Catálogo de publicaciones - libros
Oxidative Stress and Neuroprotection
H. Parvez ; P. Riederer (eds.)
Resumen/Descripción – provisto por la editorial
No disponible.
Palabras clave – provistas por la editorial
Neurology
Disponibilidad
Institución detectada | Año de publicación | Navegá | Descargá | Solicitá |
---|---|---|---|---|
No detectada | 2006 | SpringerLink |
Información
Tipo de recurso:
libros
ISBN impreso
978-3-211-33327-3
ISBN electrónico
978-3-211-33328-0
Editor responsable
Springer Nature
País de edición
Reino Unido
Fecha de publicación
2006
Información sobre derechos de publicación
© Springer-Verlag/Wien 2006
Cobertura temática
Tabla de contenidos
Isatin interaction with glyceraldehyde-3-phosphate dehydrogenase, a putative target of neuroprotective drugs: partial agonism with deprenyl
A. Medvedev; O. Buneeva; O. Gnedenko; V. Fedchenko; M. Medvedeva; Y. Ivanov; V. Glover; M. Sandler
There is evidence that the binding of deprenyl, a monoamine oxidase (MAO) B inhibitor, and other propargylamines to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is primarily responsible for their neuroprotective and antiapoptotic effects. Thus, GAPDH may be a target for other neuroprotective drugs. Using two independent approaches, radioligand analysis and an optical biosensor technique, we demonstrate here that GAPDH also interacts with the endogenous, reversible MAO B inhibitor, isatin. Deprenyl inhibited both [^3H]isatin binding to GAPDH, and the binding of this enzyme to an isatin analogue, 5-aminoisatin, immobilized on to an optical biosensor cell. Another MAO inhibitor, tranylcypromine, was ineffective. Both deprenyl and isatin inhibited GAPDH-mediated cleavage of E. coli tRNA, and their effects were not additive. We suggest that isatin may be an endogenous partial functional agonist of deprenyl in its effect on GAPDH and GAPDH-mediated RNA cleavage. Changes in level of endogenous isatin may influence the neuroprotective effect of deprenyl in vivo.
Palabras clave: Hepatitis Delta Virus; Japanese Encephalitis Virus; Optical Biosensor; Neuroprotective Drug; Sensor Chip Surface.
Pp. 97-103
Inhibition of amine oxidases by the histamine-1 receptor antagonist hydroxyzine
J. O’Sullivan; M. I. O’Sullivan; K. F. Tipton; G. Davey
The effects of the drug hydroxyzine on the activities of the rat liver monoamine oxidases (EC 1.4.3.6; MAO) and the membrane-bound and soluble forms of bovine semicarbazide-sensitive amine oxidase (EC 1.4.3.6; SSAO) were studied. Hydroxyzine was found to be a competitive inhibitor of MAO-B (K_i ∼ 38 µM), whereas it had a low potency towards MAO-A (IC_50 > 630 µM). Although it was a relatively potent competitive inhibitor of bovine plasma SSAO (K_i ∼ 1.5 µM), it was a weak inhibitor of the membrane-bound form of the enzyme from bovine lung (IC_50 ∼ 1mM). These findings extend our knowledge of the drug binding capabilities of the amine oxidases and suggest that these interactions may contribute to the complex actions of this drug.
Palabras clave: Monoamine Oxidase; Generalise Anxiety Disorder; Amine Oxidase; Bovine Lung; Semicarbazide Sensitive Amine Oxidase.
Pp. 105-112
Neuroprotection for Parkinson’s disease
P. A. LeWitt
Although still a disorder of unknown etiology, Parkinson’s disease (PD) has provided a number of clues that have led to clinical trials of neuroprotection. For example, defects in mitochondrial metabolism and evidence for oxidative stress in PD have fostered therapeutic interventions aimed at slowing disease progression. More than a dozen compounds already have been tested in PD for disease modification, and others are in planning stages for clinical trials. The challenge is to find a highly effective therapy halting disease progression (beyond the relatively modest clinical effect exemplified by recent findings with coenzyme Q-10 treatment administered at 1200 mg/day). Clinical exam-based ratings and disability assessments still serve at providing the primary evidence of efficacy. However, with surrogate biomarkers such as radiotracer neuroimaging of the dopaminergic system, the pace of clinical investigation can be increased. Recent years have seen the utilization of more sensitive study methods in PD neuroprotection research, such as staggered wash-in, 2 × 2 factorial, and “futility” trial designs. The results of several ongoing PD neuroprotection trials are planned for release in the near future.
Palabras clave: Parkinson Disease; Dopaminergic Agonist; Parkinson Study Group; Single Proton Emission Compute Tomography; SNpc Neuron.
Pp. 113-122
Marker for a preclinical diagnosis of Parkinson’s disease as a basis for neuroprotection
Daniela Berg
Neuroprotective therapy is a pivotal aim in the treatment of the relentlessly progressive disorder Parkinson’s disease. However, more than 60% of the dopaminergic neurons of the substantia nigra have already degenerated, when the diagnosis may be established. At this “advanced stage” neuroprotective strategies will — if at all — only have limited effect. It is, therefore, essential to establish markers to identify subjects at risk before motor manifestation. A number of such “premotor” signs have been discovered and investigated lately. Such signs include a genetic vulnerability and hyperechogenicity of the substantia nigra as well as premotor symptoms like olfactory and autonomic dysfunction, depression, REM sleep behaviour disorder, visual and neuropsychological impairment. Moreover, first signs of affection of the substantia nigra like PET and SPECT abnormalities and slight motor signs can be included, as they may be detected before a definite diagnosis can be made. Although most of these signs and symptoms are unspecific if singularly evaluated a combination of these features may indeed be valuable to detect a subgroup of the population at risk for PD. However, future studies are necessary to establish the predictive value of these “markers” singularly and in combination.
Palabras clave: Single Photon Emission Compute Tomography; Olfactory Dysfunction; Transcranial Sonography; Atypical Parkinsonian Syndrome; Substantia Nigra Hyperechogenicity.
Pp. 123-132
Assessing neuroprotection in Parkinson’s disease: from the animal models to molecular neuroimaging in vivo
R. Ceravolo; P. Sgadò; D. Frosini; G. U. Corsini
An important goal in Parkinson’s Disease research is to identify neuroprotective therapy, and the interaction between basic science and clinical research is needed to discover drugs that can slow or halt the disorder progression. At present there is not a perfect animal model of PD to test neuroprotective strategies, however the models that portray the basic characteristics needed are toxin-induced and gene-based models. The first group comprehends 6-OHDA e MPTP and recently rotenone, paraquat and epoxomicin treated animals that shows some of human disease characteristics. Gene-based models are various and, even if with limits, they seem suitable models to test neuroprotection in PD since they present replicable lesions, a predictable pattern of neurodegeneration and a well-characterized behavior, biochemistry and morphology to assist in the understanding of induced changes. In clinical trials researchers have first used as marker of disease progression clinical scores and motor tasks which are limited by the potential symptomatic effect of tested drugs and are not useful in the pre-clinical phases of PD. Recently has emerged the important role of neuroimaging (Dopamine Transporter SPECT, 18FDopa-PET) as surrogate biomarker of PD progression. Even if there are still concerns about the influence of regulatory effects of tested drugs, neuroimaging features could represent a good outcome measure to evaluate PD progression and putative neuroprotective effect of pharmacological and non-pharmacological manipulations.
Palabras clave: Positron Emission Tomography; Single Photon Emission Computerize Tomography; Dopamine Transporter; Single Photon Emission Computerize Tomography Study; Autosomal Recessive Juvenile Parkinsonism.
Pp. 133-141
Deprenyl: from chemical synthesis to neuroprotection
K. Magyar; M. Pálfi; V. Jenei; É. Szökő
During the last decades (-)-deprenyl has become the golden standard of MAO-B inhibitors. It possesses dopamine potentiating and antioxidant properties; however, its effects cannot be explained solely by the enzyme inhibitory action. (-)-Deprenyl prevents the toxicity of certain selective neurotoxins and recently it was demonstrated to increase cell-cell adhesion as well. The complexity of its pharmacological effects reflects the action of both the parent compound and the active metabolites. (-)-Deprenyl and related propargylamines (DRPs) show neuroprotective features in a variety of in vitro and in vivo models that is dependent on the propargyl moiety. The main presumptive targets to date include glyceraldehyde-3-phosphate dehydrogenase, poly(ADP-ribose) polymerase, some kinase cascades, as well as pro- and antiapoptotic proteins, beside the inhibition of MAO-B. The antiapoptotic activity of DRPs converges upon the maintenance of mitochondrial integrity, due to the initiation of a complex transcriptional program, the details of which are yet to be elucidated.
Palabras clave: PC12 Cell; Nerve Growth Factor; Antiapoptotic Activity; Selective Neurotoxin; Propargyl Moiety.
Pp. 143-156
The use of rasagiline in Parkinson’s disease
A. H. V. Schapira
Rasagiline is a novel, potent, irreversible inhibitor of monoamine oxidative B developed for the symptomatic treatment of Parkinson’s disease. The drug has shown efficacy in improving motor features in both early and advanced Parkinson’s disease patients. The drug appears to be well tolerated and its once daily fixed dose formulation should make for excellent compliance. Rasagiline has also demonstrated important neuroprotective properties in both in vitro and in vivo laboratory studies. A provisional study of neuroprotection in a delayed start clinical trial of early PD patients has also suggested that this benefit may be translated to the clinic. Additional clinical trials are underway to confirm this.
Palabras clave: Dopamine Agonist; Parkinson Study Group; Early Parkinson Disease; Rasagiline Group; Selegiline Hydrochloride.
Pp. 157-161
Novel neuroprotective neurotrophic NAP analogs targeting metal toxicity and oxidative stress: potential candidates for the control of neurodegenerative diseases
H. Zheng; D. Blat; M. Fridkin
A large body of data indicates that a cascade of events contributes to the neurodegeneration in Alzheimer’s disease (AD) and Parkinson’s disease (PD). Metal (Fe, Cu, Zn) dyshomeostasis and oxidative stress are believed to play a pivotal role in the pathogenesis of these diseases. Accordingly, multifunctional compounds combining metal chelating and antioxidative activity hold a great promise as potential drugs for treating AD and PD. In this study, two novel NAPVSIPQ (NAP) analogs (M98 and M99) with potential antioxidant-metal chelating ability were designed and investigated, aiming to improve the poor metal chelating and antioxidative activity of NAP. Our studies showed that both M98 and M99 formed stable metal (Fe, Cu, Zn) complexes in water and demonstrated good metal (Fe, Cu, Zn) chelating properties as opposed to the poor metal (Fe, Cu, Zn) chelating properties of their parent peptide NAP. M98 and M99 exhibited significant inhibition of iron-induced lipid peroxidation in rat brain homogenates at concentrations of ≥30 µM, while NAP failed to show any inhibition even at 100 µM. In human neuroblastoma cell (SH-SY5Y) culture, M98 and M99 at 1 µM completely protected against 6-hydroxydopamine (6-OHDA) toxicity with potency similar to NAP and desferal (DFO), a strong iron chelator and a highly potent radical scavenger. In PC12 cell culture, M98 at the range of 0.001–1 µM displayed potent protection against 6-OHDA toxicity, comparable to NAP and DFO. These results suggest that M98 and M99 deserve further investigation as potential drug candidates for neuroprotection.
Palabras clave: High Performance Liquid Chromatography; PC12 Cell; Vasoactive Intestinal Peptide; Preparative High Performance Liquid Chromatography; Central Nervous System Target.
Pp. 163-172
Acute and chronic effects of developmental iron deficiency on mRNA expression patterns in the brain
S. L. Clardy; X. Wang; W. Zhao; W. Liu; G. A. Chase; J. L. Beard; B. True Felt; J. R. Connor
Because of the multiple biochemical pathways that require iron, iron deficiency can impact brain metabolism in many ways. The goal of this study was to identify a molecular footprint associated with ongoing versus long term consequences of iron deficiency using microarray analysis. Rats were born to iron-deficient mothers, and were analyzed at two different ages: 21 days, while weaning and iron-deficient; and six months, after a five month iron-sufficient recovery period. Overall, the data indicate that ongoing iron deficiency impacts multiple pathways, whereas the long term consequences of iron deficiency on gene expression are more limited. These data suggest that the gene array profiles obtained at postnatal day 21 reflect a brain under development in a metabolically compromised setting that given appropriate intervention is mostly correctable. There are, however, long term consequences to the developmental iron deficiency that could underlie the neurological deficits reported for iron deficiency.
Palabras clave: Myelin Basic Protein; Brain Iron; Myelin Gene; Chaperonin Contain TCP1; Peripheral Myelin Protein.
Pp. 173-196
Long lasting effects of infancy iron deficiency — Preliminary results
S. Yehuda; M. Yehuda
The long-term effects of rehabilitated infancy (1 year old) iron deficiency (ID) were examined at age 10. The children were examined for the following variables: auditory system function, the level of morning cortisol, I.Q. score (WISC-R), and behavioral profile. The results indicate that while the former ID children’s hearing system appears to function well, there was a delay in brain stem processing of the auditory signals. In addition, the level of morning cortisol was reduced, the general I.Q. scores were lower than the normal group (mainly in the performed subtest), and more sleep disturbances and fatigue during day were reported. These outcomes are consistent with established reports on the effect of iron deficiency on the rate of myelination in selected brain areas during critical period of 1 year olds. The findings of increased sleep disturbances and lower I.Q. tests require further study.
Palabras clave: Salivary Cortisol; Auditory Brainstem Response; Morning Cortisol; Audiometric Test; Brain Research Institute.
Pp. 197-200