| 6691. |
- Lindvall, Olle, et al.
(författare)
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Brain repair by cell replacement and regeneration.
- 2003
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 100:13, s. 7430-7431
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Tidskriftsartikel (refereegranskat)
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| 6692. |
- Lindvall, Olle, et al.
(författare)
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Cell Therapeutics in Parkinson's Disease.
- 2011
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Ingår i: Neurotherapeutics. - : Springer Science and Business Media LLC. - 1878-7479 .- 1933-7213. ; 8, s. 539-548
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Tidskriftsartikel (refereegranskat)abstract
- The main pathology underlying motor symptoms in Parkinson's disease (PD) is a rather selective degeneration of nigrostriatal dopamine (DA) neurons. Intrastriatal transplantation of immature DA neurons, which replace those neurons that have died, leads to functional restoration in animal models of PD. Here we describe how far the clinical translation of the DA neuron replacement strategy has advanced. We briefly summarize the lessons learned from the early clinical trials with grafts of human fetal mesencephalic tissue, and discuss recent findings suggesting susceptibility of these grafts to the disease process long-term after implantation. Mechanisms underlying graft-induced dyskinesias, which constitute the only significant adverse event observed after neural transplantation, and how they should be prevented and treated are described. We summarize the attempts to generate DA neurons from stem cells of various sources and patient-specific DA neurons from fully differentiated somatic cells, with particular emphasis on the requirements of these cells to be useful in the clinical setting. The rationale for the new clinical trial with transplantation of fetal mesencephalic tissue is described. Finally, we discuss the scientific and clinical advancements that will be necessary to develop a competitive cell therapy for PD patients.
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| 6693. |
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| 6694. |
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| 6695. |
- Lindvall, O., et al.
(författare)
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Differential regulation of mRNAs for nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 in the adult rat brain following cerebral ischemia and hypoglycemic coma
- 1992
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 89:2, s. 648-652
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Tidskriftsartikel (refereegranskat)abstract
- In situ hybridization was used to study expression of mRNAs for members of the nerve growth factor (NGF) family in the rat brain after 2 and 10 min of forebrain ischemia and 1 and 30 min of insulin-induced hypoglycemic coma. Two hours after the ischemic insults, the level of brain-derived neurotrophic factor (BDNF) mRNA was markedly increased in the granule cells of the dentate gyrus, and at 24 h it was still significantly elevated. NGF mRNA showed a pronounced increase 4 h after 2 min of ischemia but had returned to a control level at 24 h. Both 2 and 10 min of ischemia caused a clear reduction of the level of mRNA for neurotrophin 3 (NT-3) in the dentate granule cells and in regions CA2 and medial CA1 of the hippocampus 2 and 4 h after the insults. The increase of BDNF mRNA could be partially blocked by the α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist NBQX but was not influenced by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801. Both NBQX and MK-801 attenuated the decrease of NT-3 mRNA after ischemia. One and 30 min of hypoglycemic coma also induced marked increases in BDNF and NGF mRNA in dentate granule cells with maximal levels at 2 h. If the changes of mRNA expression lead to alterations in the relative availability of neurotrophic factors, this could influence functional outcome and neuronal necrosis following ischemic and hypoglycemic insults.
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| 6696. |
- Lindvall, Olle, et al.
(författare)
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Role of cell therapy in Parkinson disease.
- 2002
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Ingår i: Neurosurgical Focus. - 1092-0684. ; 13:5
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Tidskriftsartikel (refereegranskat)abstract
- Clinical studies involving intrastriatal transplantation of embryonic mesencephalic tissue in patients with Parkinson disease (PD) have provided proof-of-principle for the cell replacement strategy in this disorder. The grafted dopaminergic neurons can reinnervate the denervated striatum, restore regulated dopamine release and movement-related frontal cortical activation, and produce significant symptomatic relief. In the most successful cases, patients have been able to withdraw from levodopa treatment after undergoing transplantation and resume an independent life. There are, however, several problems linked to the use of primary embryonic tissue: 1) lack of sufficient amounts of tissue for transplantation in a large number of patients; 2) variability of functional outcome (major improvement in some and modest if any clinical benefit in others); and 3) occurrence of troublesome dyskinesias in a significant proportion of patients after transplantation. Thus, neural transplantation is still at an experimental stage in the treatment of PD. For the development of a clinically useful cell therapy we need to define better criteria for patient selection and how graft placement should be optimized in each individual. Most importantly, we need to generate large numbers of viable dopamine neurons in preparations that are standardized and quality controlled. Stem cells could be useful as an unlimited source of dopamine neurons. Thus far, neurons with at least some dopaminergic characteristics have been generated from stem cells. In most cases, however, their survival after grafting in animals has been poor, and it is also unclear if they function as normal dopamine neurons. Several scientific issues need to be addressed before stem cell-based therapies can be tested in PD patients.
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| 6697. |
- Lindvall, O., et al.
(författare)
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Transplantation strategies in the treatment of Parkinson's disease : experimental basis and clinical trials
- 1989
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Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 80, s. 197-210
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Tidskriftsartikel (refereegranskat)abstract
- Abstract– Neural grafting has over the last decade emerged as a possible tool for the substitution of damaged neurons in the central nervous system and for the promotion of symptomatic recovery after brain damage. Transplantation studies in the 6‐hydroxydopamine lesion rat model of Parkinson's disease were initiated in the late seventies. The first studies were based on the neuronal replacement paradigm, using developing dopamine brain cells obtained from the substantia nigra region of embryonic cadavers. When implanted into the striatum such grafts were found to reinnervate part of the previously denervated striatum and restore dopamine turnover and release to near‐normal levels. In both rats and monkeys the nigral grafts have been shown to normalize some, but not all, Parkinson‐like symptoms in the dopamine deficient recipients. Grafting of adrenal medullary tissue was introduced in the early eighties as an alternative to the use of embryonic cadaver tissue. The adrenal medullary grafts have, however, so far shown poor long‐term survival in both rats and monkeys, and consistent with this no sustained dopamine release have been observed in the brain of long‐term grafted animals. Likewise, no long‐lasting effects of adrenal medullary grafts on spontaneous motor or sensori‐motor behavior have so far been documented in either the rat or the monkey model. The results so far reported from trials using adrenal medullary grafts in patients with Parkinson's disease appear to conform to the available animal experimental data at least in two important respects: significant long‐term graft survival has not been possible to document, and any clear‐cut functional effects consistent with sustained graft‐induced dopamine release have not been demonstrated. Initial results from ongoing trials using grafts of fetal nigral tissue are presented and discussed.
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| 6698. |
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| 6699. |
- Lindwall, Charlotta, et al.
(författare)
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The role of p-c-Jun in survival and outgrowth of developing sensory neurons
- 2005
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Ingår i: NeuroReport. - 1473-558X. ; 16:15, s. 1655-1659
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Tidskriftsartikel (refereegranskat)abstract
- c-jun activation has been implicated not only in neuronal apoptosis, but also in survival and regeneration. This Janus facet of c-Jun activation could be related to neuronal cell type or to the developmental stage of the neuron. We investigated c-Jun activation in E18 sensory neurons. Cultures of rat dorsal root ganglia neurons were maintained with or without the addition of nerve growth factor or the c-Jun N-terminal kinase inhibitor, (D)-JNKII. Few dorsal root ganglia neurons survived nerve growth factor deprivation, whereas neurons supplied with nerve growth factor survived and exhibited extensive axonal outgrowth. Activated c-Jun was present in the nuclei of neurons with regenerating axons, but not in apoptotic neurons. c-Jun N-terminal kinase inhibition reduced the number of p-c-Jun immunoreactive and regenerating neurons, and increased cell death. Thus, activation of c-Jun seems to be required for survival and regeneration of developing sensory neurons.
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| 6700. |
- Ling, Helen, et al.
(författare)
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Neurological consequences of traumatic brain injuries in sports.
- 2015
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Ingår i: Molecular and cellular neurosciences. - : Elsevier BV. - 1095-9327 .- 1044-7431. ; 66:Part B, s. 114-122
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Tidskriftsartikel (refereegranskat)abstract
- Traumatic brain injury (TBI) is common in boxing and other contact sports. The long term irreversible and progressive aftermath of TBI in boxers depicted as punch drunk syndrome was described almost a century ago and is now widely referred as chronic traumatic encephalopathy (CTE). The short term sequelae of acute brain injury including subdural haematoma and catastrophic brain injury may lead to death, whereas mild TBI, or concussion, causes functional disturbance and axonal injury rather than gross structural brain damage. Following concussion, symptoms such as dizziness, nausea, reduced attention, amnesia and headache tend to develop acutely but usually resolve within a week or two. Severe concussion can also lead to loss of consciousness. Despite the transient nature of the clinical symptoms, functional neuroimaging, electrophysiological, neuropsychological and neurochemical assessments indicate that the disturbance of concussion takes over a month to return to baseline and neuropathological evaluation shows that concussion-induced axonopathy may persist for years. The developing brains in children and adolescents are more susceptible to concussion than adult brain. The mechanism by which acute TBI may lead to the neurodegenerative process of CTE associated with tau hyperphosphorylation and the development of neurofibrillary tangles (NFTs) remains speculative. Focal tau-positive NFTs and neurites in close proximity to focal axonal injury and foci of microhaemorrhage and the predilection of CTE-tau pathology for perivascular and subcortical regions suggest that acute TBI-related axonal injury, loss of microvascular integrity, breach of the blood brain barrier, resulting inflammatory cascade and microglia and astrocyte activation are likely to be the basis of the mechanistic link of TBI and CTE. This article provides an overview of the acute and long-term neurological consequences of TBI in sports. Clinical, neuropathological and the possible pathophysiological mechanisms are discussed. This article is part of a Special Issue entitled 'Traumatic Brain Injury'.
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