| 41. |
- Brundin, Patrik, et al.
(författare)
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Improving the survival of grafted dopaminergic neurons: a review over current approaches
- 2000
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Ingår i: Cell Transplantation. - 1555-3892. ; 9:2, s. 179-195
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Tidskriftsartikel (refereegranskat)abstract
- Neural transplantation is developing into a therapeutic alternative in Parkinson's disease. A major limiting factor is that only 3-20% of grafted dopamine neurons survive the procedure. Recent advances regarding how and when the neurons die indicate that events preceding actual tissue implantation and during the first week thereafter are crucial, and that apoptosis plays a pivotal role. Triggers that may initiate neuronal death in grafts include donor tissue hypoxia and hypoglycemia, mechanical trauma, free radicals, growth factor deprivation, and excessive extracellular concentrations of excitatory amino acids in the host brain. Four distinct phases during grafting that can involve cell death have been identified: retrieval of the embryo; dissection and preparation of the donor tissue; implantation procedure followed by the immediate period after graft injection; and later stages of graft maturation. During these phases, cell death processes involving free radicals and caspase activation (leading to apoptosis) may be triggered, possibly involving an increase in intracellular calcium. We review different approaches that reduce cell death and increase survival of grafted neurons, typically by a factor of 2-4. For example, changes in transplantation procedure such as improved media and implantation technique can be beneficial. Calcium channel antagonists such as nimodipine and flunarizine improve nigral graft survival. Agents that counteract oxidative stress and its consequences, such as superoxide dismutase overexpression, and lazaroids can significantly increase the survival of transplanted dopamine neurons. Also, the inhibition of apoptosis by a caspase inhibitor has marked positive effects. Finally, basic fibroblast growth factor and members of the transforming growth factor-beta superfamily, such as glial cell line-derived neurotrophic factor, significantly improve the outcome of nigral transplants. These recent advances provide hope for improved survival of transplanted neurons in patients with Parkinson's disease, reducing the need for human embryonic donor tissue and increasing the likelihood of a successful outcome.
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| 42. |
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| 43. |
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| 44. |
- Brundin, Patrik, et al.
(författare)
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Neural grafting in Parkinson's disease: problems and possibilities
- 2010
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Ingår i: Progress in Brain Research. - 1875-7855. ; 184, s. 265-294
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Forskningsöversikt (refereegranskat)abstract
- Neural transplantation has emerged as a possible therapy for Parkinson's disease (PD). Clinical studies performed during the 1990s, where dopaminergic neurons derived from the human embryonic brain were transplanted into striatum of patients with PD, provided proof-of-principle that long-lasting therapeutic benefits can be achieved. Subsequent studies, in particular two that followed a double-blind, sham surgery, placebo-control design, showed variable and mostly negative results. They also revealed that some patients develop involuntary movements, so called graft-induced dyskinesias, as side effects. Thus, while nigral transplants clearly work well in select PD cases, the technique needs refinement before it can successfully be performed in a large series of patients. In this review, we describe the clinical neural transplantation trials in PD and the likely importance of factors such as patient selection, trial design, preparation of the donor tissue, and surgical techniques for successful outcome and avoiding unwanted side effects. We also highlight that it was recently found that neuropathological signs typical for PD can appear inside some of the grafted neurons over a decade after surgery. Finally, we discuss future possibilities offered by stem cells as potential sources of dopamine neurons that can be used for transplantation in PD.
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| 45. |
- Brundin, Patrik, et al.
(författare)
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Neuropathology in transplants in Parkinson's disease: Implications for disease pathogenesis and the future of cell therapy.
- 2012
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Ingår i: Progress in Brain Research. - 1875-7855. ; 200, s. 221-241
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Tidskriftsartikel (refereegranskat)abstract
- Neural transplantation is over a century old, but the modern era encompasses only the last 30-40 years. For most of this time period, research has focused on reversing disability engendered by neurologic disease and brain damage. Only recently was it recognized that the underlying neurological disease itself might negatively impact the grafted neurons. We have found that a subset of neurons within embryonic neural grafts that survive more than 10 years in Parkinson patients display Lewy bodies, a classical feature of Parkinson's disease neuropathology. Additionally, the grafted cells placed in the Parkinson's disease brain eventually downregulate the expression of dopamine transporter and tyrosine hydroxylase in a manner similar to what is seen in the substantia nigra dopamine neurons that are degenerating due to the disease. We discuss these findings in terms of how they might improve our understanding of Parkinson's disease pathogenesis and the effects they may have on the future of neural cell replacement strategies.
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| 46. |
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| 47. |
- Brundin, Patrik, et al.
(författare)
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Prion-like transmission of protein aggregates in neurodegenerative diseases.
- 2010
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Ingår i: Nature Reviews. Molecular Cell Biology. - : Springer Science and Business Media LLC. - 1471-0072 .- 1471-0080. ; 11:4, s. 301-307
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Forskningsöversikt (refereegranskat)abstract
- Neurodegenerative diseases are commonly associated with the accumulation of intracellular or extracellular protein aggregates. Recent studies suggest that these aggregates are capable of crossing cellular membranes and can directly contribute to the propagation of neurodegenerative disease pathogenesis. We propose that, once initiated, neuropathological changes might spread in a 'prion-like' manner and that disease progression is associated with the intercellular transfer of pathogenic proteins. The transfer of naked infectious particles between cells could therefore be a target for new disease-modifying therapies.
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| 48. |
- Brundin, Patrik, et al.
(författare)
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Research in motion: the enigma of Parkinson's disease pathology spread.
- 2008
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Ingår i: Nature Reviews Neuroscience. - : Springer Science and Business Media LLC. - 1471-003X .- 1471-0048. ; 9:10, s. 741-745
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Forskningsöversikt (refereegranskat)abstract
- Neuropathological changes in Parkinson's disease progress slowly and spread according to a characteristic pattern. Recent papers have shed light on this progression of pathology by examining the fate of neurons grafted into the brains of patients with Parkinson's disease. Two of these studies demonstrate that grafted healthy neurons can gradually develop the same pathology as host neurons in the diseased brains. According to these studies, implanted neurons developed alpha-synuclein- and ubiquitin-positive Lewy bodies more than a decade after transplantation. We discuss the possible underlying mechanisms and their implications for how pathology spreads in Parkinson's disease.
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| 49. |
- Brundin, Patrik, et al.
(författare)
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The neurobiology of cell transplantation in Parkinson's disease
- 2001
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Ingår i: Clinical Neuroscience Research. - 1873-779X. ; 1:6, s. 507-520
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Tidskriftsartikel (refereegranskat)abstract
- Over the past decade, neural grafting has emerged as a new treatment option for Parkinson's disease. When performed successfully, grafts of human embryonic neural tissue can give rise to major symptomatic relief in patients, However, a recent report on a double-blind placebo control study, which received worldwide attention, described less pronounced beneficial effects of the grafts, and found them to be significant only in patients younger than 60 years of age. Moreover, a subgroup of patients developed disabling dyskinesias as a result of the surgery. These findings, and great logistical problems in coordinating the harvesting of sufficient amounts of suitable human embryonic donor tissue with the transplantation surgery, have led the scientific community to question whether cell transplantation really has a future as a therapy for Parkinson's disease. In this review, we argue that the future of neural transplantation for Parkinson's disease is still bright. We relate clinical findings to observations made in experimental animals grafted with embryonic neural tissue and seek explanations for the variability in outcome seen in the clinical trials. We also briefly discuss alternative sources of donor tissue that may be applied in future clinical trials, and mention what features of cells may be crucial for them to be suitable as donor tissue for transplantation in Parkinson's disease.
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| 50. |
- Burguillos Garcia, Miguel, et al.
(författare)
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Caspase signalling controls microglia activation and neurotoxicity.
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 472, s. 214-319
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Tidskriftsartikel (refereegranskat)abstract
- Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C (PKC)-δ-dependent pathway. We find that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently reduced neurotoxicity. We observe that these caspases are activated in microglia in the ventral mesencephalon of Parkinson's disease (PD) and the frontal cortex of individuals with Alzheimer's disease (AD). Taken together, we show that caspase-8 and caspase-3/7 are involved in regulating microglia activation. We conclude that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves.
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