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1.
Neuropharmacology ; 48(6): 788-95, 2005 May.
Article in English | MEDLINE | ID: mdl-15829251

ABSTRACT

Kynurenine 3-mono-oxygenase (KMO, kynurenine hydroxylase) inhibitors increase brain kynurenic acid (KYNA) synthesis and cause pharmacological actions possibly mediated by a reduced activity of excitatory synapses. We used in vivo microdialysis and passive avoidance to study the effects of local KYNA or systemic KMO inhibitor administration on glutamate (GLU) neurotransmission. Local application of KYNA (30-100 nM) through reverse microdialysis reduced GLU content in caudate and cortical dialysates by 75 and 55%, respectively. No changes were found in the hippocampus. Systemic administration of Ro 61-8048 (4-40 mg/kg) increased KYNA levels in dialysates obtained from the cortex (from 10.3 +/- 1.9 to 45.5 +/- 15 nM), caudate (from 2.4 +/- 0.8 to 9.5 +/- 0.9 nM) and hippocampus (from 7.7 +/- 1.7 to 19.2 +/- 3.5 nM). It also caused a parallel robust decrease in GLU levels in the dialysates collected from the caudate (from 2.2 +/- 0.5 to 0.63 +/- 0.05 microM) but not in those collected from the parietal cortex or the hippocampus. In a passive avoidance paradigm, the administration of the NMDA receptor antagonist MK-801 (0.1 mg/kg) reduced, while Ro 61-8048 (4-80 mg/kg) did not change the latency time of entering into the dark compartment on the recall trial. Our data show that KMO inhibitors increase brain KYNA synthesis and selectively reduce GLU extracellular concentration in the basal ganglia.


Subject(s)
Basal Ganglia/drug effects , Brain Chemistry/drug effects , Extracellular Space/drug effects , Glutamic Acid/metabolism , Mixed Function Oxygenases/antagonists & inhibitors , Sulfonamides/pharmacology , Thiazoles/pharmacology , Animals , Avoidance Learning/drug effects , Basal Ganglia/metabolism , Behavior, Animal/drug effects , Calcium Channel Blockers/pharmacology , Chromatography, High Pressure Liquid/methods , Dose-Response Relationship, Drug , Drug Interactions , Extracellular Space/metabolism , Kynurenic Acid/metabolism , Kynurenic Acid/pharmacology , Kynurenine 3-Monooxygenase , Male , Microdialysis/methods , Potassium Chloride/pharmacology , Rats , Rats, Wistar , Statistics, Nonparametric , Time Factors , omega-Conotoxin GVIA/pharmacology
2.
Pain ; 102(1-2): 17-25, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12620593

ABSTRACT

NW-1029, a benzylamino propanamide derivative, was selected among several molecules of this chemical class on the basis of its affinity for the [(3)H]batracotoxin ligand displacement of the Na(+) channel complex and also on the basis of its voltage and use-dependent inhibitory action on the Na(+) currents of the rat DRG (dorsal root ganglia) sensory neuron. This study evaluated the analgesic activity of NW-1029 in animal models of inflammatory and neuropathic pain (formalin test in mice, complete Freund's adjuvant and chronic constriction injury in rats) as well as in acute pain test (hot-plate and tail-flick in rats). Orally administered NW-1029 dose-dependently reduced cumulative licking time in the early and late phase of the formalin test (ED(50)=10.1 mg/kg in the late phase). In the CFA model, NW-1029 reversed mechanical allodynia (von Frey test) after both i.p. and p.o. administration (ED(50)=0.57 and 0.53 mg/kg), respectively. Similarly, NW-1029 reversed mechanical allodynia in the CCI model after both i.p. and p.o. administration yielding an ED(50) of 0.89 and 0.67 mg/kg, respectively. No effects were observed in the hot-plate and tail-flick tests up to 30 mg/kg p.o. The compound orally administered (0.1-10 mg/kg) was well tolerated, without signs of neurological impairment up to high doses (ED(50)=470 and 245 mg/kg in rat and mice Rotarod test, respectively). These results indicate that NW-1029 has anti-nociceptive properties in models of inflammatory and neuropathic pain.


Subject(s)
Amides/therapeutic use , Pain/drug therapy , Propionates/therapeutic use , Sodium Channel Blockers/therapeutic use , Amides/administration & dosage , Animals , Ataxia/drug therapy , Behavior, Animal/drug effects , Chronic Disease/drug therapy , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Administration Routes , Drug Evaluation , Electroshock/methods , Formaldehyde/administration & dosage , Freund's Adjuvant/administration & dosage , Inflammation/chemically induced , Inflammation/drug therapy , Male , Mice , Motor Activity/drug effects , Pain/chemically induced , Pain/classification , Pain Measurement , Pain Threshold , Propionates/administration & dosage , Rats , Rats, Wistar , Reaction Time/drug effects , Sodium Channel Blockers/administration & dosage
3.
Brain Res Mol Brain Res ; 59(1): 50-7, 1998 Aug 15.
Article in English | MEDLINE | ID: mdl-9729272

ABSTRACT

Quinolinic acid (QUIN) is an endogenous neurotoxin which originates from the kynurenine pathway of tryptophan metabolism. An increase of brain QUIN level occurs in several degenerative and inflammatory disorders, but the cellular source of QUIN is still a matter of controversy. In the present study, the gerbil model of transient global ischemia was used to investigate the time course and the cellular localization of QUIN immunoreactivity. Neurodegeneration was evident in the subiculum and in the CA1 area of the hippocampus 4, 7 and 14 days after ischemia. QUIN positive cells, with microglia-like morphology, appeared in the subiculum and in the CA1, 4 days after ischemia. At 7 days post-ischemia they extended to the whole CA1, disappearing at 14 days. Neither neurodegeneration nor QUIN positive cells could be detected in ischemic gerbils sacrificed at 1 and 2 days after ischemia and in sham-operated animals. These findings suggest that microglia-like cells infiltrating the degenerating areas of the hippocampus represent the major source of QUIN following transient ischemia in the gerbil. Thus, in situ production of QUIN in vulnerable brain regions may contribute to the pathophysiological mechanisms of delayed brain injury.


Subject(s)
Hippocampus/metabolism , Ischemic Attack, Transient/metabolism , Quinolinic Acid/metabolism , Animals , Antibody Specificity , Gerbillinae , Hippocampus/pathology , Immunohistochemistry , Ischemic Attack, Transient/pathology , Male , Quinolinic Acid/immunology , Rabbits , Time Factors
6.
Life Sci ; 47(14): 1253-60, 1990.
Article in English | MEDLINE | ID: mdl-2147050

ABSTRACT

Reportedly, excitatory amino acids are involved in the control of gonadotropin secretion of rats and non-human primates. The aim of this study was to investigate the effect of chronic blockade of NMDA (N-methyl-D-aspartic acid) receptors by the non competitive receptor antagonist MK-801 on gonadotropin secretion and the onset of puberty in female rats. Moreover, since in humans alterations of the timing of puberty frequently coexist with disturbances of body growth, suggesting a common etiology for both events, we evaluated the effect of MK-801 also on the neural mechanisms controlling growth hormone (GH) secretion. Twenty-one-day-old female rats were treated with MK-801 (0.2 mg/kg ip, bid) or placebo for 10 days and were killed after 7 days of withdrawal. Administration of MK-801 induced a significant impairment of growth rate without altering food intake, and a delay in vaginal opening. Pituitaries from rats treated with MK-801 had a reduced luteinizing hormone (LH) content, and secreted in vitro lower amounts of LH both under basal and LHRH-stimulated conditions. MK-801 treated rats had a lower pituitary GH content and basal and GHRH-stimulated GH release and reduced plasma insulin-like growth factor-I levels. These data indicate that blockade of NMDA receptors in a critical period of the female rat life-span: 1) delays puberty by reducing gonadotropin secretion; 2) impairs growth rate by reducing GH secretion, with a mechanism still to be clarified.


Subject(s)
Dizocilpine Maleate/pharmacology , Growth/drug effects , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Sexual Maturation/drug effects , Animals , Body Weight/drug effects , Female , Gonadotropin-Releasing Hormone/physiology , Growth Hormone/metabolism , Insulin-Like Growth Factor I/analysis , Luteinizing Hormone/metabolism , Rats , Rats, Inbred Strains
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