The Relationship Between the Renin-Angiotensin-Aldosterone System and NMDA Receptor-Mediated Signal and the Prevention of Retinal Ganglion Cell Death.

Purpose: Excitotoxicity, which is due to glutamate-induced toxic effects on the retinal ganglion cell (RGC), is one of several mechanisms of RGC loss. The renin-angiotensin-aldosterone system (RAAS) has also been implicated in RGC death. Therefore, it is important to determine the exact relationship between the RAAS and N-methyl-d-aspartate (NMDA) receptor-mediated signal in order to prevent RGC death. Methods: N-methyl-d-aspartate or aldosterone was injected into the vitreous body. After intravitreal injection of NMDA or aldosterone, animals were treated with spironolactone or memantine. Retinal damage was evaluated by measuring the number of RGCs at 4 weeks after local administration of aldosterone or at 2 weeks after local administration of NMDA. Vitreous humor levels of aldosterone were measured using enzyme immunoassay kits. Results: A significantly decreased number of RGCs were observed after intravitreal injection of NMDA. Although spironolactone did not show any neuroprotective effects, memantine significantly reduced NMDA-induced degeneration in the retina. Furthermore, a significant decrease in the number of RGCs was observed after an intravitreal injection of aldosterone. While memantine did not exhibit any neuroprotective effects, spironolactone caused a significant reduction in the aldosterone-induced degeneration in the retina. There was no change in the aldosterone concentration in the vitreous humor after an NMDA injection. Conclusion: Our findings indirectly show that there is no relationship between the RAAS and NMDA receptor-mediated signal with regard to RGC death.

The effects of DL-AP5 and glutamate on ghrelin-induced feeding behavior in 3-h food-deprived broiler cockerels

No disponible

This study was designed to examine the effects of intracerebroventricular injection of DL-AP5 (N-methyl-D-aspartate (NMDA) receptor antagonist) and glutamate on ghrelin-induced feeding behavior in 3-h food-deprived (FD3) broiler cockerels. At first, guide cannula was surgically implanted in the right lateral ventricle of chickens. In experiment 1, birds were intracerebroventricularly injected with 0, 2.5, 5, and 10 nmol of DL-AP5. In experiment 2, chickens received 5 nmol DL-AP5 prior to the injection of 0.6 nmol ghrelin. In experiment 3, birds were administered with 0.6 nmol ghrelin after 300 nmol glutamate, and the cumulative feed intake was determined at 3-h postinjection. The results of this study showed that the intracerebroventricular injection of DL-AP5 increased food consumption in FD3 broiler cockerels (P ¡Ü 0.05), and this increase occurs in a dose-dependent manner. Moreover, the decreased food intake induced with the intracerebroventricular injection of ghrelin was additively enhanced by pretreatment with glutamate, and this effect was attenuated by DL-AP5 (..)(AU)

Neuronal gap junctions are required for NMDA receptor-mediated excitotoxicity: implications in ischemic stroke.

N-methyl-D-aspartate receptors (NMDARs) play an important role in cell survival versus cell death decisions during neuronal development, ischemia, trauma, and epilepsy. Coupling of neurons by electrical synapses (gap junctions) is high or increases in neuronal networks during all these conditions. In the developing CNS, neuronal gap junctions are critical for two different types of NMDAR-dependent cell death. However, whether neuronal gap junctions play a role in NMDAR-dependent neuronal death in the mature CNS was not known. Using Fluoro-Jade B staining, we show that a single intraperitoneal administration of NMDA (100 mg/kg) to adult wild-type mice induces neurodegeneration in three forebrain regions, including rostral dentate gyrus. However, the NMDAR-mediated neuronal death is prevented by pharmacological blockade of neuronal gap junctions (with mefloquine, 30 mg/kg) and does not occur in mice lacking neuronal gap junction protein, connexin 36. Using Western blots, electrophysiology, calcium imaging, and gas chromatography-mass spectrometry in wild-type and connexin 36 knockout mice, we show that the reduced level of neuronal death in knockout animals is not caused by the reduced expression of NMDARs, activity of NMDARs, or permeability of the blood-brain barrier to NMDA. In wild-type animals, this neuronal death is not caused by upregulation of connexin 36 by NMDA. Finally, pharmacological and genetic inactivation of neuronal gap junctions in mice also dramatically reduces neuronal death caused by photothrombotic focal cerebral ischemia. The results indicate that neuronal gap junctions are required for NMDAR-dependent excitotoxicity and play a critical role in ischemic neuronal death.

Interacción entre receptores de glutamato y receptores de nucleótidos en neuronas granulares de cerebelo en cultivo / Cross-talk between glutamate and nucleotide receptors in cerebellar granule neurons in culture

ATP elicits Ca2+ transients in cultured cerebellar granule neuronsacting through specific ionotropic (P2X) and metabotropic (P2Y)purinergic receptors. In these neurons, application of L-Glutamate(L-Glu) immediately before ATP induced a prolonged reductionof ATP-mediated responses that remains at least 5 minutes afterL-Glu wash out. alpha-amino-3-hydro-5-methyl-4-isoxazolpropionicacid (AMPA), N-methyl-D-aspartate (NMDA) and 3,5-dihydroxyphenyl-glycine (DHPG), selective agonists of ionotropic non-NMDA,NMDA and Group I metabotropic glutamate receptors respectively,mimicked Glu-induced attenuating effects. The activity of calciumcalmodulindependent protein kinase II (CaMKII) seems to beinvolved, at least at long term, because inhibitors of CaMKII, 1-[N,Obis(5-isoquinolinesulfonyl)-N-methyl-L-(KN-62) and N-[2-[[[3-(4'-chlorophenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4'-methoxybenzenesulfonamide(KN-93), abolished the inhibitory effect of L-Glu on ATP-mediatedresponses. However, it is likely that other protein kinases could beinvolved in the cross-talk process between both groups of receptorsat short term. Therefore, these results demonstrate that the activationof glutamate receptors is able to modulate nucleotide responses incerebellar granule neurons(AU)

Interacción entre receptores de glutamato y receptores denucleótidos en neuronas granulares de cerebelo en cultivoEl ATP induce un incremento de Ca2+ en neuronas granulares decerebelo en cultivo actuando a través de receptores purinérgicos específicosionótropicos (P2X) y metabotrópicos (P2Y). En estas neuronas,la aplicación de L-Glutamato (L-Glu) inmediatamente antes del ATPinduce una prolongada disminución de las respuestas mediadas porATP que se mantiene al menos durante cinco minutos tras el lavadodel L-Glu. Los agonistas selectivos de los receptores ionotrópicosde glutamato no-NMDA, NMDA y del Grupo I, el ácido alfa-amino-3-hidro-5-metil-4-isoxazolpropiónico (AMPA), el N-metil-D-aspartato(NMDA) y el 3,5-dihidroxifenil-glicina (DHPG), respectivamente, mimetizanlos efectos atenuantes inducidos por el glutamato. La actividadde la proteína calcio-calmodulina quinasa II (CaMKII) pareceestar implicada en este proceso, al menos a largo plazo, puesto quelos inhibidores de la CaMKII, 1-[N,O-bis(5-isoquinolinesulfonil)-Nmetil-L-tirosil]-4fenilpiperazine (KN-62) y N-[2-[[[3-(4'-clorofenil)-2-propenil]metilamino]metil]fenil]-N-(2-hidroxietil)-4'-metoxibenzenosulfonamida(KN-93), revierten el efecto inhibitorio del L-Glu sobrelas respuestas mediadas por ATP. Sin embargo, es probable que puedanestar implicadas otras proteín quinasas en los procesos de interacciónentre ambos grupos de receptores a corto plazo. Por lo tanto,estos resultados demuestran que la activación de los receptores deglutamato son capaces de modular las respuestas a nucleótidos enneuronas granulares de cerebelo(AU)

Mecanismos celulares que son la base de los efectos antidepresivos de la ketamina: papel de los receptores del ácido alfa-amino-3-hidroximetilisoxazol-4-propiónico / Cellular mechanisms forming the basis of the antidepressant effects of ketamine: role of alpha-amino-3-hydroxymethylisoxazol-4- propionic acid receptors

Fundamento: La ketamina tiene efectos antidepresivos potentes, rápidos y relativamente sostenidos en pacientes con depresión mayor. La comprensión de los mecanismos que son la base de los efectos fascinantes de los antagonistas de la N-metil-D-aspartato (NMDA) podría dar lugar a nuevos fármacos con un inicio rápido de acción. Métodos: Para investigar los efectos conductuales de la ketamina en ratones se usaron los exámenes de indefensión aprendida, natación forzada y evitación pasiva. Se efectuaron experimentos bioquímicos y conductuales adicionales para determinar si en las propiedades de tipo antidepresivo de la ketamina y otros antagonistas de la NMDA participa la producción del receptor del ácido alfa-amino-3-hidroxi-5-metilisoxazol-4-propiónico (AMPA). Resultados: El tratamiento con dosis de ketamina inferiores a las anestésicas dio lugar a efectos agudos y sostenidos de tipo antidepresivo. En estas dosis, la ketamina no deterioró la retención de los recuerdos relacionados con el miedo. MK-801 (dizocilpina) y RO25-6981, un antagonista NR2B selectivo, también tuvieron efectos de tipo antidepresivo; sin embargo, éstos no fueron tan sostenidos como los de ketamina. El pretratamiento con NBQX, un antagonista del receptor de AMPA, atenuó tanto la conducta de tipo antidepresivo inducida por la ketamina como la regulación de los receptores AMPA hipocámpicos Glu1R1 fosforilados. Conclusiones: Los antagonistas de la NMDA pueden producir efectos rápidos de tipo antidepresivo aumentando el AMPA en relación con la producción de NMDA en circuitos neuronales decisivos (AU)

Background: Ketamine exerts a robust, rapid, and relatively sustained antidepressant effect in patients with major depression. Understanding the mechanisms underlying the intriguing effects of Nmethyl d-aspartate (NMDA) antagonists could lead to novel treatments with a rapid onset of action. Methods: The learned helplessness, forced swim, and passive avoidance tests were used to investigate ketamine’s behavioral effects in mice. Additional biochemical and behavioral experiments were undertaken to determine whether the antidepressant-like properties of ketamine and other NMDA antagonists involve alpha-amino-3-hydroxy-5-methylisoxazole-4- propionic acid (AMPA) receptor throughput. Results: Subanesthetic doses of ketamine treatment caused acute and sustained antidepressantlike effects. At these doses, ketamine did not impair fear memory retention. MK-801 (dizocilpine) and Ro25-6981, an NR2B selective antagonist, also exerted antidepressant-like effects; these effects, however, were not sustained as long as those of ketamine. Pretreatment with NBQX, an AMPA receptor antagonist, attenuated both ketamine-induced antidepressant-like behavior and regulation of hippocampal phosphorylated GluR1 AMPA receptors. Conclusions: NMDA antagonists might exert rapid antidepressant-like effects by enhancing AMPA relative to NMDA throughput in critical neuronal circuits (AU)

Histological evidence for drug diffusion across the cerebral meninges into the underlying neocortex in rats.

Transmeningeal pharmacotherapy has been proposed to treat neurological disorders with localized pathology, such as intractable focal epilepsy. As a step toward understanding the diffusion and intracortical spread of transmeningeally delivered drugs, the present study used histological methods to determine the extent to which a marker compound, N-methyl-D-aspartate (NMDA), can diffuse into the neocortex through the meninges. Rats were implanted with bilateral parietal cortical epidural cups filled with 50 mM NMDA on the right side and artificial cerebrospinal fluid (ACSF) in the contralateral side. After 24 h, the histological effects of these treatments were evaluated using cresyl violet (Nissl) staining. The epidural NMDA exposure caused neuronal loss that in most animals extended from the pial surface through layer V. The area indicated by this neuronal loss was localized to the neocortical region underlying the epidural cup. These results suggest that NMDA-like, water soluble, small molecules can diffuse through the subdural/subarachnoid space into the underlying neocortex and spread in a limited fashion, close to the meningeal penetration site.

Effect of modulators of the polyamine site on the development of seizures induced by systemic and intracerebral administration of N-methyl-D-aspartate in albino mice.

Systemic intraperitoneal administration of polyamine agonist IEM-1460 containing the Me3N(+) group with a stable positive charge preventing permeation of this substance through the blood-brain barrier and polyamine antagonist arcaine had no effect on the development of seizures caused by intracerebral injection of N-methyl-D-aspartate in mice. Intraperitoneal injection of IEM-40 potentiated, while arcaine decreased the severity of seizures induced by intraperitoneal treatment with N-methyl-D-aspartate. This effect was related to modulation of the permeability of the blood-brain barrier for N-methyl-D-aspartate probably due to modulating effects of IEM-40 and arcaine on the polyamine site of N-methyl-D-aspartate receptors in the blood-brain barrier.

Neuroprotección con memantina (antagonista no competitivo del receptor NMDA-glutamato) frente a la excitotoxicidad asociada al glutamato en la enfermedad de Alzheimer y en la demencia vascular / Glutamate-related excitoxicity neuroprotection with memantine, an uncompetitive antagonist of nmda-glutamate receptor, in Alzheimer’s disease and vascular dementia

Objetivo. Realizar una revisión de la eficacia terapéuticade memantina, un antagonista no competitivo del receptor de Nmetil-D-aspartato (NMDA)-glutamato. Desarrollo. La enfermedadde Alzheimer (EA) es el trastorno neurodegenerativo y la causa dedemencia asociada al envejecimiento más frecuente en todo elmundo. Los síntomas principales de la EA son una pérdida gradualde la función cognitiva y el deterioro funcional. La neurotransmisiónexcitatoria glutamatérgica, un proceso importante en elaprendizaje y la memoria, se encuentra gravemente alterada en laEA, debido probablemente al estrés oxidativo asociado con el aumentodel péptido amiloide β (1-42). La excitotoxicidad asociadaal glutamato, mediada principalmente por el subtipo NMDA de losreceptores de glutamato, es un indicio frecuente de patogenia entrastornos neurodegenerativos. Conclusiones. La memantina, unantagonista no competitivo, dependiente de voltaje y con una moderadaafinidad por el receptor de NMDA, induce efectos neuroprotectoresen pacientes con EA entre moderada y grave. La memantinaes un fármaco con propiedades neuroprotectoras y potenciadorasde la cognición que se puede combinar con otros tratamientoscontra la EA. Por tanto, la memantina no detiene ni reviertela EA, pero su efecto moderador al proteger el cerebro de losniveles tóxicos de calcio permite una transmisión normal de señalesentre las neuronas cerebrales. Se describen aquí diferentesensayos clínicos que han detallado la eficacia y la seguridad de lamemantina en el tratamiento de la EA y la demencia vascular

Aim. To review the therapeutic efficacy of memantine, an uncompetitive antagonist of N-methyl-D-aspartate (NMDA)-glutamate receptor. Development. Alzheimer’s disease (AD) is the most common neurodegenerative disorder and cause ofdementia with ageing worldwide. The main AD symptoms are a gradual loss of cognitive function and a functional impairment.Glutamatergic excitatory neurotransmission, an important process in learning and memory, is severely disrupted in AD,probably due to the oxidative stress associated with the β-amyloid peptide (1-42) increase. The glutamate-related excitotoxicity,mainly mediated by NMDA subtype of the glutamate receptors, is a common clue of pathogenesis for neurodegenerativedisorders. Conclusions. Memantine, a moderate-affinity, voltage-dependent, uncompetitive antagonist of NMDAreceptor, shows neuroprotective effects in patients with moderate-to-severe AD. Memantine is a drug with neuroprotective andcognition-enhanced properties, which can be combined with other treatments for AD. Thus, memantine does not stop orreverse AD, but its moderating effect in protecting the brain from the toxic levels of calcium, allows normal signaling amongbrain neurons. The efficacy and safety profile of memantine have been reported in several clinical trials for treatment of ADand vascular dementia

A novel role for calcium-independent phospholipase A in alpha-amino-3-hydroxy-5-methylisoxazole-propionate receptor regulation during long-term potentiation.

A considerable body of evidence indicates that phospholipase A(2) (PLA(2)) enzymes participate in long-term potentiation (LTP) of excitatory synaptic transmission. In the present study, we have undertaken experiments to identify which calcium-independent isoform of PLA(2) is involved in synaptic plasticity and to determine whether calcium-independent PLA(2) (iPLA(2)) contributes to post-synaptic processes of LTP. Using field recordings from rat CA1 hippocampal slices, we found that theta-burst stimulation (TBS)-induced LTP of field excitatory post-synaptic potentials (fEPSPs) was abolished by the iPLA(2) inhibitor bromoenol lactone (BEL) but not by the Ca(2+)-dependent PLA(2) inhibitor arachidonyl trifluoromethyl ketone (AACOCF(3)). The ionic currents generated during TBS were not affected during iPLA(2) inhibition as BEL by itself had no effect on the magnitude of facilitation during burst responses. In addition, (R)-BEL, an enantioselective inhibitor of iPLA(2)gamma, precluded TBS-induced LTP, an action that was not replicated by the iPLA(2)beta inhibitors (S)-BEL and methyl arachidonyl fluorophosphonate. (R)-BEL was, however, ineffective on pre-established LTP. Finally, BEL also prevented the potentiation of fEPSPs elicited by brief exposure to 50 microM N-methyl-d-aspartate, as well as the associated up-regulation of alpha-amino-3-hydroxy-5-methylisoxazole-propionate (AMPA) receptor GluR1 subunit levels and the increase of (3)H-AMPA binding in crude synaptic fractions. Collectively, these results unravel a new role for iPLA(2)gamma in LTP, which appears to favor the insertion of AMPA receptors at post-synaptic membranes.

Review of NMDA antagonist-induced neurotoxicity and implications for clinical development.

NMDA receptor antagonists have been investigated for many years as therapeutic agents for the treatment of neurological disorders such as stroke, epilepsy, pain and Parkinson's disease. It has been discovered, however, that many of these compounds cause adverse behavioral (psychotomimetic) effects and can produce neurotoxicity characterized by neuronal vacuolization, induction of heat-shock protein, neuronal/axonal degeneration and regional brain cell death in several animal species. It is unknown whether NMDA antagonists induce neurotoxicity in humans. The mechanism of NMDA antagonist-induced neurotoxicity is not completely known, but some evidence suggests disinhibition of GABAergic inputs to the affected neurons. Several classes of compounds have been shown to prevent NMDA antagonist-induced neurotoxicity. The extent of neurotoxicity produced by NMDA antagonists is affected by many factors, including type of antagonist, dose, length of exposure, age, sex and species. While there are no published regulatory guidelines regarding how NMDA antagonist compounds should be evaluated, sponsors and investigators of these compounds should make every effort to assess the potential for neurotoxicity. NMDA receptor antagonists, as well as other CNS-active compounds need to be analyzed for neurotoxicity through careful experimental design, adequate tissue sampling and through the use of a sensitive method of detection.

Behavioral effects of NMDA receptor agonists and antagonists in combination with nitric oxide-related compounds.

Responding of rats was maintained under a 120-response fixed ratio (FR) schedule of food delivery, and animals received individual and combined injections of N-methyl-D-aspartic acid (NMDA), phencyclidine hydrochloride, (+)-MK-801 hydrogen maleate (MK-801), (+/-)-2-amino-5-phosphonopentanoic acid (AP5), 7-chlorokynurenic acid (7CK), ifenprodil tartrate, N(G)-nitro-L-arginine methyl ester hydorchloride (L-NAME), 7-nitroindazole, aminoguanidine hemisulfate, L-arginine, molsidomine, sodium nitroprusside, and 8-(diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride (TMB-8). Behavioral suppression after NMDA was completely and dose-dependently reversed by MK-801, phencyclidine, AP5, and aminoguanidine; partially and dose-dependently attenuated by molsidomine, ifenprodil, and 7CK; and not attenuated at all by L-NAME, 7-nitroindazole, or TMB-8. These findings suggested that behavioral suppression after NMDA was associated with nitric oxide from the inducible synthase. In a second series of experiments, comparable behavioral suppression by 0.1 mg/kg MK-801, but not 3 mg/kg phencyclidine, was attenuated by nitroprusside, molsidomine, and L-arginine, suggesting that suppressions from MK-801 and phencyclidine were mediated by different final common pathways, and that behavioral suppression from MK-801, but not phencyclidine, may be associated with Ca(2+)-dependent nitric oxide.

Effect of some convulsants on the protective activity of loreclezole and its combinations with valproate or clonazepam in amygdala-kindled rats.

Loreclezole (5 mg/kg) exerted a significant protective action in amygdala-kindled rats, reducing both seizure and afterdischarge durations. The combinations of loreclezole (2.5 mg/kg) with valproate, clonazepam, or carbamazepine (applied at their subprotective doses) also exhibited antiseizure effect in this test. However, only two first combinations occurred to be of pharmacodynamic nature. Among several chemoconvulsants, bicuculline, N-methyl-D-aspartic acid and BAY k-8644 (the opener of L-type calcium channels) reversed the protective activity of loreclezole alone and its combination with valproate. On the other hand, bicuculline, aminophylline and BAY k-8644 inhibited the anticonvulsive action of loreclezole combined with clonazepam. The results support the hypothesis that the protective activity of loreclezole and its combinations with other antiepileptics may involve potentiation of GABAergic neurotransmission and blockade of L-type of calcium channels.

N-Methyl-D-aspartate receptor subtype-selectivity of homoquinolinate: an electrophysiological and radioligand binding study using both native and recombinant receptors.

Homoquinolinate, a derivative of the endogenous NMDA agonist, quinolinate, has been shown to display higher affinity for Xenopus oocytes expressing NR2A- and NR2B-containing receptors, compared to NR2C- and NR2D-containing receptors, whilst autoradiographical experiments subsequently showed that [3H]homoquinolinate labelled a subpopulation of NMDA receptors in rat brain sections, with a similar distribution to NR2B-containing receptors. In this study, we have shown that NMDA-specific [3H]homoquinolinate binding to rat brain membranes comprised 44% of total binding with a Bmax value of 5.73 pmol/mg protein, which was inhibited by NMDA with Ki=0.867 micro m. However, NMDA-specific [3H]homoquinolinate binding was not observed for a number of human recombinant NMDA receptors investigated, suggesting that there are subtle differences between the binding sites of recombinant and native receptors. Electrophysiological experiments revealed that homoquinolinate activated human recombinant NR1a/NR2A, NR1a/NR2B and NR1a/NR2A/NR2B receptors with EC50 values of 25.2, 13.8 and 9.04 micro m, respectively, with intrinsic activities of 148, 93.3 and 125%, respectively, compared to glutamate (=100%). In contrast to an autoradiographical study, these radioligand binding and electrophysiological experiments suggest that homoquinolinate is not highly selective for NR2B-containing receptors.

Age-Dependent vasopressinergic modulation of Noc/oFQ-induced impairment of NMDA cerebrovasodilation after brain injury.

This study was designed to characterize the role of vasopressin in nociceptin/orphanin FQ (NOC/oFQ)-induced impairment of NMDA cerebrovasodilation after fluid percussion brain injury (FPI) as a function of age in newborn (1-5 days old) and juvenile (3-4 weeks old) pigs equipped with a closed cranial window. Previous studies have observed that NOC/oFQ is released into CSF and contributes to impaired NMDA induced pial artery dilation following FPI to a greater extent in newborn versus juvenile pigs. Topical vasopressin (40 pg/mL), a concentration approximating that observed in CSF following FPI in the newborn, increased CSF NOC/oFQ from 69 +/- 3 to 102 +/- 8 pg/mol under non-FPI conditions. CSF NOC/oFQ was elevated within 60 min of FPI (70 +/- 3 to 444 +/- 51 pg/mL), but release was attenuated by MEAVP, a vasopressin antagonist, in the newborn (71 +/- 3 to 146 +/- 11 pg/mL). CSF vasopressin and NOC/oFQ were not elevated as greatly in the juvenile following FPI and MEAVP correspondingly did not attenuate CSF NOC/oFQ release as much as in the newborn. Under noninjury conditions, vasopressin (40 pg/mL) coadministered with NMDA (10(-8), 10(-6) M) attenuated pial dilation to this excitatory amino acid (9 +/- 1% and 16 +/- 1% vs. 3 +/- 1% and 5 +/- 2%). Following FPI in the newborn, NMDA-induced pial artery dilation was reversed to vasoconstriction, and both NOC/oFQ and vasopressin receptor antagonists partially prevented these alterations (9 +/- 1%) and 16 +/- 1%, sham control; -7 +/- 1% and -12 +/- 1%, FPI; -2 +/- 1% and -3 +/- 1%, FPI-NOC/oFQ antagonist; and 1 +/- 1% and 4 +/- 1%, FPI-vasopressin antagonist). NMDA-induced pial dilation was only attenuated following FPI in the juvenile and modestly restored by NOC/oFQ and vasopressin receptor antagonists. These data show that vasopressin, in concentrations present in CSF following FPI, contributes to the release of CSF NOC/oFQ following such an insult. The greater release of vasopressin following FPI in the newborn contributes to the corresponding greater release of NOC/oFQ in the newborn versus the juvenile. Moreover, vasopressin also contributes to the impairment of NMDA cerebrovasodilation after brain injury to a greater extent in newborn versus juveniles. These data suggest that vasopressin modulates NOC/oFQ-induced impairment of NMDA cerebrovasodilation after brain injury in an age-dependent manner.

Organization of cortico-cortical associative projections in a rat model of microgyria.

Microgyria was experimentally induced by focal freezing lesions of the frontal cortex in newborn rats. Adult microgyric animals received cortical injections of biotinylated dextran amine combined with NMDA, in order to obtain a Golgi-like retrograde labeling of cortico-cortical association neurons. Injections were performed either rostrally or caudally to the microgyric lesion. Results demonstrate that long-range association projections traveling across the zone of the microgyric lesion arise mainly from infragranular layers. In normal animals the same projections originate both from supragranular and infragranular layers. The analysis of single basal dendrites of layer 2/3 in microgyric animals demonstrates a simplified branching pattern, with a number of end points lower than in control animals. Potential implications for microgyria-associated epilepsy are discussed.

Lead-induced changes in NMDA receptor complex binding: correlations with learning accuracy and with sensitivity to learning impairments caused by MK-801 and NMDA administration.

This study sought to further evaluate potential mechanistic relationships between Pb-induced alterations in glutamate neurotransmission and behavioral toxicity. It examined correlations between Pb-induced changes in [3H]MK-801 and [3H]CGP-39653 binding sites in 4 different brain regions (frontal cortex, dentate gyrus, CA1 and striatum) and (1) changes in learning accuracy on a multiple repeated acquisition and performance schedule, and (2) sensitivity to the accuracy-impairing effects of MK-801 and NMDA on this learning baseline. All data were obtained from a single population of rats that had been chronically exposed from weaning to 0, 50 or 250 ppm Pb acetate in drinking water and demonstrated selective learning impairments and altered sensitivity to the effects of MK-801 and NMDA on learning accuracy. Pb exposure decreased MK-801 binding and possibly increased CGP-39653 binding, effects statistically significant in some brain regions, but generally exhibiting similar trends across regions. At 0 ppm, higher levels, particularly of MK-801 binding, were associated with higher accuracy levels in the learning paradigm and with greater decrements in learning accuracy following MK-801 or NMDA administration. These linear correlations were negated and in some cases even reversed by 50 and 250 ppm Pb, an effect that might be attributable to an alteration of NMDA receptor complex subunit composition and thus, ligand binding. Of the 4 brain regions examined, striatal MK-801 binding proved to be the best predictor of learning accuracy levels. These data provide additional support for an involvement of the NMDA receptor complex in Pb-induced learning impairments. The fact that these effects were noted most frequently in striatum also raises the possibility that dopamine-glutamatergic interactions contribute to Pb's effects.

Introducción al estudio del receptor al N-Metil-D-Aspartato / Introduction to the study of the N-Methyl-D-Aspartate receptor

Objetivos: Analizar toda la información publicada en los últimos diez años sobre el receptor al N-Metil-D-Aspartato (NMDA). Establecer una correlación farmaco-clínica con respecto a la modulación del dolor y determinar su importancia en anestesiología. Lugar: Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo. Base de datos: Base electrónica Medline de donde se seleccionaron todos los trabajos publicados en idioma inglés sobre el tema y búsqueda de información en castellano de lo publicado en los últimos 10 años. Estrategia de búsqueda: NMDA, dolor, modulación del dolor, protección cerebral. Discusión: Los receptores celulares son estructuras que permiten comandar el metabolismo íntimo de las células que los poseen. Estos interactúan en forma directa a través de un segundo mensajero citoplasmático. En el neuroeje de los mamíferos, se encuentran numerosas neuronas que contienen en su membrana el receptor al NMDA. El bloqueo de éste por drogas que actúan en forma competitiva o no competitiva, produciría analgesia, permitiría la modulación del estímulo doloroso y algunos trabajos demuestran su importancia como protectores cerebrales ante la isquemia. Conclusión: Los inhibidores de los receptores al NMDA como la dizocilpina, actualmente en fase experimental, o la ketamina, adquirirían un rol muy importante en nuestra especialidad en el manejo del dolor y la protección cerebral.(AU)

Introducción al estudio del receptor al N-Metil-D-Aspartato / Introduction to the study of the N-Methyl-D-Aspartate receptor

Objetivos: Analizar toda la información publicada en los últimos diez años sobre el receptor al N-Metil-D-Aspartato (NMDA). Establecer una correlación farmaco-clínica con respecto a la modulación del dolor y determinar su importancia en anestesiología. Lugar: Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo. Base de datos: Base electrónica Medline de donde se seleccionaron todos los trabajos publicados en idioma inglés sobre el tema y búsqueda de información en castellano de lo publicado en los últimos 10 años. Estrategia de búsqueda: NMDA, dolor, modulación del dolor, protección cerebral. Discusión: Los receptores celulares son estructuras que permiten comandar el metabolismo íntimo de las células que los poseen. Estos interactúan en forma directa a través de un segundo mensajero citoplasmático. En el neuroeje de los mamíferos, se encuentran numerosas neuronas que contienen en su membrana el receptor al NMDA. El bloqueo de éste por drogas que actúan en forma competitiva o no competitiva, produciría analgesia, permitiría la modulación del estímulo doloroso y algunos trabajos demuestran su importancia como protectores cerebrales ante la isquemia. Conclusión: Los inhibidores de los receptores al NMDA como la dizocilpina, actualmente en fase experimental, o la ketamina, adquirirían un rol muy importante en nuestra especialidad en el manejo del dolor y la protección cerebral.

Evaluación del efecto neuroprotector de lidocaína y ketamina en un modelo de hipoxia-isquemia cerebral en la rata: estudio histopatológico en estriado, hipocampo y corteza cerebral / Evaluation of the neuroprotective effect of lidocaine and ketamine on a cerebral hypoxia-ischemia model in the rat: histopathological analysis of the striatum, hippocampus and cerebral cortex

Los fectos de la lidocaína como droga protectora del Sistema Nervioso central por isquemia y traume han sido extensamente investigados sin conclusiones definitivas. Algunos experimentos que mostraban un efecto neuroprotector promisorio de la lidocaína utilizan como agente anestésico la ketamina sin considerar su posible contribución neuroprotectora en los resultados comunicados. Esto también se observa en otros experimentos que evalúan los efectos de varias drogas: bloqueadores orgánicos de los canales de calcio, recolectores de radicales libres, esteroides y ganglioosidos. La ketamina anestésico disociativo, es un análogo de feniciclidina, que actúa como un análogo de fenciclidina, que actúa como un antagonista no competitivo en le sitio del N-metil-D-aspartato, receptor subtipo glutamato, dela fenciclidina, y su acción neuroprotectora ha sido comunicada en varios modelos experimentales. El presente trabajo evalúa los efectos de la lidocaína y ketamina en el modelo de hipoxia-isquemia incompleta cerebral de la rata neonata (modelo Levine). Los resultados muestran un efcto neuroprotector significativo de la lidocaína y ketamina, evaluados por análisis hitopatológico del estriado, hipocampo y corteza cerebral-estriado en el modelo de la hipoxia-isquemia en modelo roedor vivo