Nuevos blancos terapéuticos en el tratamiento de las depresiones resistentes: Moduladores glutamatérgicos / New Therapeutic Targets in the Treatment of Resistant Depression: glutamatergic modulators

Dentro de los trastornos del estado de ánimo, los trastornos depresivos son padecimientos generalmente recurrentes que tienen, según las estadísticas, una prevalencia anual de un 3 % a un 6 % en la población. Desde la década de los 60' la hipótesis aminérgica de Schildkraut y posteriores, establecieron que las depresiones estaban vinculadas a alteraciones en la neurotransmisión catecolaminérgica y serotoninérgica. Los fármacos antidepresivos apuntaron a esas disfunciones pero las dificultades terapéuticas, retraso en el inicio de la acción y limitaciones en la eficacia, llevaron a la búsqueda de otras posibilidades, que surgieron de las investigaciones sobre la neurotransmisión glutamatérgica. En modelos animales se descubrió en los comienzos de los 90' la acción antidepresiva de los fármacos que antagonizaban la neurotransmisión de los receptores N-metil-D-aspartato (NMDA). El objetivo de este trabajo se orienta a establecer los fundamentos de la teoría glutamatérgica de las depresiones y a describir los fármacos que potencialmente podrían utilizarse en la clínica...

Depressive disorders are usually recurrent diseases that, according to statistics, afects from 3 % to 6 % of the population. Since the early '60s the Schildkraut aminergic hypothesis and subsequent, established that depressions were associated with alterations in cahtecolaminegic and serotonergic neurotransmission. Antidepressant drugs aimed at these dysfunctions but the therapeutic difficulties, delayed onset of action and efficacy limitations, led to the search of other possibilities that emerged from the research on glutamatergic neurotransmission. In animal models it was discovered in the early 90's the antidepressant action of drugs antagonized the NMDA receptor neurotransmission. The objective of this work is aimed at establishing the foundations of the glutamatergic theory of depressions and describe drugs that potentially could be used in the clinic...

Recent advance in the discovery of allosteric inhibitors binding to the AMP site of fructose-1,6-bisphosphatase / 药学学报

Fructose-1, 6-bisphosphatase (FBPase), a rate-limiting enzyme involved in the pathway of gluconeogenesis, can catalyze the hydrolysis of fructose-1, 6-bisphosphate to fructose-6-phosphate. Upon inhibiting the activity of FBPase, the production of endogenous glucose can be decreased and the level of blood glucose lowered. Therefore, inhibitors of FBPase are expected to be novel potential therapeutics for the treatment of type II diabetes. Recent research efforts were reviewed in the field of developing allosteric inhibitors interacting with the AMP binding site of FBPase.

Actualización en la patofisiología de la esquizofrenia desde la perspectiva de la neurociencia de sistemas / Update on the pathophysiology of schizophrenia from the systems neuroscience point of view

La patofisiología de la esquizofrenia (EQZ) sólo podrá entenderse en una aproximación integrativa, basada en la neurociencia de sistemas, para tratar de explicar cómo múltiples genes y neurotransmisores pueden actuar de manera sinérgica para producir el trastorno. En este trabajo se analizarán por separado los diversos endofenotipos de esta enfermedad para tratar de explicar, sobre la base de aproximaciones sistémicas, cómo ocurren los cambios en las interneuronas GABAérgicas en la EQZ, comenzando con la hipofunción GABAérgica y sus consecuencias sobre las neuronas piramidales corticales y la disfunción dopaminérgica a punto de origen hipocampal, lo que permite conciliar eventos neurobiológicos con sus consecuencias conductuales (consilience). Los circuitos involucrados por Lisman, Grace, Coyle, Green y otros autores en esta revisión integran las neurotransmisiones glutamatérgica, GABAérgica, dopaminérgica y colinérgica en un marco sistémico en que también se involucran factores de riesgo genético, para intentar demostrar sus acciones sinérgicas dentro del circuito y generar una aproximación desde la neurociencia de sistemas. Se intentará desarrollar estrategias de distinto orden para comprender la EQZ como enfermedad que produce sus consecuencias devastadoras a través de la acción sinérgica de genes y diversos neurotransmisores integrados en circuitos de procesamiento que operan en complejas dinámicas de tipo no-lineal.

Understanding the pathophysiology of schizophrenia (SZ) entails adopting a holistic approach based on systems neuroscience that allows to explain how multiple genes and neurotransmitters can act synergistically to trigger the disorder. In this article, the different endophenotypes of schizophrenia are analysed separaately, with the aim of explaining, by means of systemic approaches, how changes take place in GABAergic interneurons in SZ, starting from the GABAergic hypofunction and ists effects on cortical pyramidal neurons, as well as on the dopaminergic dysfunction at he pont of origin of the hippocampus, which enables to reconcile neurobiological events with their behavioural consequences ("consilience"). The circuits proposed by Lisman, Grace, Coyle, Green and other authors, that make up glutamatergic, GABAerci, dopaminergic and cholinergic neurotransmissions embedded in a systemic framework in whic genetic risk factors are also involved, are included in this review to demonstrate their synergistic actions within the circuit, as well as to develop an approach based on systems neuroscience. The present article will also provide different types of strategies intended to understand SZ as a disease that causes its devastating effects through the synergistic action of genes and the different neurotransmitters organized in processing circuits that operte in complex non-linear dynamics.

Allosteric inhibition of [[125]I] ET-1 binding to ETA receptors by salicylic acid dimers

Endothelin-1 [ET-1], a potent vasoconstrictor peptide, exerts its physiological effects by binding and activating specific G protein-coupled receptors, named ETA and ETB. An unique property of ET-1 is its ability to bind almost irreversibly to its receptors. Aspirin and salicylic acid [SA] are allosteric inhibitors of ET-1 binding to ETA receptors. Dihalogenated derivatives of SA have been identified as more potent allosteric inhibitors than aspirin. In this study, dihalosalicylic acid dimers were synthesized and tested as inhibitors of [[125]I] ET-1 binding to ETA receptors in rat embryonic cardiomyocyte [H9c2 cell] membranes in aim to development of new potential allosteric inhibitors of ET-1. Some dihalo- salicylic acid dimers synthesized in this study showed promising activity as inhibitor of [[125]I] ET-1 binding to ETA receptors in comparing with the dihalosalicylic acid reported in literature, the bromo substituted compound B showed very interesting activity than other halogen substituted dimers, it causes about 40% inhibition at 100 microM and causes 100% inhibition at 500 microM. we conclude that dihalosalicylic acid dimers can mediate good inhibition activity in comparison to sole dihalosalicylic acid molecule

Inhibition of [[125]I] ET-1 binding to ETA receptors by salicylic acid dimers

Endothelin-1 [ET-1], a potent vasoconstrictor peptide, exerts its physiological effects by binding and activating specific G protein-coupled receptors, named ETA and ATB. A unique property of ET-1 is its ability to bind almost irreversibly to its receptors. Aspirin and salicylic acid [SA] are allosteric inhibitors of ET-1 binding to ETA receptors. Dihalogenated derivatives of SA have been identified as more potent allosteric inhibitors than aspirin. In this study, dihalosalicylic acid dimers were synthesized and tested as inhibitors of [[125]I] ET-1 binding to ETA receptors in rat embryonic cardiomyocyte [H9c2 cell] membranes in aim to development of new potential allosteric inhibitors of ET-1. Some dihalosalicylic acid dimers synthesized in this study showed promising activity as inhibitor of [[125]I] ET-1 binding to ETA receptors in comparing with the dihalosalicylic acid reported in literature. The bromo substituted compound b showed more remarkable activity than other halogen substituted dimers, it causes about 40% inhibition at 100 microM and causes 100% inhibition at 500 microM. We conclude that dihalosalicylic acid dimers can mediate good inhibition activity in comparison to sole dihalosalicylic acid molecule

NMDA receptor channel / 한양의대학술지

Glutamate receptor channels have been classified into three major subtypes, the alpha-amino-3 - hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainite and N-Methyl-D-aspartate (NMDA) receptor channels. The NMDA receptor channel differs in fundamental ways from the non-NMDA receptor channels, and these properties relate directly to its physiological roles. NMDA ion channels play important roles in various physiological or pathologic functions in neuroprotection, neurodegeneration, long-term potentiation, memory, cognition, neurological disorders, psychiatric disorders, and neuropathic pain syndromes. The NMDA receptor channel is gated in a unique manner both by ligands and by voltage. The voltage dependence is caused by Mg2+ block within the ion channel. The NMDA receptor is highly permeable to Ca2+ unlike most other ions. In addition, it can be modulated at a number of sites other than glutamate recognition site. Among these sites, an allosteric site through glycine modulates the NMDA response. The molecular cloning and diversity of the NMDA receptor channel have been identified. The mechanisms that control the opening and closing, or gating, of the channel of NMDA receptors are among the most basic determinants of receptor function, and yet are not well understood. This review summarizes from a molecular perspective the recent advances in our understanding of the pharmacological properties of NMDA receptor channels.

Lag kinetics of tyrosinase: its physiological implications.

The various theories put forward to explain the characteristic lag kinetics of oxidation of L-tyrosine by tyrosinase a rate regulatory step in the biosynthesis of melanin are reviewed Examination of the evidence in the literature and from experiments in the author's laboratory indicate that one of the hypotheses, that is, competition of tyrosine and dopa for met-tyrosinase and the formation of a dead-end complex of met-enzyme with tyrosine as explanation for lag kinetics is not consistent with available information. The alternative hypothesis that tyrosinase is an allosteric enzyme with tyrosine having negative effector site on the enzyme and dopa competing for it as an explanation for lag kinetics of tyrosinase is not yet disproved. Irrespective of the actual explanation for the lag kinetics of tyrosinase, it is suggested that the highly conserved lag kinetics may serve a physiological function. It is suggested that this function is to keep the enzyme essentially inactive during its transport to the specific organelle, namely the melanosome, in which an acidic environment exists. Only at acidic pH is the enzyme able to catalyze the biosynthesis of melanin.

An overview on chemical modification of enzymes. The use of group-specific reagents

Chemical modification is an important approach to the study of enzyme active sites. This article presents an overview of the methods used. The basic concepts, applications and limitations of chemical modification are outlined. The use of reagents specific for different amino acid side chains is also discussed

Chemical modification of allosteric properties of enzymes

Chemical modification is usually employed to study enzyme active sites. Valuable information can also be obtained, however, when this technique is used to probe allosteric sites. This approach is discussed in this article, and it is exemplified in chemical modification studies of the allosteric enzyme phosphofructokinase