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J Garcia de Yebenes

Publications and source records attributed to J Garcia de Yebenes.

7 recordsLinked to original sources
PubMed2000

Neurotrophic factors in neurodegenerative disorders: model of Parkinson's disease.

Neurotrophic factors are compounds that enhance neuronal survival and differentiation. Most of these compounds exert their pharmacological actions on selective types of neurons, and therefore, are considered promising new therapeutic agents for the treatment of different neurodegenerative disorders characterized by selective degeneration of certain neuronal groups. Those compounds have been used in humans for several neurological disorders including amyotrophic lateral sclerosis--ciliary derived neurotrophic factor (CNTF) and brain derived neurotrophic factor (BDNF), Alzheimer's disease and peripheral neuropathy--nerve growth factor (NGF) and Parkinson's disease (PD)--glial derived neurotrophic factor (GDNF). In spite of well founded clinical experiments by previous experimental work in animal models some of these trials have been negative. For instance, animal models of PD have shown that several neurotrophic factors, including GDNF and other compounds, reduce apoptosis and increase resistance of dopamine neurons to neurotoxins in vitro. These compounds prevent or recover the damage to dopamine neurons of rodents and primates produced by chemical or mechanical acute lesions including 6-OH-DA, MPTP, methamphetamine and axotomy. The differences between the promising results obtained in experimental models and the lack of clinical results or excessive toxicity found in humans could be attributed to the following reasons: (a) Lack of relevance between the pathogenesis of the experimental lesion and the corresponding neurodegenerative disorder. (b) Poor correlation between results obtained in acute, self-limited, selective deficit produced to experimental animals and those available in more complex, chronic and progressive disorders involving patients. (c) Inadequate delivery of the active product to the target area in the human brain. (d) Poor information from acute experiments in animals which does not predict long-term effects of chronic infusion in humans. Further experimental work, therefore, is needed to transfer these neurotrophic factors to the clinic.

Journal Article↗
PubMed1995

Fibroblast growth factors: structure-activity on dopamine neurons in vitro.

We investigated the effect of neurotrophic factors on dopamine (DA) cells in vitro. At concentrations of nanograms/c.c. basic fibroblast growth factor (bFGF) is a more potent DA-trophic agent than brain derived neurotrophic factor (BDNF) or epidermal growth factor (EGF) in fetal mid brain neurons. In these cells, bFGF produces a greater increase of DA levels and percentage of cells positive for tyrosine hydroxylase (TH+) than BDNF and EGF. Acidic fibroblast growth factor (aFGF) was not tested in fetal DA cells since aFGF requires heparin for its effect and fetal mid brain cultures do not grow well in the presence of a high concentration of heparin. We further investigated the effect of bFGF and aFGF, and two of their analogs, in catecholamine rich human neuroblastoma cells NB69. In these cells aFGF, at concentrations of picograms/c.c., increases DA levels, while its analogs, E118 and super short, have no effect. Acidic FGF also increases norepinephrine levels, the number of TH+ cells, and the percentage of TH+ with respect to the total number of nuclei. Basic fibroblast growth factor (bFGF) produced similar, but less potent effects. Acidic FGF was active only in the presence of heparin; the effect of bFGF was independent of heparin. FGFs are promising drugs for the treatment of PD, though further investigations with these compounds should be performed before their use in clinical trials.

Animals↗
PubMed1989

Biochemical properties of monoamine-rich human neuroblastoma cells.

The biochemical, pharmacological and immunological characterization of cells derived from human neuroblastoma tumors recently acquired great interest, since these cells may be a putative donor source for transplantation in animal models of neurological disorders. We measured monoamine levels, tyrosine hydroxylase (TH) immunostaining, and the expression of major histocompatibility cell surface antigens (MHC) in 7 human neuroblastoma cell lines. Three cell lines (LAN5, NB69 and CHP126) had high levels of monoamines. TH immunostaining was strongly positive in CHP126 and LAN5, and NB69. MHC were not detected in any of the cells with high catecholamine levels. Treatment with neuroleptics increased the metabolism of dopamine in LAN5 but not in NB69. The implantation of LAN5 cells in immunocompetent, unilaterally 6-hydroxydopamine-lesioned rats decreased the apomorphine-induced contralateral rotation. The effect of the implant was greatest in animals in which LAN5 neuroblastoma cells, pretreated with dibutyryl cyclic adenosine monophosphate (DBcAMP) and prostaglandin E1 (PGE1, were implanted into the cerebral ventricle ipsilateral to the lesion, and then irrigated with DBcAMP administered through a totally implanted drug delivery system. The effect of the implant decreased after the second week. Neuroblastoma cells were found in approximately 50% of the implanted animals. TH immunostaining was weak or absent in the grafted animals. Inflammatory changes were present in the majority of the brains examined. Extensive tumor growth was present in one animal implanted with untreated cells. Grafting of cells treated with DBcAMP and PGE1 plus with mitomycin C and bromodeoxyuridine in animals immunosuppressed with cyclosporin A reduced the apomorphine-induced rotation to 40-60% of baseline levels and this reduction persisted beyond the period of infusion with DBcAMP. Intraventricular infusion of DBcAMP in animals injected with cell culture medium produced a transient reduction of rotation to 70% of baseline. The amphetamine-induced rotation was not significantly reduced during the 4 weeks follow up. Atypical cells, consistent with surviving neuroblastoma cells, were observed in the brain of all transplanted animals. TH immunostaining was weak or negative in most cases. Human neuroblastoma cells may be an alternative donor tissue for the study of the effects of transplantation in animal models of Parkinson's disease.

Animals↗
PubMed1978

The effect of beta-alanine on motor behaviour, body temperature and cerebral monoamine metabolism in rat.

Intracerebroventricular (ICV) injection of beta-alanine produced a decrease in rectal temperature, inhibition of exploratory behaviour and motility, and changes in the metabolism of cerebral monoamines. Dopa and 5-HTP accumulation after inhibition of L-aromatic amino acid decarboxylase, NSD 1015 (3-hydroxybencylhydrazine HCl, 100 mg/kg i.p.) was found to be significantly increased in all the dissected cerebral regions of animals treated with beta-alanine, as compared to the controls. Levels of tyrosine and tryptophan did not show any significant change. Endogenous levels of dopamine (DA), noradrenaline (NA), serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA), did not change. After inhibition of the catecholamines synthesis with alpha-methyltryrosine (alpha-MT), dopamine depletion was retarded and noradrenaline accelerated, but without reaching statistical significance. After intraperitoneal (i.p.) injection of beta-alanine, significant changes in motor behaviour were found. Body temperature and metabolism of brain catecholamine were unchanged. This lack of effect could be explained by poor penetration through the blood-brain barrier.

Alanine↗
PubMedDate not supplied

Bradykinesia in Huntington's disease.

Huntington's disease (HD) is characterized by the presence of hyperkinesias, but bradykinesia is also present in most patients. We studied the motor performance of 18 patients with genetically proven HD (age, 38.5 +/- 10 y; clinical stage, 1.7 +/- 1.7; (CAG) triplet length, 49.2 +/- 6.8 triplets; all but three patients were free from neuroleptics) and compared with a control group (n = 18) and with a typical Parkinson's disease (PD) group (n = 20). Motor study included the four timed tests commonly used for PD: Pronation-supination (PS), finger dexterity (FD), movement between two points (MTP) and walking test (WT). Tests were done at 9 AM. The PD group was studied in "off" condition, with no medication given for 12 hours. The HD group was slower than the controls on all tasks (all tests significant, p < 0.01, Mann-Whitney U test) and even slower than PD group (for FD, p < 0.05). A significant correlation was found between each test and clinical stage (for PS, r = 0.84; for FD, r = 0.75; for MTP, r = 087, and for WT, r = 0.77, Pearson). Severe bradykinesia was present in HD, and motor impairment is related to clinical stage.

Adult↗
PubMedDate not supplied

Intracerebroventricular infusion of dopamine and its agonists in rodents and primates. An experimental approach to the treatment of Parkinson's disease.

The authors investigated the effects of chronic intracerebroventricular (ICV) infusion of dopamine (DA) and DA agonists in animal models of DA deficiency in rodents and primates. Rats with unilateral nigrostriatal lesions induced by 6-OH-DA received infusions of DA, pergolide, lisuride, and (+)-4-propyl-9-hydroxynaphthoxacine (PHNO) for from 1 to 2 weeks through a catheter implanted into the cerebral ventricle ipsilateral to the lesion and connected to an osmotic minipump filled with the active substance. The infused animals had persistent contralateral rotation during the period of infusion. The DA infusion restored DA levels in lesioned animals. In animals treated chronically with reserpine, the ICV DA infusion restored DA levels in the brain, but akinesia was not reversed unless monoamine oxidase inhibiters were also given, intraperitoneally or ICV, with the DA infusion. An ICV infusion of PHNO reversed reserpine-induced akinesia. The infusion of DA or PHNO restored normal patterns of behavior in monkeys made akinetic by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), but the infusion was complicated by intolerance to the pump or frequent disconnection of the catheter. An ICV infusion of PHNO may be an alternative experimental approach to the treatment of fluctuations in patients with Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗