Sándor L. Erdö

γ‐Aminobutyric Acid Outside the Mammalian Brain

Article de synthese sur le role du GABA en dehors du systeme nerveux central chez les mammiferes: role dans le systeme nerveux peripherique, aspects biochimiques, biologiques morphologiques et fonctionnels

Peripheral GABAergic mechanisms

Abstract The early assumption that γ-aminobutyric acid (GABA) is present in vertebrates and plays a neurotransmitter role solely in the CNS has been disproved. Increasing evidence has shown that GABA is present and may even be a neurotransmitter in certain peripheral tissues of mammals. In spite of the fact that specific GABAergic responses have also been demonstrated in numerous peripheral tissues, little attention has been paid to the functional importance of GABAergic mechanisms outside the brain. In the present review Sandor L. Erdo summarizes the current knowledge of GABAergic systems in peripheral tissues and emphasizes the functional relevance of GABA in a series of peripheral organs.

Memantine is highly potent in protecting cortical cultures against excitotoxic cell death evoked by glutamate and N-methyl-D-aspartate

The capacity of memantine to protect cultured cerebrocortical cells against N-methyl-D-aspartate (NMDA)- and glutamate-induced cell death was examined. Excitotoxic cell death was evaluated by phase contrast microscopy and quantified by estimating the release of lactic dehydrogenase from damaged cells. Memantine showed a strong, long-lasting and concentration-dependent protective effect against the excitotoxic damage induced by glutamate and NMDA, with almost complete protection being attained at a memantine concentration of 0.1 mM. The present findings indicate that memantine has potential value as a drug against excitotoxic brain damage.

Higher GABA Concentrations in Fallopian Tube Than in Brain of the Rat

Abstract: The GABA content was determined simultaneously in two peripheral organs, i.e., ovary and Fallopian tube. Moreover, the effects of inhibitors of glutamate decarboxylase or γ‐aminobutyrate transaminase (GABA‐T) on the GABA concentrations of the two organs were examined, to point out similarities and differences between central and peripheral pathways of GABA biosynthesis and degradation. In ovary, GABA concentration was found to be about 30% of that in total brain tissue. Furthermore, isoniazid and thiosemicarbazide caused significant reduction of GABA levels in peripheral organs. In contrast to the CNS, aminooxyacetic acid failed to increase, but even produced a significant diminution in peripheral GABA content. Gabaculine did not change GABA levels. In conclusion, it has been demonstrated for the first time that a peripheral organ, i.e. fallopian tube, contained higher GABA concentrations than the CNS. On the other hand, in the organs examined GABA seemed to be synthesized similarly, but metabolized by a pathway different from that in the brian.

Excitatory amino acid receptors in the mammalian periphery

Aspartate and glutamate occur ubiquitously in free and chemically bound forms and have been considered primarily as substances of metabolic relevance. This focus has changed with the more recent discovery of their specific role as excitatory synaptic transmitters in the mammalian CNS. Enthusiasm for this concept has overshadowed the possibility that glutamate and aspartate may also have specific, receptor-mediated functions in the periphery. In this review, Sándor Erdö summarizes the current knowledge of excitatory amino acid (EAA) receptors outside the CNS, through which EAAs may modulate various functions in peripheral organs and tissues.

Lack of excitotoxic cell death in serum-free cultures of rat cerebral cortex

The excitotoxicity of glutamate, N-methyl-D-aspartate (NMDA), quisqualate and kainate were compared in rat cerebro-cortical cell cultures grown in different media. Excitotoxic cell death was examined by phase contrast microscopy and by the measurement of lactic dehydrogenase (LDH) activity released in the culture medium. Cells grown for 14 days in a serum-free, defined (N2) medium were resistant, while sister cultures maintained in the presence of serum responded to the excitotoxins by a significant degree of cell death. Cells cultured in serum-free medium for 7 days, and fed by a serum-containing one for an additional week exhibited vulnerability to the excitotoxins. It is concluded that the development of excitotoxicity in rat cortical cultures depends on one or more serum constituents.

Heterogeneity of N-methyl-D-aspartate receptors regulating the release of dopamine and acetylcholine from striatal slices.

In an attempt to examine some functional characteristics of the N‐methyl‐D‐aspartate (NMDA) receptor complex, the NMDA‐evoked effluxes of endogenous dopamine (DA) and [3H]acetylcholine ([3H]ACh) were simultaneously examined in a rat Striatal slice preparation. NMDA induced release of both DA and ACh in a concentration‐dependent, Ca2+‐, Mg2+‐, and tetrodotoxin‐sensitive manner. These release responses were remarkably reduced by long‐term pre‐treatment with a low concentration of NMDA. an indication of the desensitization of the NMDA receptor. Glycine was potent in reversing the desensitization‐related reduction of DA release but failed to reverse the diminution of ACh release in the same slices. Our results indicate that the NMDA receptors regulating the release of DA and ACh are different with respect to their glycine modulatory site. This finding is consistent with a functional heterogeneity of the NMDA receptor complex in the rat striatum.

Vinpocetine is a highly potent neuroprotectant against veratridine-induced cell death in primary cultures of rat cerebral cortex

The effects of vinpocetine and phenytoin against veratridine-induced cell death were investigated in primary cultures of rat cerebral cortex. Toxicity was evaluated by phase contrast microscopy and quantified by measuring lactic dehydrogenase leakage from damaged cells. Vinpocetine was highly potent in inhibiting the cell death evoked by veratridine. The concentrations of the drug evoking 50% protection (IC50 values) against 100 microM (maximal response) and 50 microM (half-maximal response) veratridine were 490 nM and 63 nM, respectively. The protective efficacy of vinpocetine exceeded about 100-fold that of phenytoin (IC50 = 44.2 microM against 100 microM veratridine), a prototype sodium-channel blocker. These data suggest that the blockade of voltage-gated sodium channels is a possible mechanism of action for the well-known neuroprotective and anticonvulsant properties of vinpocetine.

Postnatal development of the excitatory amino acid system in visual cortex of the rat. Changes in ligand binding to NMDA, quisqualate and kainate receptors.

The postnatal development of the ligand binding to N‐methyl‐d‐aspartate (NMDA), quisqualate and kainate receptor sites was examined in whole homogenates of the visual cortex of rats, aged 2–360 days. As selective ligands, [3H]CPP (3‐(2‐carboxypyperazine‐4‐yl)‐propyl‐1‐phosphonic acid, [3H]AMPA (RS‐alpha‐amino‐3‐hydroxy‐5‐methyl‐isoxazole‐4‐propionic acid) and [3H]KA (kainic acid) were used, respectively. The binding of CPP was low in newborns, rapidly increased from the second postnatal week, reached its maximum between weeks 2 and 3, then slowly declined up to the age of 1 year. In contrast, the binding of AMPA and kainate was high perinatally, increased rapidly up to day 6 after birth to reach an early maximum value, then gradually decreased to adult values which were attained at an age of 3–4 weeks. These age‐related changes were derived from alterations in the density of binding sites, which, in the case of AMPA, was accompanied by an increase in binding affinity. The results, compared with the developmental time‐course of excitatory synapses, indicate that, in the immature cerebral cortex, NMDA receptors may be primarily involved in synaptic transmission, whereas quisqualate and kainate receptors may play some other (e.g. trophic) roles.

Immunohistochemical localization of glutamate decarboxylase in the rat oviduct and ovary: further evidence for non-neural GABA systems

SummaryThe distribution of L-glutamate decarboxylase (GAD), a major biosynthetic enzyme for gamma-aminobutyric acid (GABA), was examined in the oviduct and ovary of the rat by means of an immunohistochemical technique. The polyclonal antiserum raised against brain GAD showed specific immunoreaction in some non-neuronal elements of the sex organs. In the oviduct, the inner layer of the mucosa was predominantly labelled. The selective distribution of GAD immunoreactivity in epithelial cells of the oviduct is consistent with former findings for GABA-like immunoreactivity in the same organ, indicating that the GAD-catalyzed reaction may be a major biosynthetic pathway for GABA even in these cells. In the ovary, vacuole-like formations within the follicular fluid and oocytes showed intense, specific staining. The occurrence of GAD immunoreactivity inside developing ovarian follicles including the oocyte may suggest a role for GABA related to follicular development and certain functions concerning the ovum.