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1.
J Neurosci ; 33(49): 19176-93, 2013 Dec 04.
Article in English | MEDLINE | ID: mdl-24305814

ABSTRACT

Coding a wide range of light intensities in natural scenes poses a challenge for the retina: adaptation to bright light should not compromise sensitivity to dim light. Here we report a novel form of activity-dependent synaptic plasticity, specifically, a "weighted potentiation" that selectively increases output of Mb-type bipolar cells in the goldfish retina in response to weak inputs but leaves the input-output ratio for strong stimuli unaffected. In retinal slice preparation, strong depolarization of bipolar terminals significantly lowered the threshold for calcium spike initiation, which originated from a shift in activation of voltage-gated calcium currents (ICa) to more negative potentials. The process depended upon glutamate-evoked retrograde nitric oxide (NO) signaling as it was eliminated by pretreatment with an NO synthase blocker, TRIM. The NO-dependent ICa modulation was cGMP independent but could be blocked by N-ethylmaleimide (NEM), indicating that NO acted via an S-nitrosylation mechanism. Importantly, the NO action resulted in a weighted potentiation of Mb output in response to small (≤-30 mV) depolarizations. Coincidentally, light flashes with intensity ≥ 2.4 × 10(8) photons/cm(2)/s lowered the latency of scotopic (≤ 2.4 × 10(8) photons/cm(2)/s) light-evoked calcium spikes in Mb axon terminals in an NEM-sensitive manner, but light responses above cone threshold (≥ 3.5 × 10(9) photons/cm(2)/s) were unaltered. Under bright scotopic/mesopic conditions, this novel form of Mb output potentiation selectively amplifies dim retinal inputs at Mb → ganglion cell synapses. We propose that this process might counteract decreases in retinal sensitivity during light adaptation by preventing the loss of visual information carried by dim scotopic signals.


Subject(s)
Goldfish/physiology , Neuronal Plasticity/physiology , Nitric Oxide/physiology , Nitroso Compounds/metabolism , Retinal Bipolar Cells/physiology , Algorithms , Animals , Axotomy , Calcium Channels, L-Type/physiology , Calcium Signaling/physiology , Cyclic GMP/physiology , Data Interpretation, Statistical , Electrophysiological Phenomena , Ethylmaleimide/pharmacology , Glutamic Acid/physiology , In Vitro Techniques , Light , Patch-Clamp Techniques , Photic Stimulation , Potassium Channels, Voltage-Gated/physiology , Retina/physiology , Retinal Rod Photoreceptor Cells/physiology
2.
J Neurophysiol ; 110(6): 1393-403, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23803324

ABSTRACT

The occupancy of coagonist binding sites of NMDA receptors (NMDARs) by glycine or d-serine has been thought to mediate NMDAR-dependent excitatory signaling, as simultaneous binding of glutamate and a coagonist is obligatory for NMDAR activation. Amacrine cells (ACs) mediating GABAergic feedback inhibition of mixed bipolar cells (Mbs) in the goldfish retina have been shown to express NMDARs. Here we studied whether NMDAR-mediated GABAergic inhibitory currents (IGABA) recorded from the axon terminals of Mbs are influenced by experimental manipulations altering retinal glycine and d-serine levels. Feedback IGABA in Mb axon terminals was triggered by focal NMDA application or by synaptically released glutamate from depolarized Mb terminals. In both cases, blocking the coagonist binding sites of NMDARs eliminated the NMDAR-dependent IGABA, demonstrating that coagonist binding is critical in mediating NMDAR activity-triggered GABA release. Glycine transporter 1 (GLYT1) inhibition increased IGABA, indicating that coagonist binding sites of NMDARs on ACs providing GABAergic feedback inhibition to Mbs were not saturated. Focal glycine application, in the presence of the ionotropic glycine receptor blocker strychnine, triggered a GLYT1-dependent current in ACs, suggesting that GLYT1 expressed by putative glycinergic ACs controls the saturation level of NMDARs' coagonist sites. External d-serine also increased NMDAR activation-triggered IGABA in Mbs, further substantiating that the coagonist sites were unsaturated. Together, our findings demonstrate that coagonist modulation of glutamatergic input to GABAergic ACs via NMDARs is strongly reflected in the AC neuronal output (i.e., transmitter release) and thus is critical in GABAergic signal transfer function in the inner retina.


Subject(s)
Amacrine Cells/metabolism , Fish Proteins/metabolism , Glycine Plasma Membrane Transport Proteins/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , gamma-Aminobutyric Acid/metabolism , Amacrine Cells/physiology , Animals , Axons/metabolism , Axons/physiology , Binding Sites , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Glutamic Acid/metabolism , Glycine/metabolism , Glycine/pharmacology , Glycine Agents/pharmacology , Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Goldfish , Inhibitory Postsynaptic Potentials , N-Methylaspartate/pharmacology , Receptors, N-Methyl-D-Aspartate/agonists , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/chemistry , Serine/metabolism , Strychnine/pharmacology
3.
J Neural Transm (Vienna) ; 117(2): 183-8, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19953278

ABSTRACT

Kynurenic acid is an endogenous product of the tryptophan metabolism, and as a broad-spectrum antagonist of excitatory amino acid receptors may serve as a protective agent in neurological disorders. The use of kynurenic acid as a neuroprotective agent is rather limited, however, because it has only restricted ability to cross the blood-brain barrier. Accordingly, new kynurenic acid analogues which can readily cross the blood-brain barrier and exert their complex anti-excitotoxic activity are greatly needed. Such a novel analogue, 2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one hydrochloride, has been developed and tested. In an in vitro electrophysiological study, in which its properties were compared with those of kynurenic acid, the new analogue behaved quite similarly to kynurenic acid: in the micromolar range, its administration led to a decrease in the amplitudes of the field excitatory postsynaptic potentials in the CA1 region of the hippocampus, while in nanomolar concentrations it did not give rise to inhibition, but, in fact, facilitated the field excitatory postsynaptic potentials. Moreover, the new analogue demonstrated similar protective action against PTZ-induced facilitation to that observed after kynurenic acid administration. The findings strongly suggest that the neuroactive effects of the new analogue are comparable with those of kynurenic acid, but, in contrast with kynurenic acid, it readily crosses the blood-brain barrier. The new analogue may therefore be considered a promising candidate for clinical studies.


Subject(s)
CA1 Region, Hippocampal/drug effects , Excitatory Amino Acid Antagonists/pharmacology , Kynurenic Acid/analogs & derivatives , Kynurenic Acid/pharmacology , 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology , Animals , CA1 Region, Hippocampal/physiology , Dose-Response Relationship, Drug , Evoked Potentials/drug effects , Excitatory Amino Acid Antagonists/chemistry , Excitatory Postsynaptic Potentials/drug effects , In Vitro Techniques , Kynurenic Acid/chemistry , Microelectrodes , Neural Inhibition/drug effects , Rats , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/metabolism , Time Factors
4.
Neurobiol Dis ; 32(2): 302-8, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18761090

ABSTRACT

The neuroprotective effect of L-kynurenine sulfate (KYN), a precursor of kynurenic acid (KYNA, a selective N-methyl-D-aspartate receptor antagonist), was studied. KYN (300 mg/kg i.p., applied daily for 5 days) appreciably decreased the number of injured pyramidal cells from 1850+/-100/mm(2) to 1000+/-300/mm(2) (p<0.001) in the CA1 region of the hippocampus in the four-vessel occlusion (4VO)-induced ischemic adult rat brain. A parallel increase in the number of intact, surviving neurons was demonstrated. Post-treatment with KYN (applied immediately right after reperfusion) proved to be much less effective. In parallel with the histology, a protective effect of KYN on the functioning of the CA1 region was observed: long-term potentiation was abolished in the 4VO animals, but its level and duration were restored by pretreatment with KYN. It is concluded that the administration of KYN elevates the KYNA concentration in the brain to neuroprotective levels, suggesting its potential clinical usefulness for the prevention of neuronal loss in neurodegenerative diseases.


Subject(s)
Excitatory Amino Acid Antagonists/therapeutic use , Hippocampus/drug effects , Hippocampus/physiopathology , Infarction, Middle Cerebral Artery/drug therapy , Infarction, Middle Cerebral Artery/pathology , Kynurenine/therapeutic use , Adjuvants, Pharmaceutic/therapeutic use , Animals , Chromatography, High Pressure Liquid/methods , Disease Models, Animal , Electric Stimulation/methods , Hippocampus/metabolism , In Vitro Techniques , Kynurenic Acid/metabolism , Kynurenine/metabolism , Long-Term Potentiation/drug effects , Long-Term Potentiation/physiology , Male , Patch-Clamp Techniques , Phosphopyruvate Hydratase/metabolism , Probenecid/therapeutic use , Rats , Rats, Wistar
5.
Brain Res Bull ; 76(5): 474-9, 2008 Jul 30.
Article in English | MEDLINE | ID: mdl-18534254

ABSTRACT

The kynurenine pathway converts tryptophan into various compounds, including L-kynurenine, which in turn can be converted into the excitatory amino acid receptor antagonist kynurenic acid. The ionotropic glutamate receptors have been considered to be attractive targets for new anticonvulsants in neurological disorders such as epileptic seizure. This study was designed to examine the conversion of L-kynurenine to kynurenic acid and to investigate the effects of kynurenic acid on pentylenetetrazole-treated rat brain slices, and in parallel to draw attention to the fact that a well-designed in vitro model has many advantages in pharmacological screening. Schaffer collateral stimulation-evoked field EPSPs were recorded from area CA1 of rat hippocampal slices in vitro; drugs were bath-applied. Pretreatment with the kynurenic acid precursor L-kynurenine led to the elimination of the effect of pentylenetetrazole on hippocampal slices in vitro. N-Omega-nitro-L-arginine, which inhibits kynurenine aminotransferase I and II, abolished this neuroprotective effect. This study has furnished the first in vitro electrophysiological evidence that rat brain slices have the enzymatic capacity to convert exogenously administered L-kynurenine (16 microM) to kynurenic acid in an amount sufficient to protect them against pentylenetetrazole (1 mM)-induced hyperexcitability.


Subject(s)
Convulsants/metabolism , Excitatory Amino Acid Antagonists/metabolism , GABA Antagonists/metabolism , Hippocampus/metabolism , Kynurenic Acid/metabolism , Kynurenine/metabolism , Pentylenetetrazole/metabolism , Animals , Dose-Response Relationship, Drug , Electrophysiology , Enzyme Inhibitors/metabolism , Hippocampus/cytology , Hippocampus/drug effects , Kynurenic Acid/pharmacology , Kynurenine/pharmacology , Nitroarginine/metabolism , Pentylenetetrazole/pharmacology , Rats , Rats, Wistar
6.
J Neural Transm (Vienna) ; 115(8): 1087-91, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18446262

ABSTRACT

Kynurenic acid is an endogenous product of the tryptophan metabolism. Studies on the mechanism of its action have revealed that kynurenic acid at high concentrations is a competitive antagonist of the N-methyl-D-aspartate receptor and acts as a neuroprotectant in different neurological disorders. This in vitro investigation was designed to show that kynurenic acid acts differently at low concentrations. In vitro electrophysiological examinations on the young rat hippocampus confirmed the well-known finding that kynurenic acid in micromolar concentrations exerts an inhibitory effect. However, in nanomolar concentrations, kynurenic acid does not give rise to inhibition, but in fact facilitates the field excitatory postsynaptic potentials. The results available so far are compatible with the idea that kynurenic acid in the concentration range between a few hundred nanomolar and micromolar displays different effects. Its probable action on different receptors, inducing the different mechanisms, is discussed. The findings strongly suggest the neuromodulatory role of kynurenic acid under both physiological and pathological circumstances.


Subject(s)
Excitatory Amino Acid Antagonists/pharmacology , Hippocampus/drug effects , Kynurenic Acid/pharmacology , Animals , Dose-Response Relationship, Drug , Electric Stimulation , Electrophysiology , Excitatory Postsynaptic Potentials/drug effects , In Vitro Techniques , Rats , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/drug effects , Tryptophan/pharmacology
7.
Life Sci ; 82(17-18): 915-9, 2008 Apr 23.
Article in English | MEDLINE | ID: mdl-18387638

ABSTRACT

L-kynurenine is a metabolic precursor of kynurenic acid, which is one of the few known endogenous N-methyl-D-aspartate receptor inhibitors. In contrast with kynurenic acid, L-kynurenine is transported across the blood-brain barrier, and it may therefore come into consideration as a therapeutic agent in certain neurobiological disorders, e.g. ischaemia-induced events. The present study evaluated the effect of L-kynurenine administration (300 mg/kg i.p.) on the global ischaemic brain cortex both pre- and post-ischemic intervention. The statistical evaluation revealed that L-kynurenine administration beneficially decreased the number of neurones injured per mm(2) in the cortex, not only in the pre-treated animals, but also in those which received L-kynurenine after the ischaemic insult. It is concluded that even the post-traumatic administration of L-kynurenine may be of substantial therapeutic benefit in the treatment of global brain ischaemia. This is the first histological proof of the neuroprotective effect achieved by the post-traumatic administration of L-kynurenine in the global ischaemic cortex.


Subject(s)
Brain Ischemia/drug therapy , Cerebral Cortex/pathology , Kynurenine/pharmacology , Neuroprotective Agents , Animals , Brain Ischemia/pathology , Cerebrovascular Circulation/drug effects , Fluoresceins , Organic Anion Transporters/antagonists & inhibitors , Organic Chemicals , Probenecid/pharmacology , Rats , Rats, Wistar , Vertebral Artery/physiology
8.
FASEB J ; 20(8): 1191-3, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16636106

ABSTRACT

The underlying cause of Alzheimer's disease (AD) is thought to be the beta-amyloid aggregates formed mainly by Abeta1-42 peptide. Protective pentapeptides [e.g., Leu-Pro-Phe-Phe-Asp (LPFFD)] have been shown to prevent neuronal toxicity of Abeta1-42 by arresting and reversing fibril formation. Here we report that an endogenous tetrapeptide, endomorphin-2 (End-2, amino acid sequence: YPFF), defends against Abeta1-42 induced neuromodulatory effects at the cellular level. Although End-2 does not interfere with the kinetics of Abeta fibrillogenesis according to transmission electron microscopic studies and quasielastic light scattering measurements, it binds to Abeta1-42 during aggregation, as revealed by tritium-labeled End-2 binding assay and circular dichroism measurements. The tetrapeptide attenuates the inhibitory effect on cellular redox activity of Abeta1-42 in a dose-dependent manner, as measured by 3-(4,5-dimethylthiazolyl-2)-2,-5-diphenyltetrazolium bromide (MTT) assay. In vitro and in vivo electrophysiological experiments show that End-2 also protects against the field excitatory postsynaptic potential attenuating and the NMDA-evoked response-enhancing effect of Abeta1-42. Studies using [D-Ala (2), N-Me-Phe (4), Gly (5)-ol]-enkephalin (DAMGO), a mu-opioid receptor agonist, show that the protective effects of the tetrapeptide are not mu-receptor modulated. The endogenous tetrapeptide End-2 may serve as a lead compound for the drug development in the treatment of AD.


Subject(s)
Amyloid beta-Peptides/antagonists & inhibitors , Neuroprotective Agents/pharmacology , Oligopeptides/pharmacology , Peptide Fragments/antagonists & inhibitors , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/ultrastructure , Animals , Cell Line, Tumor , Cell Survival/drug effects , Cells, Cultured , Circular Dichroism , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Evoked Potentials , Excitatory Postsynaptic Potentials/drug effects , Iontophoresis , Light , Microscopy, Electron, Transmission , N-Methylaspartate/metabolism , Neurons/drug effects , Neurons/physiology , Neuroprotective Agents/metabolism , Oligopeptides/metabolism , Peptide Fragments/chemistry , Peptide Fragments/ultrastructure , Radioligand Assay , Rats , Rats, Wistar , Scattering, Radiation
9.
Endocrinology ; 147(2): 683-6, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16293666

ABSTRACT

Dehydroepiandrosterone and its sulfate (DHEAS) are sex hormone precursors that exert marked neurotrophic and/or neuroprotective activity in the central nervous system. The present study evaluated the effects of DHEAS and 17beta-estradiol (E2) in a focal cortical cold lesion model, in which DHEAS (50 mg/kg, sc) and E2 (35 mg/kg, sc) were administered either as pretreatment (two subsequent injections 1 d and 1 h before lesion induction) or posttreatment (immediately after lesion induction). The focal cortical cold lesion was induced in the primary motor cortex by means of a cooled copper cylinder placed directly onto the cortical surface. One hour later, the animals were killed, the brains cut into 0.4-mm-thick slices, and the sections stained with 1% triphenyltetrazolium chloride. The volume of the hemispheric lesion was calculated for each animal. The results demonstrated that the lesion area was significantly attenuated in both the DHEAS- and E2- pre- and posttreated groups and that in the presence of letrozole, a nonsteroidal aromatase inhibitor, no neuroprotection was observed, suggesting that the beneficial effect of DHEAS on the cold injury might depend on the conversion of DHEAS to E2 within the brain. It is concluded that even a single posttraumatic administration of DHEAS may be of substantial therapeutic benefit in the treatment of focal brain injury with vasogenic edema.


Subject(s)
Brain Injuries/prevention & control , Cold Temperature , Dehydroepiandrosterone/administration & dosage , Estradiol/physiology , Motor Cortex/injuries , Neuroprotective Agents/administration & dosage , Animals , Brain Injuries/etiology , Dehydroepiandrosterone/metabolism , Drug Administration Schedule , Estradiol/administration & dosage , Male , Models, Animal , Motor Cortex/drug effects , Motor Cortex/metabolism , Neuroprotective Agents/metabolism , Rats , Rats, Wistar
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