptotic protein), and citrate synthase activity (mitochondrial enzyme). We propose that the presence of exon 1 of the mutant HD gene induces profound changes in striatal neurons that render these cells resistant to excessive NMDA receptor activation.
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| 4. |
- Schierle, Gabriele, et al.
(författare)
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Caspase inhibition reduces apoptosis and increases survival of nigral transplants
- 1999
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 5:1, s. 97-100
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Tidskriftsartikel (refereegranskat)abstract
- Transplantation of embryonic nigral tissue ameliorates functional deficiencies in Parkinson disease. The main practical constraints of neural grafting are the shortage of human donor tissue and the poor survival of dopaminergic neurons grafted into patients, which is estimated at 5-10% (refs. 3,4). The required amount of human tissue could be considerably reduced if the neuronal survival was augmented. Studies in rats indicate that most implanted embryonic neurons die within 1 week of transplantation, and that most of this cell death is apoptotic. Modified peptides, such as acetyl-tyrosinyl-valyl-alanyl-aspartyl-chloro-methylketone (Ac-YVAD-cmk), that specifically inhibit proteases of the caspase family effectively block apoptosis in a plethora of experimental paradigms, such as growth factor withdrawal, excitotoxicity, axotomy, cerebral ischemia and brain trauma. Here we examined the effects of caspase inhibition by Ac-YVAD-cmk on cell death immediately after donor tissue preparation and on long-term graft survival. Treatment of the embryonic nigral cell suspension with Ac-YVAD-cmk mitigated DNA fragmentation and reduced apoptosis in transplants. It also increased survival of dopaminergic neurons grafted to hemiparkinsonian rats, and thereby substantially improved functional recovery.
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| 5. |
- Schierle, Gabriele, et al.
(författare)
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Flunarizine improves the survival of grafted dopaminergic neurons
- 1999
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Ingår i: Neuroscience. - 1873-7544. ; 94:1, s. 17-20
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Tidskriftsartikel (refereegranskat)abstract
- Embryonic nigral grafts can survive, reinnervate the striatum and reverse functional deficits in both experimental and clinical Parkinsonism. A major drawback is that only around 10% of the implanted dopaminergic neurons survive. The underlying mechanisms leading to this 90% cell death are not fully understood, but oxidative stress and a substantial loss of neurotrophic support are likely to be involved. Hypoxia and mechanical trauma, which are unavoidable during tissue preparation, may be a trigger for cell death. Recent studies have provided evidence that the type of cell death occurring is, to a large extent, apoptotic. Flunarizine is an antagonist of L-, T- and N-type calcium channels, which permits calcium entry into cells via a voltage-dependent mechanism. Flunarizine has been shown to protect neurons against death induced by serum deprivation, nerve growth factor deprivation, oxidative stress, axotomy and ischemia. This study was designed to investigate whether flunarizine can protect grafted embryonic dopaminergic neurons from death when implanted in a rat model of Parkinson's disease. Addition of 1 microM flunarizine inhibited cell death in a suspension of cells derived from the rat's ventral mesencephalon and when such a treated suspension was injected into the neostriatum there was a 2.6-fold greater number of surviving dopaminergic neurons, a doubling of the graft volume and a doubling of the volume of the host neostriatum innervated by dopaminergic fibers from the graft, compared with suspensions not exposed to flunarizine. Furthermore, rats injected with cells that had been exposed to flunarizine displayed a greater recovery of function in the amphetamine-induced rotation test.
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| 6. |
- Schierle, Gabriele, et al.
(författare)
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Neuronal death in nigral grafts in the absence of poly (ADP-ribose) polymerase activation
- 1999
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Ingår i: NeuroReport. - 1473-558X. ; 10:16, s. 3347-3351
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Tidskriftsartikel (refereegranskat)abstract
- The exact causes of the extensive cell death in nigral transplants are still unknown. Since poly-(ADP-ribose) polymerase (PARP) overactivation has been implicated in neuronal death, we examined the effects of PARP on the survival of nigral grafts by using donor tissue from PARP knock-out or wild-type mice. Eight hours after preparation of the nigral cell suspension, cell damage was quantified by measurement of lactate dehydrogenase release, DNA fragmentation and caspase activation. At this stage, PARP deletion had no protective effect. Moreover, neither the survival of transplanted dopaminergic neurons, nor the functional recovery of hemiparkinsonian graft recipients were improved by the absence of PARP. We conclude that cell death in embryonic nigral grafts is not affected by the absence of PARP activation.
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