Showing papers by "Anders Björklund published in 1999"
TL;DR: Grafted neurons can continue for a decade to store and release dopamine and give rise to substantial symptomatic relief in a patient with Parkinson's disease.
Abstract: Synaptic dopamine release from embryonic nigral transplants has been monitored in the striatum of a patient with Parkinson's disease using [11C]-raclopride positron emission tomography to measure dopamine D2 receptor occupancy by the endogenous transmitter. In this patient, who had received a transplant in the right putamen 10 years earlier, grafts had restored both basal and drug-induced dopamine release to normal levels. This was associated with sustained, marked clinical benefit and normalized levels of dopamine storage in the grafted putamen. Despite an ongoing disease process, grafted neurons can thus continue for a decade to store and release dopamine and give rise to substantial symptomatic relief.
692 citations
TL;DR: The ability of the human neural progenitors to respond in vivo to guidance cues and signals that can direct their differentiation along multiple phenotypic pathways suggests that they can provide a powerful and virtually unlimited source of cells for experimental and clinical transplantation.
Abstract: Neural progenitor cells obtained from the embryonic human forebrain were expanded up to 107-fold in culture in the presence of epidermal growth factor, basic fibroblast growth factor, and leukemia inhibitory growth factor. When transplanted into neurogenic regions in the adult rat brain, the subventricular zone, and hippocampus, the in vitro propagated cells migrated specifically along the routes normally taken by the endogenous neuronal precursors: along the rostral migratory stream to the olfactory bulb and within the subgranular zone in the dentate gyrus, and exhibited site-specific neuronal differentiation in the granular and periglomerular layers of the bulb and in the dentate granular cell layer. The cells exhibited substantial migration also within the non-neurogenic region, the striatum, in a seemingly nondirected manner up to ∼1–1.5 mm from the graft core, and showed differentiation into both neuronal and glial phenotypes. Only cells with glial-like features migrated over longer distances within the mature striatum, whereas the cells expressing neuronal phenotypes remained close to the implantation site. The ability of the human neural progenitors to respond in vivo to guidance cues and signals that can direct their differentiation along multiple phenotypic pathways suggests that they can provide a powerful and virtually unlimited source of cells for experimental and clinical transplantation.
589 citations
TL;DR: This new understanding of the pathogenesis of Parkinson's disease now offers novel prospects for therapy based on targeted neuroprotection of vulnerable neurons and effective strategies for their replacement.
Abstract: The degeneration of forebrain dopamine systems in Parkinson's disease has been an effective target for pharmaceutical research over the past four decades. However, although dopamine replacement may alleviate the symptoms of the disease, it does not halt the underlying neuronal degeneration. The past decade has seen major advances in identifying discrete genetic and molecular causes of parkinsonism and mapping the events involved in nigral cell death. This new understanding of the pathogenesis of the disease now offers novel prospects for therapy based on targeted neuroprotection of vulnerable neurons and effective strategies for their replacement.
557 citations
TL;DR: Findings indicate that sequential transplantation in patients does not compromise the survival and function of either the first or the second graft, and putamen grafts that restore fluorodopa uptake to normal levels can give improvements of major therapeutic value.
Abstract: Five parkinsonian patients who had received implants of human embryonic mesencephalic tissue unilaterally in the striatum 10-56 months earlier were grafted with tissue from four to eight donors into the putamen (four patients) or the putamen plus the caudate nucleus (one patient) on the other side, and were followed for 18-24 months. After 12-18 months, PET showed a mean 85% increase in 6-L-[18F]fluorodopa uptake in the putamen with the second graft, whereas there was no significant further change in the previously transplanted putamen. Two patients exhibited marked additional improvements after their second graft: 'on-off' fluctuations virtually disappeared, movement speed increased, and L-dopa could be withdrawn in one patient and reduced by 70% in the other. The improvement in one patient was moderate. Two patients with atypical features, who responded poorly to the first graft, worsened following the second transplantation. These findings indicate that sequential transplantation in patients does not compromise the survival and function of either the first or the second graft. Moreover, putamen grafts that restore fluorodopa uptake to normal levels can give improvements of major therapeutic value.
269 citations
TL;DR: GDNF is highly effective as a neuroprotective and axon growth‐stimulating agent in the IS 6‐OHDA lesion model after both IS and ICV administration, and the lower efficacy of NTN after IS, and particularly ICV, administration may be explained by the poor solubility and diffusion properties at neutral pH.
Abstract: Both glial cell line-derived neurotrophic factor (GDNF) and its recently discovered congener, neurturin (NTN), have been shown to exert neuroprotective effects on lesioned nigral dopamine (DA) neurons when administered at the level of the substantia nigra. In the present study, we have explored the relative in vivo potency of these two neurotrophic factors using two alternative routes of administration, into the striatum or the lateral ventricle, which may be more relevant in a clinical setting. In rats subjected to an intrastriatal (IS) 6-hydroxydopamine (6-OHDA) lesion, GDNF and NTN were injected every third day for 3 weeks starting on the day after the 6-OHDA injection. GDNF provided almost complete (90-92%) protection of the lesioned nigral DA neurons after both IS and intracerebroventricular (ICV) administration. NTN, by contrast, was only partially effective after IS injection (72% sparing) and totally ineffective after ICV injection. Although the trophic factor injections protected the nigral neurons from lesion-induced cell death, the level of expression of the phenotypic marker, tyrosine hydroxylase (TH), was markedly reduced in the rescued cell bodies. The extent of 6-OHDA-induced DA denervation in the striatum was unaffected by both types of treatment; consistent with this observation, the high rate of amphetamine-induced turning seen in the lesioned control animals was unaltered by either GDNF or NTN treatment. In the GDNF-treated animals, and to a lesser extent also after IS NTN treatment, prominent axonal sprouting was observed within the globus pallidus, at the level where the lesioned nigrostriatal axons are known to end at the time of onset of the neurotrophic factor treatment. The results show that GDNF is highly effective as a neuroprotective and axon growth-stimulating agent in the IS 6-OHDA lesion model after both IS and ICV administration. The lower efficacy of NTN after IS, and particularly ICV, administration may be explained by the poor solubility and diffusion properties at neutral pH.
261 citations
TL;DR: It is proposed that intranigral striatal transplants, by a GABA-mediated inhibitory action, can reduce the overactivity of the host SN projection neurons and can induce significant recovery in complex motor behavior in the rat PD model and that such grafts may be used to increase the overall functional efficacy of intrastriatal VM grafts.
121 citations
TL;DR: A deficit in attentional function as a result of the aging process is suggested, markedly similar to that observed following lesions of the basalo-cortical cholinergic system.
60 citations
TL;DR: The results indicate that intranigral grafts can be placed accurately and survive well within the substantia nigra region at various time points during postnatal development.
54 citations
TL;DR: It is concluded that administration of NTN may be a powerful way to increase survival of transplanted fetal DA neurons.
Abstract: We investigated here the effect of the novel glial cell line-derived neurotrophic factor (GDNF)-family member neurturin (NTN) on transplanted fetal dopamine (DA) neurons. Three groups of rats with complete unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal DA system received intrastriatal grafts of embryonic ventral mesencephalic tissue. Following transplantation animals received repeated injections of vehicle or NTN (0.3 microg or 3.0 microg) over three weeks posttransplantation. NTN-treated animals had significantly (1.8-fold) more tyrosine hydroxylase-immunoreactive (TH-IR) neurons. Graft volume, TH-IR cell volume and overall dopaminergic host reinnervation remained unchanged. Amphetamine-induced rotation was rapidly compensated in all grafted rats. We conclude that administration of NTN may be a powerful way to increase survival of transplanted fetal DA neurons.
41 citations
TL;DR: Anders BjoÈrklund is Professor of Histology at the Wallenberg Neuroscience Center at Lund University in Sweden, where he has been active throughout his career in brain regeneration and repair and cell transplantation as a tool for in vivo gene therapy.
Abstract: Anders BjoÈrklund is Professor of Histology at the Wallenberg Neuroscience Center at Lund University in Sweden, where he has been active throughout his career. He initially trained as a neuroanatomist, and became interested in brain regeneration and repair in the early seventies. Together with his close collaborators Ulf Stenevi, Olle Lindvall, Fred Gage (now at the Salk institute in La Jolla, USA) and Steve Dunnett (at the Brain Repair Centre in Cambridge, UK) he started to explore the use of fetal neural transplants for neuronal replacement and functional repair in the damaged CNS, which led to the ®rst application of dopamine neuron transplants in patients with advanced Parkinson's disease. Cell transplantation as a tool for in vivo gene therapy has been part of the Lund program since the early nineties.
41 citations
TL;DR: Two studies indicate that neural stem cells are not only much more widespread in the central nervous system than previously thought, but that they can somehow cross from the brain and develop into blood cells.
Abstract: Stem cells have the remarkable ability to become one of any number of different cell types. Take neural stem cells, for example, which can develop into neurons or different types of glial cell. Two studies indicate that these cells are not only much more widespread in the central nervous system than previously thought, but that they can somehow cross from the brain and develop into blood cells.
Journal Article•
TL;DR: A review of experience in current trials is given in the light of the practical and ethical problems that need to be solved in order to develop the neuronal graft technique as a useful and generally acceptable form of therapy.
Abstract: During the past decade neuronal grafting has been explored as a novel approach to the treatment of neurodegenerative disease. About 250 patients with advanced Parkinson's disease and 20-30 patients with Huntington's disease have received embryonic neuronal grafts. The results have shown such grafts to survive and function for many years in the diseased brain, and to induce significant and lasting therapeutic effects. The article gives a review of experience in current trials, discussed in the light of the practical and ethical problems that need to be solved in order to develop the neuronal graft technique as a useful and generally acceptable form of therapy.