Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is estimated that only 5-10% of dopamine (DA) neurons implanted into the striatum of patients undergoing fetal-nigral transplantation as a treatment for Parkinson's Disease survive. Because it is often necessary to store fetal tissue prior to transplantation, we evaluated various storage parameters that could influence DA neuron viability in rostral mesencephalic tegmentum (RMT) cultures using tyrosine hydroxylase immunoreactive (THir) cell counts as an index of DA neuron survival. A high K+ hibernation media (HM) was used in all studies. We found that RMT cell viability and THir cell counts decreased as storage duration increased (up to 120 h). Storage at 37 degrees C in HM killed all cells, while storage at 10 degrees C yielded higher survival rates than 4 degrees C. In comparison to trypsinization, mechanical dissociation of tissue increased cell viability. Neutral pH and a storage density of at least 1 x 10(6) cells/mL were found to be optimal, while striatal coculture of RMT cells with striatal feeder layers increased THir viability up to 16-fold in comparison to monocultures. The nurturing effect of striatal coculture may be explained by the release of autotrophic factors, and we tested this hypothesis by supplementing the HM with human placental cord serum (HPCS, 8%), glial-derived neurotrophic factor (GDNF; 10 microg/mL), and brain-derived neurotrophic factor (BDNF; 10 microg/mL). GDNF and HPCS supplements increased RMT cell viability by 10-15%, while GDNF, BDNF, and HPCS increased viability of THir cells by approximately 40% at all time points studied. As Klenow enzyme labeling technique indicated that 33% of stored RMT cells were undergoing apoptosis, we found that GDNF, BDNF, and HPCS reduced apoptosis by 50%. DNA laddering and DAPI nuclear stain confirmed the presence of apoptosis in hibernated RMT cells, leading us to postulate that the high viability counts seen with trypan blue exclusion are misleading.
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PMID:The effects of storage conditions and trophic supplementation on the survival of fetal mesencephalic cells. 917 Nov 62

Intrastriatal grafting of dopamine-rich embryonic ventral mesencephalon (VM) is a potential therapeutic treatment for Parkinson's disease. However, it has been suggested that the efficacy of this procedure might be improved by enhancing the survival and/or degree of neurite outgrowth by the grafted VM, since these parameters are currently suboptimal. In the present study, we tested the ability of astrocytes retrovirally transduced to produce recombinant brain-derived neurotrophic factor (BDNF) to enhance the survival and/or function of embryonic VM in the unilateral 6-hydroxydopamine (6-OHDA) lesioned rat, a well-characterized rodent model of Parkinson's disease. In culture, primary astrocytes derived from Postnatal Day 0 (P0) rat striatum and transduced with the BDNF vector increased the survival of Embryonic Day 15 (E15) dopaminergic VM neurons by approximately threefold and reduced the loss of dopaminergic neurons following 6-OHDA treatment by approximately 20%. The cultured astrocytes were then mixed 1:1 with freshly dissociated E15 VM and co-grafted into the dopamine-denervated striatum. Unexpectedly, the control nontransduced astrocytes reduced the survival of dopaminergic neurons by 60% and restricted the pattern of neurite outgrowth by the co-grafted VM, compared to grafts of VM alone at 7 weeks postgrafting. These effects were paralleled by an attenuated rate and degree of behavioral recovery. The detrimental effects of the control astrocytes were partially reversed when the astrocytes were transduced to express BDNF, although dopaminergic neuron survival was still reduced by 30% compared to that within VM-only grafts. To begin to assess whether the detrimental effects of the astrocytes were related to the maturational state of the cultured astrocytes, astrocytes were obtained from E18 striatum and maintained in short-term culture (9 days vs several weeks for P0 cultures) prior to co-grafting with VM. Interestingly, the younger astrocytes did not reduce graft survival and allowed for better graft integration. These results suggest that primary astrocytes maintained in long-term culture are detrimental to embryonic neural grafts, an effect that is not completely overcome by expression of recombinant BDNF, and that astrocyte age may be an important consideration in the use of these cells as CNS gene delivery vehicles.
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PMID:Astrocytes promote or impair the survival and function of embryonic ventral mesencephalon co-grafts: effects of astrocyte age and expression of recombinant brain-derived neurotrophic factor. 921 87

Glial cell line-derived neurotrophic factor (GDNF) promotes survival of mesencephalic dopaminergic neurons in vitro and when injected locally into the brains of lesioned adult animals. Here, we show that GDNF (3 micrograms per day and higher) can promote the survival of all (retrogradely labeled) axotomized nigrostriatal dopaminergic neurons of adult rats when continuously infused for 2 weeks close to the substantia nigra, compared to only approximately 30% survival with control infusions. Based on our previous observations, GDNF was as potent as ciliary neurotrophic factor and neurotrophin-4 and approximately five to ten times more potent than brain-derived neurotrophic factor and was most effective in promoting survival. GDNF prevented neuronal death induced by 6-hydroxydopamine to a lesser extent than after axotomy. GDNF treatments begun 1 week after axotomy could maintain those neurons that had not yet died. When a 2 week GDNF treatment was interrupted, most of the GDNF-rescued neurons died over the following 2 weeks. This suggests that longer trophic factor treatments or nigrostriatal connections are needed to achieve permanent survival. Measurements of tyrosine hydroxylase (TH) immunoreactivity of the rescued neuronal cell bodies suggest that GDNF cannot prevent the lesion-induced loss of this rate-limiting enzyme for dopamine synthesis. In fact, GDNF induced a decrease in TH in normal animals, suggesting an active down-regulation of TH synthesis. Levels of TH immunoreactivity were recovered between 7 and 14 days after withdrawal of a 2 week GDNF infusion, in the neurons that survived axotomy. These results may have implications for developing new treatment strategies for Parkinson's disease.
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PMID:Glial cell line-derived neurotrophic factor prevents death, but not reductions in tyrosine hydroxylase, of injured nigrostriatal neurons in adult rats. 936 55

Glial cell line-derived neurotrophic factor, the newest member of the transforming growth factor-beta superfamily, has been shown to promote the survival and differentiation of dopaminergic neurons in the ventral mesencephalon. Glial cell line-derived neurotrophic factor has been implicated in both the in vitro and in vivo recovery of mesencephalic dopaminergic cells challenged with the neurotoxins 1-methyl-4-phenylpyridinium and 6-hydroxydopamine. Previous studies have shown increased survival of intrastriatally transplanted dopaminergic cells when followed by infusion of neurotrophic factors such as basic fibroblast growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. However, the effects of glial cell line-derived neurotrophic factor co-administered with dopaminergic cells prior to implantation in the host striatum have not been studied. In the present study, the hypothesis was that treating fetal ventral mesencephalic tissue containing the dopaminergic substantia nigra with glial cell line-derived neurotrophic factor either during storage or at the time of transplantation, would enhance grafted dopaminergic cell survival and functional reinnervation of the host striatum in the unilaterally 6-hydroxydopamine-lesioned rat. To test this hypothesis, two experiments were performed. In the first experimental group (n = 7), fetal ventral mesencephalons from embryonic day 14 rats were maintained in hibernation medium containing glial cell line-derived neurotrophic factor (1 migrogram/ml) at 4 degrees C for six days prior to dissociation and stereotactic implantation into the host striatum: the control group (n = 5) received tissue hibernated without glial cell line-derived neurotrophic factor. The second experimental group (n = 8) received fresh fetal ventral mesencephalic tissue treated with glial cell line-derived neurotrophic factor (0.2 microgram/microliter) while the control group (n = 5) received the fresh graft with no glial cell line-derived neurotrophic factor. Transplantation success was assessed by behavioural analysis (rotometry) and tyrosine hydroxylase immunohistochemistry. Cell counts of tyrosine hydoxylase-stained sections revealed a statistically significant increase in tyrosine hydroxylase-positive neurons in grafts exposed to glial cell line-derived neurotrophic factor during hibernation as compared to control grafts. In addition, there was a statistically significant enhancement of fibre density in the glial cell line-derived neurotrophic factor hibernation graft group as compared to the glial cell line-derived neurotrophic factor fresh graft group. Behavioural analysis three weeks post-grafting exhibited a statistically significant decrease in amphetamine-induced rotations in animals transplanted with glial cell line-derived neurotrophic factor grafts as compared to control grafts. These findings suggest that storing dopaminergic cells in a glial cell line-derived neurotrophic factor-containing medium prior to transplantation increases graft survival, graft derived fibre outgrowth, and behavioural recovery in the adult host. This observation has potential implications for enhancing the efficacy of neural transplantation in the treatment of Parkinson's disease.
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PMID:Glial cell line-derived neurotrophic factor improves intrastriatal graft survival of stored dopaminergic cells. 946 Jul 46

Several findings show a neuroprotective effect of nicotine treatment in different experimental models, and a negative correlation has been observed between cigarette smoking and the incidence of Parkinson's disease. It seems possible that nicotine may in part exert its neuroprotective actions by favouring the synthesis of neurotrophic factors. The aim of this study was to determine whether the nicotine treatment could be associated with the induction of a neurotrophic factor in brain regions with nicotinic receptors. Thus, we analysed by in situ hybridization and RNAse protection assay the effects of (-)nicotine on basic fibroblast growth factor messenger RNA and by immunocytochemistry fibroblast growth factor-2 protein in the tel- and diencephalon of rats following single or acute intermittent (-)nicotine treatment. The present results showed that acute intermittent (-)nicotine treatment (four i.p. injections at intervals of 30 min), but not single injections, lead to a substantial and dose-related (0.1-2 mg/kg) up-regulation of fibroblast growth factor-2 messenger RNA levels in the cerebral cortex, in the hippocampus, in the striatum and ventral midbrain. This induction of fibroblast growth factor-2 expression peaked 4 h after the first injection and returned to normal levels within 24 h. The change of fibroblast growth factor-2 messenger RNA levels was associated with increased fibroblast growth factor-2 immunoreactivity mainly localized to nerve cells. The treatment was effective also when repeated in the same animals three or five days after the first injection. The pre-treatment with the non-competitive (-)nicotine receptor antagonist mecamylamine blocked the (-)nicotine effects on fibroblast growth factor-2 messenger RNA levels. In the above areas, no changes were observed in the fibroblast growth factor-1, 2 and 3 receptor messenger RNA levels nor in brain-derived neurotrophic factor messenger RNA levels. The present data indicate an ability of intermittent (-)nicotine to increase fibroblast growth factor-2 in many tel- and diencephalic areas. In view of the trophic function of fibroblast growth factor-2, the previously observed neuroprotective effects of (-)nicotine may at least in part involve an activation of the neuronal fibroblast growth factor-2 signalling, and open up new avenues for treatment of Parkinson's disease and Alzheimer's disease based on the existence of nicotinic receptor subtypes enhancing fibroblast growth factor-2 signalling in many regions of the tel- and diencephalon.
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PMID:Acute intermittent nicotine treatment produces regional increases of basic fibroblast growth factor messenger RNA and protein in the tel- and diencephalon of the rat. 948 57

GABAergic neurons in the rat substantia nigra die after inhibitory inputs to the nigra have been killed, and glutamatergic inputs disinhibited, by striatal-pallidal injections of ibotenic acid. This delayed transneuronal injury model imitates the neuron loss observed in Huntington's disease, and may also imitate neuron loss distant from the primary injury in stroke and Parkinson's disease. Because the neurotrophins brain-derived neurotrophic factor and neurotrophin-3 can prevent excitotoxic killing of cultured GABA neurons, we tested whether either factor could protect nigral neurons from transneuronal degeneration. A continuous, three week supranigral infusion of brain-derived neurotrophic factor completely prevented the loss of nigral neurons caused by the ibotenic acid-induced destruction of the caudate-putamen and globus pallidus, and brain-derived neurotrophic factor increased nigral neuron size by 25%. These effects were specific to the TrkB tyrosine kinase receptor that mediates brain-derived neurotrophic factor actions, since supranigral infusions of saline or the TrkC preferring neurotrophin-3, did not prevent nigral neuron loss or induce a hypertrophic response. Neither trophic factor influenced the ibotenic acid destruction of striatal or pallidal neurons. These results demonstrate that exogenously supplied brain-derived neurotrophic factor can prevent delayed, transneuronal loss, and implicate decreased excitatory amino acid transmission or diminished nigral neuron susceptibility to glutamate inputs in the protective effect of brain-derived neurotrophic factor.
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PMID:Brain-derived neurotrophic factor prevents the loss of nigral neurons induced by excitotoxic striatal-pallidal lesions. 948 58

The repeated finding of an apparent protective effect of cigarette smoking on the risk of Parkinson's disease is one of the few consistent results in the epidemiology of this disorder. Among the innumerous substances that originate from tobacco smoke, nicotine is by far the most widely studied, and the most likely candidate for a protective effect against neuronal degeneration in Parkinson's disease. Nicotine is a natural alkaloid that has considerable stimulatory effects on the central nervous system (CNS). Its effects on the CNS are mediated by the activation of neuronal heteromeric acetylcholine-gated ion channel receptors (nAChR, also termed nicotinic acetylcholine receptors). In the present study, we describe the neuroprotective effects of (-)nicotine in two animal models of parkinsonism: the diethyldithiocarbamate (DDC)-induced enhancement of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice, and the methamphetamine-induced neurotoxicity in rats and mice. In parallel experiments, we found that (-)nicotine induces the basic fibroblast growth factor (FGF-2) and the brain-derived neurotrophic factor (BDNF) in rat striatum. As FGF-2 and BDNF have been reported to be neuroprotective for dopaminergic cells, our data indicate that the increase in neurotrophic factors is a possible mechanism by which (-)nicotine protects from experimental parkinsonisms. Moreover, they suggest that nAChR agonists could be of potential benefit in the progression of Parkinson's disease.
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PMID:Striatal increase of neurotrophic factors as a mechanism of nicotine protection in experimental parkinsonism. 950 63

Neural transplantation is an experimental therapy for Parkinson's disease. Pretreatment of fetal donor tissue with neurotrophic factors may improve survival of grafted dopaminergic neurons. Free-floating roller tube cultures of fetal rat ventral mesencephalon were treated with brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), or a combination of both. Dopamine content of the culture medium, the number of tyrosine hydroxylase-immunoreactive neurons, and culture volumes were moderately increased in the BDNF- and GDNF-treated cultures but significantly increased by 6.8-, 3.2- and 2.4-fold, respectively after treatment with the combination of both factors. We conclude that pretreatment of dopaminergic tissue in culture with a combination of BDNF and GDNF may be an effective means to improve the quality of tissue prior to grafting.
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PMID:Effects of combined BDNF and GDNF treatment on cultured dopaminergic midbrain neurons. 960 74

Gene transfer techniques have been explored as therapeutic modalities and neurobiologic tools to understand the role of various genes in animal models of Parkinson's disease. The gene for tyrosine hydroxylase, the rate-limiting step of dopamine synthesis, has been transferred into animal models by viral vectors or by implantable cells that have been modified by retrovirus vectors. The role of additional genes such as GTP cyclohydrolase 1 and aromatic L-amino acid decarboxylase in optimal delivery of dopamine in animal models is reviewed. Gene therapy also allows goals beyond replacement of dopamine. Neurotrophic factors such as brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor can be introduced to promote sprouting of neurites and protect the dopaminergic neurons from degeneration. Genes involved in apoptosis, free radical scavenger pathway, or other cell death mechanism could also be used to prevent the degeneration of the neurons. Current technology of gene therapy is limited in its long-term expression and ability to regulate the gene expression. However, recent developments provide better understanding of these limitations and suggest potential solutions to these technical hurdles.
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PMID:Potential of gene therapy for Parkinson's disease: neurobiologic issues and new developments in gene transfer methodologies. 961 21

We investigated the expression of BDNF and its high affinity receptor trkB in fetal dopaminergic grafts in a rat model of Parkinson's disease. Grafts were allowed to differentiate for 7, 14, 28, or 56 days, respectively and were analyzed immunocytochemically thereafter with antibodies directed against tyrosine hydroxylase, BDNF and trkB. At all time points investigated, grafts contained tyrosine hydroxylase immunoreactive neurons. Immature grafts (7 days) displayed no immunoreactivity for BDNF which was restricted to glial cells at the graft-host interface. After longer differentiation periods BDNF-immunoreactivity was detectable in neurons and astrocytes within the grafts. No trkB immunoreactivity was found in immature grafts but a strong signal for trkB emerged in grafted neurons older than 14 days whereas glial cells remained unlabeled at all time points investigated. Expression of BDNF and trkB in grafted neurons and of BDNF in surrounding glial cells suggests an autocrine or paracrine action of BDNF on dopaminergic neurons possibly mediated by activated glia.
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PMID:BDNF and TrkB expression in intrastriatal ventral mesencephalic grafts in a rat model of Parkinson's disease. 966 Jan 3


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