Agathisflavone, a flavonoid derived from Poincianella pyramidalis (Tul.), enhances neuronal population and protects against glutamate excitotoxicity.

Flavonoids are bioactive compounds that are known to be neuroprotective against glutamate-mediated excitotoxicity, one of the major causes of neurodegeneration. The mechanisms underlying these effects are unresolved, but recent evidence indicates flavonoids may modulate estrogen signaling, which can delay the onset and ameliorate the severity of neurodegenerative disorders. Furthermore, the roles played by glial cells in the neuroprotective effects of flavonoids are poorly understood. The aim of this study was to investigate the effects of the flavonoid agathisflavone (FAB) in primary neuron-glial co-cultures from postnatal rat cerebral cortex. Compared to controls, treatment with FAB significantly increased the number of neuronal progenitors and mature neurons, without increasing astrocytes or microglia. These pro-neuronal effects of FAB were suppressed by antagonists of estrogen receptors (ERα and ERß). In addition, treatment with FAB significantly reduced cell death induced by glutamate and this was associated with reduced expression levels of pro-inflammatory (M1) microglial cytokines, including TNFα, IL1ß and IL6, which are associated with neurotoxicity, and increased expression of IL10 and Arginase 1, which are associated with anti-inflammatory (M2) neuroprotective microglia. We also observed that FAB increased neuroprotective trophic factors, such as BDNF, NGF, NT4 and GDNF. The neuroprotective effects of FAB were also associated with increased expression of glutamate regulatory proteins in astrocytes, namely glutamine synthetase (GS) and Excitatory Amino Acid Transporter 1 (EAAT1). These findings indicate that FAB acting via estrogen signaling stimulates production of neurons in vitro and enhances the neuroprotective properties of microglia and astrocytes to significantly ameliorate glutamate-mediated neurotoxicity.

Aloysia gratissima prevents cellular damage induced by glutamatergic excitotoxicity.

OBJECTIVES: Aloysia gratissima aqueous extract (AE) was investigated as a putative protective agent against quinolinic acid (QA)-induced seizures in mice and hippocampal cell damage. Additionally, AE and ferulic acid (FA), the major compound of AE, were tested against neurotoxicity evoked by glutamate or its N-methyl-D-aspartate receptor (NMDAR) agonist, QA on hippocampal slices, in vitro. METHODS: Mice were treated with AE before QA infusion (36.8 nmol/site) and seizures were analysed. Cellular viability and modulation of excitatory amino acid transport were verified in hippocampal slices. In-vitro AE or FA was tested against neurotoxicity induced by glutamate or QA. KEY FINDINGS: AE did not prevent QA-induced seizures; however, it prevented cellular death and disruption of excitatory amino acid transport. In-vitro AE (0.1 or 1.0 mg/ml) or FA (1 or 10 µm), improved cell viability against citotoxicity exerted by glutamate or QA, respectively. Both AE and FA have protective effects depending on activation of the phosphatidylinositol-3 kinase (PI3K) signalling pathway. CONCLUSIONS: AE attenuated QA-induced cell damage possibly involving the glutamate transport modulation through NMDAR interaction. FA shows a similar profile of neuroprotection promoted by AE. Therefore, AE treatment might be a useful strategy in preventing brain damage caused by exacerbation of glutamatergic toxicity in nervous system disorders.

Neuroprotective effect of the proanthocyanidin-rich fraction in experimental model of spinal cord injury.

OBJECTIVES: In this study, we evaluated the effect of the proanthocyanidins-rich fraction (PRF) obtained from Croton celtidifolius bark in an experimental animal model of spinal cord injury and cell death induced by glutamate. METHODS: Experiments were conducted using adult male Wistar rats (10 weeks old and weighing 270-300g). Experimental groups were randomly allocated into the following groups: spinal cord injury (SCI) + vehicle group: rats were subjected to SCI plus intraperitoneal administration of vehicle (saline 10 ml/kg); SCI + PRF: rats were subjected to SCI plus intraperitoneal administration of PRF (10 mg/kg) at 1 and 6 h after injury and sham operated. KEY FINDINGS: The treatment with the proanthocyanidin-rich fraction significantly improved not only motor recovery and grip force but also H2 O2 or glutamate-induced cell death and reactive oxygen species generation induced by glutamate in dorsal root ganglion cells. In this study we demonstrate that the neuroprotective effect triggered by the proanthocyanidins-rich fraction appears to be mediated in part by the inhibition of N-methyl-D-aspartate-type glutamate receptors. CONCLUSIONS: Taken together, our results demonstrate that PRF treatment ameliorates spinal cord injury and glutamatergic excitotoxicity and could have a potential therapeutic use.

Global and ocular hypothermic preconditioning protect the rat retina from ischemic damage.

Retinal ischemia could provoke blindness. At present, there is no effective treatment against retinal ischemic damage. Strong evidence supports that glutamate is implicated in retinal ischemic damage. We investigated whether a brief period of global or ocular hypothermia applied 24 h before ischemia (i.e. hypothermic preconditioning, HPC) protects the retina from ischemia/reperfusion damage, and the involvement of glutamate in the retinal protection induced by HPC. For this purpose, ischemia was induced by increasing intraocular pressure to 120 mm Hg for 40 min. One day before ischemia, animals were submitted to global or ocular hypothermia (33°C and 32°C for 20 min, respectively) and fourteen days after ischemia, animals were subjected to electroretinography and histological analysis. Global or ocular HPC afforded significant functional (electroretinographic) protection in eyes exposed to ischemia/reperfusion injury. A marked alteration of the retinal structure and a decrease in retinal ganglion cell number were observed in ischemic retinas, whereas global or ocular HPC significantly preserved retinal structure and ganglion cell count. Three days after ischemia, a significant decrease in retinal glutamate uptake and glutamine synthetase activity was observed, whereas ocular HPC prevented the effect of ischemia on these parameters. The intravitreal injection of supraphysiological levels of glutamate induced alterations in retinal function and histology which were significantly prevented by ocular HPC. These results support that global or ocular HPC significantly protected retinal function and histology from ischemia/reperfusion injury, probably through a glutamate-dependent mechanism.

Hyptis pectinata: redox protection and orofacial antinociception.

Hyptis pectinata L. Poit, known as 'sambacaitá', is used in Brazil to treat inflammatory and painful disorders. In this study, the antioxidant and orofacial antinociceptive properties of the aqueous extract of H. pectinata leaves (AEPH) were assessed using in vitro and in vivo models. Thus, AEPH reduced the 2,2-diphenyl-1-picrylhydrazyl radical up to 72.10% with an EC50 of 14.56 µg/ml. It also inhibited 40.80% of the lipoperoxidation induced by 2'-azobis (2-amidinopropane) dihydrochloride in the thiobarbituric acid-reactive substances assay. The orofacial antinociceptive activity was evaluated in mice pre-treated with AEPH (100, 200 and 400 mg/kg, p.o.) and morphine (5 mg/kg, i.p.), which received afterwards formalin- (20 µl, 2% solution, s.c.), glutamate- (40 µl, 25 mM, s.c.) and capsaicin- (20 µl, 2.5 µg, s.c.) to induce orofacial nociception. AEPH at all doses reduced (p < 0.001) the nociceptive response in the first (43-62%) and second (47-80%) phases of the formalin test. Besides, the effect of AEPH (400 mg/kg) was not changed in the presence of naloxone (1.5 mg/kg, i.p.), an opioid antagonist. AEPH significantly inhibited mice face rubbing for capsaicin (23-69%, p < 0.05) and glutamate (48-77%, p < 0.001) at all doses. The findings suggested the AEPH has peripheral and central antinociceptive activities, which are not related to opioid receptors.

Pathophysiology of neurodegeneration following traumatic brain injury / Patofisiología de la neurodegeneración tras una lesión traumática del cerebro

Acute neuropathological conditions, including brain and spinal cord trauma, are leading causes of death and disabilities worldwide, especially in children and young adults. The causes of brain and spinal cord injuries include automobile accidents, accidents during recreational activities, falls and violent attacks. In the United States of America alone, around 1.7 million people each year seek medical care for some kind of head injury. About fifty-two thousand of these people will die, while the same number will present with permanent functional disability. Considering the high worldwide prevalence of these acute pathological conditions, research on the mechanisms underlying central nervous system damage is of extreme importance. Nowadays, a number of experimental models of acute neural disorders have been developed and the mechanisms of tissue loss have been investigated. These mechanisms include both primary and secondary pathological events contributing to tissue damage and functional impairment. The main secondary pathological mechanisms encompass excitotoxicity, ionic imbalances, inflammatory response, oxidative stress and apoptosis. The proper elucidation of how neural tissue is lost following brain and spinal cord trauma is fundamental to developing effective therapies to human diseases. The present review evaluates the main mechanisms of secondary tissue damage following traumatic brain and spinal cord injuries.

Las condiciones neuropatológicas agudas, incluyendo los traumas del cerebro y la médula espinal, se hallan entre las principales causas de muerte y discapacidades a nivel mundial, sobre todo en niños y adultos jóvenes. Las causas de las lesiones del cerebro y la médula espinal, incluyen los accidentes automovilísticos, accidentes en actividades recreativas, caídas y ataques violentos. Sólo en los Estados Unidos de Norte América, alrededor de 1.7 millones de personas buscan anualmente atención médica para algún tipo de lesión craneal. Cincuenta y dos mil de estas personas morirán, mientras que un número similar presentará alguna discapacidad funcional permanente. Dada la alta prevalencia de estas condiciones patológicas agudas a nivel mundial, la investigación de los mecanismos que subyacen en los daños al sistema nervioso central, constituye un asunto de suma importancia. Hoy día, se han desarrollado varios modelos experimentales de trastornos neurales agudos, y se han investigado los mecanismos de la pérdida de tejido. Estos mecanismos incluyen tanto las manifestaciones patológicas primarias como las secundarias, que contribuyen al daño del tejido y al deterioro funcional. Los mecanismos patológicos secundarios principales abarcan la excitotoxicidad, los desequilibrios iónicos, la respuesta inflamatoria, el estrés oxidativo, y la apoptosis. Dilucidar correctamente como ocurre la pérdida del tejido neuronal luego del trama del cerebro o la médula espinal, es fundamental para poder desarrollar terapias efectivas en relación con las enfermedades humanas. La presente revisión evalúa los mecanismos principales del daño secundario al tejido, tras las lesiones traumáticas del cerebro y la médula espinal.

Pathophysiology of neurodegeneration following traumatic brain injury.

Acute neuropathological conditions, including brain and spinal cord trauma, are leading causes of death and disabilities worldwide, especially in children and young adults. The causes of brain and spinal cord injuries include automobile accidents, accidents during recreational activities, falls and violent attacks. In the United States of America alone, around 1.7 million people each year seek medical care for some kind of head injury. About fifty-two thousand of these people will die, while the same number will present with permanent functional disability. Considering the high worldwide prevalence of these acute pathological conditions, research on the mechanisms underlying central nervous system damage is of extreme importance. Nowadays, a number of experimental models of acute neural disorders have been developed and the mechanisms of tissue loss have been investigated. These mechanisms include both primary and secondary pathological events contributing to tissue damage and functional impairment. The main secondary pathological mechanisms encompass excitotoxicity, ionic imbalances, inflammatory response, oxidative stress and apoptosis. The proper elucidation of how neural tissue is lost following brain and spinal cord trauma is fundamental to developing effective therapies to human diseases. The present review evaluates the main mechanisms of secondary tissue damage following traumatic brain and spinal cord injuries.

In vitro properties and performance of glutaraldehyde-crosslinked bovine pericardial bioprostheses treated with glutamic acid.

Calcification is one of the major causes of failure of heart valve bioprostheses (HVBs) derived from glutaraldehyde (GA)-processed bovine pericardium (BP) or porcine aortic valves. New crosslinking reagent procedures are still far from giving satisfactory results, and this is the main reason why GA is still the reagent of choice for the fixation of native tissue intended for HVB manufacture. Nevertheless, two new findings with respect to GA processing may significantly improve HVB performance postimplantation: the finding that increasing concentrations of GA result in a decrease in calcification; the blocking of free aldehyde usually by nucleophyles or the treatment of processed material at low pH. This work investigates the in vitro properties of BP fixed with GA followed by the treatment with glutamic acid under alkaline conditions in order to prepare BP materials with lower calcification potential postimplantation. In comparison to conventional processing, except for the tensile strength that was slightly lower, elongation and toughness were higher than the accepted values. No significant differences were observed in the performance indexes (mean pressure gradient, mean effective area, regurgitant fraction, performance and efficiency indexes) with wear resistance over 150 × 106 cycles. These results indicate that the processing of BP described in this work may be of potential use in the manufacture of HVBs.

The antinociceptive effects of AR-A014418, a selective inhibitor of glycogen synthase kinase-3 beta, in mice.

UNLABELLED: We investigated the antinociceptive effects of AR-A014418, a selective inhibitor of glycogen synthase kinase-3ß (GSK-3ß) in mice. A 30-minute pretreatment with AR-A014418 (.1 and 1 mg/kg, intraperitoneal [ip]) inhibited nociception induced by an ip injection of acetic acid. AR-A014418 pretreatment (.1 and .3 mg/kg, ip) also decreased the late (inflammatory) phase of formalin-induced licking, without affecting responses of the first (neurogenic) phase. In a different set of experiments, AR-A014418 (.1-10 µg/site) coinjected intraplantarly (ipl) with formalin inhibited the late phase of formalin-induced nociception. Furthermore, AR-A014418 administration (1 and 10 ng/site, intrathecal [it]) inhibited both phases of formalin-induced licking. In addition, AR-A014418 coinjection (10 ng/site, it) inhibited nociception induced by glutamate, N-methyl-D-aspartate (NMDA), (±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD), tumor necrosis factor-alpha (TNF-α), and interleukin-1beta (IL-1ß) by 47 ± 12%, 48 ± 11%, 31 ± 8%, 46 ± 13%, and 44 ± 11%, respectively. In addition, a 30-minute pretreatment with NP031115 (3 and 10 mg/kg, ip), a different GSK-3 ß inhibitor, also attenuated the late phase of formalin-induced nociception. Collectively, these results provide convincing evidence that AR-A014418, given by local, systemic, and central routes, produces antinociception in several mouse models of nociception. The AR-A014418-dependent antinociceptive effects were induced by modulation of the glutamatergic system through metabotropic and ionotropic (NMDA) receptors and the inhibition of the cytokine (TNF-α and IL-1ß) signaling. PERSPECTIVE: These results suggest that GSK-3ß may be a novel pharmacological target for the treatment of pain.

Involvement of cellular prion protein in the nociceptive response in mice.

The role of the cellular prion protein (PrP(c)) in neuronal functioning includes neuronal excitability, cellular adhesion, neurite outgrowth and maintenance. Here we investigated the putative involvement of the PrP(c) function on the nociceptive response using PrP(c) null (Prnp(0/0)) and wild-type (Prnp(+/+)) mice submitted to thermal and chemical models of nociception. PrP(c) null mice were more resistant than wild-type mice to thermal nociception of the tail-flick test. However, no significant difference was found on the hot plate test. In the acetic acid-induced visceral nociception, PrP(c) null mice showed an enhanced response when compared to wild-type mice. However, there was no difference between Prnp(0/0) and wild-type mice on glutamate- and formalin-induced licking behaviour and Freund's Complete Adjuvant (FCA)-induced mechanical allodynia. PrP(c) null mice developed significantly lower paw edema than wild-type mice. In addition, the visceral conditioning stimuli produced by a previous injection of acetic acid (20 days before testing) significantly reduced early and late phases of formalin-induced nociception in wild-type mice. In contrast, the same pre-treatment did not alter the formalin response in PrP(c) null mice. These results indicate a role of PrP(c) in the nociceptive transmission, including the thermal tail-flick test and visceral inflammatory nociception (acetic acid-induced abdominal constriction). Our findings show that PrP(c) is involved with a response mediated by inflammation (paw edema) and by visceral conditioning stimuli.

Investigação do efeito do glutamato sobre o conteúdo de rEGF em linhagens celulares derivadas de glioblastomas humanos estabelecidas e caracterizadas

Os gliomas são as neoplasias cerebrais primárias que mais freqüentemente acometem o Sistema Nervoso Central (SNC). Cerca de 50% dos casos de gliomas são neoplasias com fenótipo maligno, incluindo os glioblastomas. Os glioblastomas possuem grande capacidade de expansão e invasão do tecido cerebral adjacente, o que contribui para o seu prognóstico sombrio. O glutamato é o principal neurotransmissor excitatório do SNC, mas sob condições patológicas a ativação excessiva do sistema glutamatérgico provoca danos citotóxicos às células neurais. A toxicidade glutamatérgica está associada a uma série de doenças agudas e crônico-degenerativas que acometem o SNC. Os glioblastomas humanos são capazes de liberar quantidades tóxicas de glutamato sobre os tecidos adjacentes e esta liberação parece favorecer o crescimento e a expansão tumoral. A fim de avaliarmos se a progressão tumoral mediada pelo glutamato é desencadeada por elementos das vias de sinalização, investigamos o efeito do glutamato sobre o conteúdo e expressão do receptor do fator de crescimento epitelial (rEGF). Desta forma, os cultivos primários Gli1, Gli2 e Gli3, assim como a linhagem estabelecida U87MG, foram tratados com doses crescentes de glutamato (5-200 mM) por 48 horas e após o tratamento a viabilidade celular, os conteúdos de rEGF e de Akt foram avaliados. Os cultivos analisados apresentaram suscetibilidades distintas aos efeitos citotóxicos do glutamato, porém em todos os casos as doses efetivas foram muito superiores (valores de ICso de 45mM a 100mM) às concentrações tóxicas descritas para células neurais (valores de ICso de100uM a 1mM). A expressão protéica de rEGF e o conteúdo de Akt fosforilado aumentaram após o tratamento com 5mM de glutamato, sugerindo que a ativação dos receptores de EGF possam exercer função na via de sinalização desencadeada pelo glutamato. Após o término dos experimentos com glutamato dois dos três cultivos primários utilizados (Gli1 e Gli2) se mantiveram viáveis em cultivo por mais de 50 passagens, o que sugere estabilidade das alterações moleculares e a seleção de uma subpopulação especifica de células que pode ser denominada linhagem celular. Assim, em os à caracterização destas duas novas linhagens celulares derivadas de glioblastomas - Gli1 e Gli2. Para tal avaliamos as suas taxas de proliferação, morfologia celular, o perfil de cariótipo de ambas e os conteúdos de rEGF, Hsp70, 6, p53 e MMP2, marcadores relacionados à progressão tumoral. Em suma, os cultivos Gli1 e Gli2 demonstraram alterações cromossômicas e expressão de marcadores compatíveis com as anomalias descritas para a manifestação do fenótipo de glioblastomas. Igualmente, comparamos o crescimento destas linhagens glioblastomas cultivadas como monocamada com o cultivo tridimensional em esferóides multicelulares. Os resultados obtidos revelaram padrões de crescimento e conteúdos dos marcadores diferentes entre as condições de cultivo

The gliomas are the primary brain tumors that more frequntIy accomplished the Central Nervous System (CNS). About 50% of the glioma cases presented malignant phenotype, including glioblastomas. Glioblastoma are tumors with high capacity of proliferation and invasion through the adjacent healthy nervous tissue, which largely contributes for its poor prognosis. The glutamate is the main excitatory neurotransmitter of the CNS, but under pathological conditions the extreme activation of the glutamatergic system induces cytotoxic damages to the neural cells. The glutamatergic citotoxicity is associated with severaI acute and chronic-degenerative diseases of the CNS. Human glioblastomas are capable of release toxic amounts of glutamate on adjacent brain tissue and this release seems to favor tumoral growth and expansion. In order to evaluate if the tumoral progression mediated by glutamato is a product of the activation of elements 6f1he signaling pathways, we investigated the glutamate effect on the content and expression of EGFi . For this reason, the primary culture cells Gli1, Gli2 and Gli3, as well as the established cell line U-87MG, were treated with increasing doses of glutamate (5-200 mM) for 48 hours and after the treatment the cell viability, EGFr and Akt contents were evaluated. The studied cells presented distinct susceptibilities to the cytotoxic effects of glutamate, however in all the cell cultures the toxicity was revealed only with very high glutamate doses (values of ICso range from 45mM to 100mM) when compared to the described toxic concentrations for neural cells (ICso values range from 100uM to 1 mM). The EGFr protein expression and the phosphor-Akt content increased after the treatment with 5mM of glutamate, suggesting that the activation of the EGF receptors can have a role in the glutamate signaling pathways. After the conclusion of these set of experiments, twoof out three tested primary cultures remained viable in cell culture for more than 50 passages, which suggests stability of the molecular profile and the selection of a specific ce11 subpopulation that can be named by 0011 line. Thus, in order to characterize these two new glioblastoma cell lines (Gli1 and Gli2), we carry out a series of experiments. The experiments had included the evaluation of the cellular growth rate, the cellular morphology, the kariotype profile and the identification of molecular markers related to tumor progression (EGF, Hsp70, Ki76, p53 e MMP2). 80th glioblastoma cell lines had demonstrated chromosomic alterations and expression of molecular markers similar to those described for glioblastoma phenotype. Equally, we compared the growth of these cells in monolayer cultures to three-dimensional multicellular spheroids cultures. Accordingly the results demonstrated different standarts of growth and molecular markers between the culture conditions

Nerve growth factor, ganglioside and vitamin E reverse glutamate cytotoxicity in hippocampal cells.

The present work showed that glutamate decreased hippocampal cell viability in a dose-dependent manner. While no significant effect was observed after cell exposure to 0.1 mM glutamate, cell incubation for 0.5 h caused a progressive decrease of cell viability, which at 5 mM concentration reached 68% as compared to controls. No further effect was observed in the presence of 10 mM glutamate. While nerve growth factor (NGF) at the dose of 0.5 ng/ml presented no effect, it significantly reduced glutamate cytotoxicity at a higher dose (1 ng/ml) increasing the cell viability to 66%. Similarly, cell viabilities in the presence of the ganglioside GM, (5 and 10 ng/ml) after glutamate exposure were 19 and 73%, respectively. A dose-response relationship was observed after cell incubation with vitamin E (0.5 and 1 mM) which resulted in cell viability of the order of 34 and 70%, respectively. Surprisingly, a potentiation of the effect was observed after the association of NGF (0.5 ng/ml) plus ganglioside GM1 (5 ng/ml) or vitamin E (0.5 mM) plus ganglioside GM1 (5 ng/ml), after pre-incubation with glutamate. In these conditions, significantly higher viabilities were demonstrated (66 and 71% for the two associations, respectively) as compared to each one of the compounds alone (NGF 0.5 ng/ml--29.5%; ganglioside GM1 5 ng/ml--19.4%). However, no potentiation was seen after the association of NGF plus vitamin E on glutamate pre-exposed cells. These results showed a cytoprotective effect of ganglioside GM1, NGF and vitamin E on the glutamate-induced cytotoxicity in rat hippocampal cells.

Cambios en los niveles estriatales de glutamato y aspartato en un modelo de la corea de Huntington: prevención de la neurotoxicidad del ácido quinolínico por kinurenina y probenecid / Changes in the striatal levels of glutamate and aspartante in a Huntington chorea model: prevention of quinolinic acid induced neurotoxicity by kynurenine and probenecid

La kinurenina (KYN) es el metabolito precursor del antagonista de los receptores glutamatérgicos para N-metil-D-as-partato (NMDA), el ácido kinurénico (KYNA). Por su pate, el probenecid (PROB) bloquea la excreción del KYNA desde el fluido extracelular. El KYNA antagoniza la neurotoxicidad ácido quinolínico (QUIN), en el cerebro de mamíferos. En este trabajo evaluamos el efecto de la administración sistémica de KYN y del PROB por separado o en combinación, sobre el contenido estriatal de dos aminoácidos excitadores del sistema nervioso, los ácidos glutámico (Glu) y aspártico (Asp), después de la administración intraestriatal unilateral de QUIN (240 nmol/ml) a las ratas. Los contenidos estriales de Glu y Asp. Analizados por cromatografía de líquidos, se encontraron disminuidos en ratas lesionadas por QUIN al compararse contra valores control (-44 por ciento y -43 por ciento, respectivamente). Los cambios en las concentraciones de estos aminoácidos fueron parcial o totalmente prevenidos por la administración de los pretratamientos con KYN (150, 300 ó 450 mg/kg, i.p.) o PROB (100, 200 ó 300 mg/kg, i.p.) a las ratas 2 horas antes de la inyección del QUIN. La coadministración de ambos fármacos previno la pérdida estriatal de Glu y Asp mediada por QUIN. Por su parte, la administración de un conocido antagonista de los receptores para NMDA, la dizocilpina (MK-80 1, 10 mg/kg, i.p.) previno totalmente la disminución estriatal de ambos aminoácidos. Estos hallazgos sugieren un papel farmacológico de la KYN y del PROB como inductores del antagonismo del KYNA sobre los receptores para NMDA