RESUMEN
The N-acylhydrazone (NAH) analogues N-methyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-785) and N-benzyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-786) were prepared from 2-thienylidene 3,4-methylenedioxybenzoylhydrazine (LASSBio-294). The ability of LASSBio-785 and LASSBio-786 to decrease central nervous system activity was investigated in male Swiss mice. LASSBio-785 or LASSBio-786 (30â mg/kg, ip) reduced locomotor activity from 209 ± 26 (control) to 140 ± 18 (P < 0.05) or 146 ± 15 crossings/min (P < 0.05), respectively. LASSBio-785 (15 or 30â mg/kg, iv) also reduced locomotor activity from 200 ± 15 to 116 ± 29 (P < 0.05) or 60 ± 16 crossings/min (P < 0.01), respectively. Likewise, LASSBio-786 (15 or 30â mg/kg, iv) reduced locomotor activity from 200 ± 15 to 127 ± 10 (P < 0.01) or 96 ± 14 crossings/min (P < 0.01), respectively. Pretreatment with flumazenil (20â mg/kg, ip) prevented the locomotor impairment induced by NAH analogues (15â mg/kg, iv), providing evidence that the benzodiazepine (BDZ) receptor is involved. This finding was supported by the structural similarity of NAH analogues to midazolam. However, LASSBio-785 showed weak binding to the BDZ receptor. LASSBio-785 or LASSBio-786 (30â mg/kg, ip, n = 10) increased pentobarbital-induced sleeping time from 42 ± 5 (DMSO) to 66 ± 6 (P < 0.05) or 75 ± 4â min (P < 0.05), respectively. The dose required to achieve 50% hypnosis (HD50) following iv injection of LASSBio-785 or LASSBio-786 was 15.8 or 9.5â mg/kg, respectively. These data suggest that both NAH analogues might be useful for the development of new neuroactive drugs for the treatment of insomnia or for use in conjunction with general anesthesia.
Asunto(s)
Hidrazinas/farmacología , Hidrazonas/farmacología , Hipnóticos y Sedantes/farmacología , Actividad Motora/efectos de los fármacos , Receptores de GABA/efectos de los fármacos , Tiofenos/farmacología , Animales , Hidrazinas/química , Hidrazonas/química , Masculino , Ratones , Receptores de GABA/fisiología , Tiofenos/químicaRESUMEN
The N-acylhydrazone (NAH) analogues N-methyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-785) and N-benzyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-786) were prepared from 2-thienylidene 3,4-methylenedioxybenzoylhydrazine (LASSBio-294). The ability of LASSBio-785 and LASSBio-786 to decrease central nervous system activity was investigated in male Swiss mice. LASSBio-785 or LASSBio-786 (30 mg/kg, ip) reduced locomotor activity from 209 ± 26 (control) to 140 ± 18 (P < 0.05) or 146 ± 15 crossings/min (P < 0.05), respectively. LASSBio-785 (15 or 30 mg/kg, iv) also reduced locomotor activity from 200 ± 15 to 116 ± 29 (P < 0.05) or 60 ± 16 crossings/min (P < 0.01), respectively. Likewise, LASSBio-786 (15 or 30 mg/kg, iv) reduced locomotor activity from 200 ± 15 to 127 ± 10 (P < 0.01) or 96 ± 14 crossings/min (P < 0.01), respectively. Pretreatment with flumazenil (20 mg/kg, ip) prevented the locomotor impairment induced by NAH analogues (15 mg/kg, iv), providing evidence that the benzodiazepine (BDZ) receptor is involved. This finding was supported by the structural similarity of NAH analogues to midazolam. However, LASSBio-785 showed weak binding to the BDZ receptor. LASSBio-785 or LASSBio-786 (30 mg/kg, ip, n = 10) increased pentobarbital-induced sleeping time from 42 ± 5 (DMSO) to 66 ± 6 (P < 0.05) or 75 ± 4 min (P < 0.05), respectively. The dose required to achieve 50% hypnosis (HD50) following iv injection of LASSBio-785 or LASSBio-786 was 15.8 or 9.5 mg/kg, respectively. These data suggest that both NAH analogues might be useful for the development of new neuroactive drugs for the treatment of insomnia or for use in conjunction with general anesthesia.
Asunto(s)
Animales , Masculino , Ratones , Hidrazinas/farmacología , Hidrazonas/farmacología , Hipnóticos y Sedantes/farmacología , Actividad Motora/efectos de los fármacos , Receptores de GABA/efectos de los fármacos , Tiofenos/farmacología , Hidrazinas/química , Hidrazonas/química , Receptores de GABA/fisiología , Tiofenos/químicaRESUMEN
In the present study, we describe the antinociceptive effect of filicene, a triterpene isolated from Adiantum cuneatum (Adiantaceae) leaves, in several models of pain in mice. When evaluated against acetic acid-induced abdominal constrictions, filicene (10, 30 and 60 mg/kg, i.p.) produced dose-related inhibition of the number of constrictions, being several times more potent [ID(50)=9.17 (6.27-13.18) mg/kg] than acetaminophen [ID(50)=18.8 (15.7-22.6) mg/kg], diclofenac [ID(50)=12.1(9.40-15.6) mg/kg] and acetylsalicylic acid [ID(50)=24.0(13.1-43.8) mg/kg] in the same doses as those used for the standard drugs. Filicene also produced dose-related inhibition of the pain caused by capsaicin and glutamate, with mean ID(50) values of 11.7 (8.51-16.0) mg/kg and <10 mg/kg, respectively. Its antinociceptive action was significantly reversed by atropine, haloperidol, GABA(A) and GABA(B) antagonists (bicuculline and phaclofen, respectively), but was not affected by L-arginine-nitric oxide, serotonin, adrenergic and the opioid systems. Together, these results indicate that the mechanisms involved in its action are not completely understood, but seem to involve interaction with the cholinergic, dopaminergic, glutamatergic, GABAergic and tachykinergic systems.
Asunto(s)
Adiantum/química , Analgésicos/aislamiento & purificación , Analgésicos/farmacología , Triterpenos/aislamiento & purificación , Triterpenos/farmacología , Ácido Acético/toxicidad , Analgésicos/administración & dosificación , Analgésicos/química , Animales , Capsaicina/toxicidad , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ácido Glutámico/toxicidad , Masculino , Ratones , Estructura Molecular , Dolor/tratamiento farmacológico , Dolor/fisiopatología , Fitoterapia , Plantas Medicinales/química , Receptores Colinérgicos/efectos de los fármacos , Receptores Colinérgicos/fisiología , Receptores Dopaminérgicos/efectos de los fármacos , Receptores Dopaminérgicos/fisiología , Receptores de GABA/efectos de los fármacos , Receptores de GABA/fisiología , Receptores de Neurotransmisores/efectos de los fármacos , Receptores de Neurotransmisores/fisiología , Receptores de Taquicininas/efectos de los fármacos , Receptores de Taquicininas/fisiología , Triterpenos/administración & dosificación , Triterpenos/químicaRESUMEN
The dorsolateral and medial prefrontal cortex are critical for immediate memory processing. The possibility has been raised that those two areas may also contribute to long-term memory formation. Here, we studied the role of specific receptors in dorsolateral and medial prefrontal cortex in immediate and in long-term memory formation of one-trial inhibitory avoidance. Four different specific receptor ligands were infused into these two areas: the dopamine D1 receptor antagonist, SCH23390, the GABA(A) receptor agonist, muscimol, the AMPA glutamatergic receptor antagonist, ciano-nitro-quinoxaline-dione (CNQX), and the NMDA glutamatergic receptor antagonist, aminophosphonovaleric acid (AP5). In all cases the doses used had been previously shown to affect immediate or long-term memory. In the experiments on immediate memory the drugs were given 5 min before training and the animals were tested 3s post-training. These animals were then also tested 24h later for long-term memory. The effect of the treatments on long-term memory was studied by their infusion 0, 90, 180 or 270 min post-training, testing the animals 24h after training. Immediate memory was inhibited by SCH23390, muscimol and CNQX, but not by AP5, given into any of the two subregions. Long-term memory formation was inhibited by SCH23390, muscimol and CNQX, but not by AP5, given pre-training or 0, 90 or 180 but not 270 min post-training into the dorsolateral region; or 90 but not 0 or 180 min post-training into the medial region. Thus, there is a time- and receptor-dependent correlation in the two areas between their role in immediate and in long-term memory processing. Both roles require intact glutamate AMPA and dopamine D1 receptors, are inhibited by GABAergic synapses, and are unaffected by AP5. In the dorsolateral prefrontal cortex the link between immediate and long-term memory appears to be direct; in the medial area the link suffers a 90 min delay.
Asunto(s)
Memoria a Corto Plazo/efectos de los fármacos , Muscimol/farmacología , Corteza Prefrontal/efectos de los fármacos , Retención en Psicología/efectos de los fármacos , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Animales , Antagonistas de Aminoácidos Excitadores/farmacología , Masculino , Memoria/efectos de los fármacos , Ratas , Ratas Wistar , Receptores AMPA/efectos de los fármacos , Receptores de Dopamina D1/antagonistas & inhibidores , Receptores de GABA/efectos de los fármacos , Receptores de Glutamato/efectos de los fármacos , Factores de TiempoRESUMEN
This work was designed to study the influence of drugs during seizures and status epilepticus (SE) induced by pilocarpine and mortality in adult rats. Glutamate (10 and 20 mg/kg), N-methyl-d-aspartate (NMDA, 5 and 10 mg/kg), ketamine (1.5 and 2.0 mg/kg), gabapentin (200 and 250 mg/kg), phenobarbital (50 and 100 mg/kg) and vigabatrin (250 and 500 mg/kg) were administered intraperitoneally, 30 min prior to pilocarpine (400 mg/kg, i.p.). The animals were observed (24 h) to determine: number of peripheral cholinergic signs, tremors, stereotyped movements, seizures, SE, latency to first seizure and number of deaths after pilocarpine treatment. NMDA and glutamate had pro-convulsive effects in both doses tested. Smaller and higher doses of these drugs no protected and increased pilocarpine-induced seizures and/or mortality. Gabapentin, vigabatrin, phenobarbital and ketamine protected against seizures and increased the latency to first seizure. Thus, these results suggest that caution should be taken in the selection of pharmacotherapy and dosages for patients with seizures and SE because of the possibility of facility the convulsive process toxicity, SE and the mortality of adult animals in this seizures model that is similar temporal lobo epilepsy in humans.
Asunto(s)
Anticonvulsivantes/farmacología , Receptores de GABA/efectos de los fármacos , Receptores de Neurotransmisores/efectos de los fármacos , Convulsiones/fisiopatología , Estado Epiléptico/fisiopatología , Aminas/farmacología , Animales , Ácidos Ciclohexanocarboxílicos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Gabapentina , Ácido Glutámico/farmacología , Glutamina/metabolismo , Ketamina/farmacología , Masculino , Agonistas Muscarínicos/toxicidad , N-Metilaspartato/farmacología , Fenobarbital/farmacología , Pilocarpina/toxicidad , Ratas , Ratas Wistar , Convulsiones/inducido químicamente , Estado Epiléptico/inducido químicamente , Vigabatrin/farmacología , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
Insomnia is a disorder that affects a large part of the population. Agents that are used to treat this sleep disorder have evolved: benzodiazepines replaced barbiturates, but there is still concern about their residual effects and about the development of dependence and the risk of withdrawal symptoms. Currently the benzodiazepines receptor agonists (zolpidem, zaleplon, zopiclone and eszopiclone) are the agents most widely prescribed. Pharmaceutical technology and the advances in the knowledge of sleep physiology have led to the availability of some novelties like modified release zolpidem (indicated not only to initiate but also to maintain sleep., ramelteon and agomelatine (melatonine receptors agonists). This article summarises these subjects as well as the pharmacology of investigational drugs, such as indiplon (another benzodiazepine receptor agonist), gaboxadol ( a selective extrasynaptic GABAA agonist -SEGA-), and some anticonvulsant drugs that could be useful as hypnotics: tiagabine ( a GABA transporter inhibitor), pregabaline and gabapentine (GABA analogs). The possible usefulness of 5-HT2A/2C antagonists is also addressed.
Asunto(s)
Hipnóticos y Sedantes/uso terapéutico , Sueño/fisiología , Humanos , Hipnóticos y Sedantes/farmacología , Melatonina/fisiología , Receptores de GABA/efectos de los fármacos , Receptores de GABA/fisiologíaRESUMEN
In the somatosensory system, the flow of sensory information is regulated at early stages by presynaptic inhibition. Recent findings have shown that the mechanisms generating the primary afferent depolarization (PAD) associated with presynaptic inhibition are complex, with some components mediated by a non-spiking mechanism. How sensory inputs carried by neighbouring afferent fibres interact to regulate the generation of PAD, and thus presynaptic inhibition, is poorly known. Here, we investigated the interaction between neighbouring primary afferents for the generation of PAD in an in vitro preparation of the turtle spinal cord. To monitor PAD we recorded the dorsal root potential (DRP), while the simultaneous cord dorsum potential (CDP) was recorded to assess the population postsynaptic response. We found that the DRP and the CDP evoked by a primary afferent test stimulus was greatly reduced by a conditioning activation of neighbouring primary afferents. This depression had early and late components, mediated in part by GABAA and GABAB receptors, since they were reduced by bicuculline and SCH 50911 respectively. However, with the selective stimulation of C and Adelta fibres in the presence of TTX, the early and late depression of the DRP was replaced by facilitation of the GABAergic and glutamatergic components of the TTX-resistant DRP. Our findings suggest a subtle lateral excitatory interaction between primary afferents for the generation of PAD mediated by a non-spiking mechanism that may contribute to shaping of information transmitted by C and Adelta fibres in a spatially confined scale in analogy with the retina and olfactory bulb.
Asunto(s)
Potenciales de Acción/fisiología , Inhibición Neural/fisiología , Neuronas Aferentes/metabolismo , Médula Espinal/metabolismo , Raíces Nerviosas Espinales/metabolismo , Transmisión Sináptica/fisiología , Potenciales de Acción/efectos de los fármacos , Vías Aferentes/efectos de los fármacos , Vías Aferentes/metabolismo , Animales , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Antagonistas del GABA/farmacología , Ácido Glutámico/metabolismo , Fibras Nerviosas Mielínicas/efectos de los fármacos , Fibras Nerviosas Mielínicas/metabolismo , Fibras Nerviosas Amielínicas/efectos de los fármacos , Fibras Nerviosas Amielínicas/metabolismo , Inhibición Neural/efectos de los fármacos , Neuronas Aferentes/efectos de los fármacos , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/metabolismo , Receptores de GABA/efectos de los fármacos , Receptores de GABA/metabolismo , Reflejo/efectos de los fármacos , Reflejo/fisiología , Bloqueadores de los Canales de Sodio/farmacología , Médula Espinal/anatomía & histología , Raíces Nerviosas Espinales/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Tortugas , Ácido gamma-Aminobutírico/metabolismoRESUMEN
The aim of the present study was to evaluate the interaction between a classic GABAergic antagonist -- pentylenetetrazol (PTZ) with an organoselenium compound -- diphenyl diselenide (PhSe)(2) and with the metal chelating agent -- 2,3 dimercaptopropanol (BAL). Mice were pre-treated with 150 micromol/kg (PhSe)(2) or BAL (250, 500 or 1000 micromol/kg) before treatment with PTZ. Pre-treatment with (PhSe)(2) reduced the latency for PTZ-induced seizure at doses of 40 and 60 mg/kg and cause a decrease in the latency for PTZ-induced death at the dose of 60 mg/kg. However, treatment with PTZ at dose of 80 mg/kg was not affected by (PhSe)(2) pre-treatment. Pre-treatment with BAL reduced the latency for PTZ-induced seizure at doses of 40 and 50 mg/kg. In addition, the latency for PTZ-induced death at the dose of 40 mg/kg was decreased significantly by pre-treatment with all doses of BAL. At the dose of 50mg/kg, a significant decrease in the latency for death occurred only in mice pre-treated with 500 and 1000 micromol/kg of BAL. Our results indicate that the PTZ-induced chemical seizures and mortality was enhanced by (PhSe)(2) and BAL. These results indicated that (PhSe)(2) and BAL interact with PTZ possibly by modulating the GABAergic system.
Asunto(s)
Derivados del Benceno/toxicidad , Convulsivantes/toxicidad , Dimercaprol/toxicidad , Compuestos de Organoselenio/toxicidad , Pentilenotetrazol/toxicidad , Convulsiones/inducido químicamente , Ácido gamma-Aminobutírico/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatología , Quelantes/toxicidad , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Antagonistas del GABA/toxicidad , Masculino , Ratones , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Receptores de GABA/efectos de los fármacos , Receptores de GABA/metabolismo , Convulsiones/metabolismo , Convulsiones/fisiopatología , Tasa de Supervivencia , Factores de TiempoRESUMEN
We studied the effects of injecting agonists of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) muscimol (GABA-A receptor agonist) and baclofen (GABA-B receptor agonist) in the medial preoptic area (MPOA) and neighboring brain regions, the bed nucleus of the stria terminalis (BNST), and lateral preoptic area (LPO) on maternal behavior. Lactating female rats were implanted with bilateral cannulae in the MPOA/BNST on day 1 postpartum. On day 5, a maternal behavior test was conducted in the home cage after females received injections of muscimol or baclofen (0, 12.5, 50 or 200 ng per side). On day 7, after MPOA/BNST injections, a second maternal behavior test was conducted with pups placed at the end of a T-runway projecting from the home cage. Finally, after injections on day 9 maternal aggression, olfaction, and locomotor behavior were tested. The GABA receptor agonists injected in the MPOA/BNST produced dose-dependent deficits in all components of maternal behavior, including maternal aggression, except licking. Muscimol produced deficits in the active component, nest building at lower doses than baclofen, both agonists produced deficits in retrieving, while baclofen produced deficits in passive components (hovering and crouching over pups) at lower doses than muscimol. Both GABA receptor agonists increased locomotor activity and reduced olfactory responsiveness but these were only correlated with deficits in retrieving and crouching in baclofen-treated females.
Asunto(s)
Agonistas del GABA/administración & dosificación , Lactancia/fisiología , Conducta Materna/fisiología , Área Preóptica/efectos de los fármacos , Receptores de GABA/fisiología , Núcleos Septales/efectos de los fármacos , Análisis de Varianza , Animales , Baclofeno/administración & dosificación , Distribución de Chi-Cuadrado , Femenino , Conducta Materna/efectos de los fármacos , Microinyecciones , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Muscimol/administración & dosificación , Área Preóptica/fisiología , Ratas , Ratas Wistar , Receptores de GABA/efectos de los fármacos , Núcleos Septales/fisiología , Estadísticas no ParamétricasRESUMEN
The main goal of this work was to analyze the electrophysiological properties of cultured hippocampal neurons from a particular epileptic rat strain, called Wistar Audiogenic Rats (WAR). The whole-cell patch-clamp technique was used to record both active and passive membrane responses in an attempt to detect alterations in their characteristics in relation to controls from Wistar rats. Neurons from WARs show a significant reduction in the magnitude of the inhibitory GABAergic currents ( approximately 45%), in spite of maintaining a normal level of the excitatory glutamatergic currents. In addition, the magnitude of potassium currents, measured at +80 mV, is reduced by about 30% in comparison to controls. Surprisingly, we also found important changes in the passive cellular properties in WAR neurons such as membrane potential (-50.0 mV in WARs and -63.1 mV in controls) and input resistance (647 MOmega in WARs and 408 MOmega in controls). The changes described here, could be the basis of the neurophysiological and behavioral alterations present in these hyperexcitable animals, contributing to a better understanding of epileptogenesis in this particular animal model.
Asunto(s)
Membrana Celular/fisiología , Epilepsia Refleja/fisiopatología , Hipocampo/fisiopatología , Inhibición Neural/fisiología , Neuronas/fisiología , Receptores de GABA/fisiología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Animales Recién Nacidos , Membrana Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Impedancia Eléctrica , Predisposición Genética a la Enfermedad , Ácido Glutámico/metabolismo , Ácido Glutámico/farmacología , Hipocampo/citología , Inhibición Neural/efectos de los fármacos , Neuronas/efectos de los fármacos , Técnicas de Placa-Clamp , Canales de Potasio/fisiología , Ratas , Ratas Wistar , Receptores de GABA/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
Benzodiazepines are effective and widely used in anxiety disorders, but they produce sedation and dependency. Molecular studies have shown that binding benzodiazepines to GABAA receptors containing the Alpha1 subunit mediates the sedative properties of benzodiazepines. Other strategies are being developed including the use of the selective GABA reuptake inhibitor tiagabine and the voltage gated calcium ion channel ligand pregabalin. Several novel strategies are being developed based on preclinical observations, including corticotrophin-releasing factor (CRF) antagonists, substance P antagonists, and drugs inhibiting glutamate neurotransmission.
Asunto(s)
Trastornos de Ansiedad/tratamiento farmacológico , Benzodiazepinas/farmacología , Benzodiazepinas/uso terapéutico , Biología Molecular/métodos , Ácido gamma-Aminobutírico/análogos & derivados , Benzodiazepinas/efectos adversos , Ácido Glutámico/metabolismo , Humanos , Ácidos Nipecóticos/efectos adversos , Pregabalina , Receptores de GABA/efectos de los fármacos , Tiagabina , Ácido gamma-Aminobutírico/efectos adversosRESUMEN
Alzheimer's disease (AD) and several other neurological disorders have been linked to the overactivation of glutamatergic transmission and excitotoxicity as a common pathway of neuronal injury. The beta-amyloid peptide (Abeta) is centrally related to the pathogenesis of AD, and previous reports have demonstrated that the blockade of glutamate receptors prevents Abeta-induced neuronal death. We show that taurine, a beta-amino acid found at high concentrations in the brain, protects chick retinal neurons in culture against the neurotoxicity of Abeta and glutamate receptor agonists. The protective effect of taurine is not mediated by interaction with glutamate receptors, as demonstrated by binding studies using radiolabeled glutamate receptor ligands. The neuroprotective action of taurine is blocked by picrotoxin, an antagonist of GABA(A) receptors. GABA and the GABA(A) receptor agonists phenobarbital and melatonin also protect neurons against Abeta-induced neurotoxicity. These results suggest that activation of GABA receptors decreases neuronal vulnerability to excitotoxic damage and that pharmacological manipulation of the excitatory and inhibitory neurotransmitter tonus may protect neurons against a variety of insults. GABAergic transmission may represent a promising target for the treatment of AD and other neurological disorders in which excitotoxicity plays a relevant role.
Asunto(s)
Precursor de Proteína beta-Amiloide/toxicidad , Proteínas del Ojo/efectos de los fármacos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Receptores de GABA/efectos de los fármacos , Receptores de Glutamato/efectos de los fármacos , Taurina/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Células Cultivadas , Senescencia Celular , Embrión de Pollo , Maleato de Dizocilpina/farmacología , Agonistas de Aminoácidos Excitadores/farmacología , Proteínas del Ojo/fisiología , Ácido Glutámico/farmacología , Ácido Kaínico/toxicidad , N-Metilaspartato/farmacología , Fármacos Neuroprotectores/uso terapéutico , Picrotoxina/farmacología , Receptores AMPA/efectos de los fármacos , Receptores de GABA/fisiología , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/fisiología , Receptores de Glutamato/fisiología , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Retina/citología , Retina/embriología , Taurina/uso terapéutico , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/farmacologíaRESUMEN
The modulation of ionotropic gamma-aminobutyric acid (GABA) receptors (GABA-gated Cl(-) channels) by a group of natural and synthetic flavonoids was studied in electrophysiological experiments. Quercetin, apigenin, morine, chrysin and flavone inhibited ionic currents mediated by alpha(1)beta(1)gamma(2s) GABA(A) and rho(1) GABA(C) receptors expressed in Xenopus laevis oocytes in the micromolar range. alpha(1)beta(1)gamma(2s) GABA(A) and rho(1) GABA(C) receptors differ largely in their sensitivity to benzodiazepines, but they were similarly modulated by different flavonoids. Quercetin produced comparable actions on currents mediated by alpha(4)beta(2) neuronal nicotinic acetylcholine, serotonin 5-HT(3A) and glutamate AMPA/kainate receptors. Sedative and anxiolytic flavonoids, like chrysin or apigenin, failed to potentiate but antagonized alpha(1)beta(1)gamma(2s) GABA(A) receptors. Effects of apigenin and quercetin on alpha(1)beta(1)gamma(2s) GABA(A) receptors were insensitive to the benzodiazepine antagonist flumazenil. Results indicate that mechanism/s underlying the modulation of ionotropic GABA receptors by some flavonoids differs from that described for classic benzodiazepine modulation.
Asunto(s)
Flavonoides/farmacología , Receptores de GABA-A/fisiología , Receptores de GABA/fisiología , Animales , Apigenina , Benzoflavonas/farmacología , Femenino , Humanos , Potenciales de la Membrana/efectos de los fármacos , Microinyecciones , Oocitos/efectos de los fármacos , Oocitos/fisiología , Quercetina/farmacología , ARN Complementario/administración & dosificación , ARN Complementario/genética , Ratas , Receptores de GABA/efectos de los fármacos , Receptores de GABA/genética , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/genética , Receptores de Neurotransmisores/efectos de los fármacos , Receptores de Neurotransmisores/genética , Receptores de Neurotransmisores/fisiología , Xenopus laevisRESUMEN
The beta-amyloid peptide (Abeta) is centrally related to the pathogenesis of Alzheimer's disease (AD). Previous studies have suggested that the neurotoxicity of Abeta may be related to the overactivation of glutamatergic transmission and excitotoxicity, and that blockade of glutamate receptors prevents Abeta-induced cell death. Here, we show that melatonin, a pineal hormone, protects chick retinal neurons in culture against the neurotoxicity of Abeta and glutamate. Right-angle light scattering and thioflavin T fluorescence measurements, as well as light microscopy analysis, indicated that, under our experimental conditions, melatonin had no effect on the aggregation of Abeta. Interestingly, the neuroprotective action of melatonin against the toxicity of Abeta was significantly decreased in the presence of picrotoxin, an antagonist of GABA(A)-like receptors. By itself, picrotoxin had no effect. These results suggest that the neuroprotective effects of melatonin against Abeta neurotoxicity could be at least in part related to a decrease in the excitatory tonus, mediated by activation of GABA receptors and the resulting hyper-polarization of the neurons. Thus, selective pharmacological manipulation of neuronal excitatory/inhibitory tonus could be a potentially interesting new approach in the treatment of AD.
Asunto(s)
Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/toxicidad , Antioxidantes/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Ácido Glutámico/toxicidad , Melatonina/farmacología , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/toxicidad , Receptores de GABA/efectos de los fármacos , Animales , Benzotiazoles , Embrión de Pollo , Colorantes Fluorescentes , Antagonistas del GABA/farmacología , Luz , Neuronas/efectos de los fármacos , Picrotoxina/farmacología , Retina/citología , Retina/efectos de los fármacos , Dispersión de Radiación , TiazolesRESUMEN
The effect of baclofen, a GABA(B) agonist, has been studied in the hot plate test in mice, to analyze the possible involvement of the GABAergic system in baclofen analgesia. Baclofen (1-3 mg kg(-1) intraperitoneal (i.p.)) was found to elicit a dose-dependent antinociceptive effect. The antinociceptive effect of baclofen cannot be due to motor incoordination or sedation as the doses of baclofen which produce analgesia did not induce these effects during the rota-rod test. The antinociceptive effect of baclofen was reversed by 2-hydroxysaclofen, a GABA(B) antagonist by both systemic (3 mg kg(-1)) and intra cisterna magna (intracisternal (i.c.)) (0.3 mg kg(-1)) administration. The antagonist dose administered via i.c. produced a complete blockade and was 10-fold lower than the dose employed in i.p. administration. The data suggest that the antinociceptive effect of baclofen is GABA(B) receptor-mediated and reveal a central location of the analgesic effect of baclofen.
Asunto(s)
Analgésicos/farmacología , Baclofeno/análogos & derivados , Baclofeno/farmacología , Agonistas del GABA/farmacología , Animales , Relación Dosis-Respuesta a Droga , Antagonistas del GABA/farmacología , Inyecciones Intraperitoneales , Masculino , Ratones , Relajación Muscular/efectos de los fármacos , Receptores de GABA/efectos de los fármacosRESUMEN
The effects of central administration of opioid antagonists on the aversive responses elicited by electrical (at the freezing and escape thresholds) or chemical stimulation (crossings, rearings, turnings and jumps, induced by microinjections of bicuculline) of the midbrain tectum were determined. Central microinjections of naloxone and naltrexone in the mesencephalic tectum caused a significant increase in the freezing and escape thresholds elicited by electrical midbrain tectum stimulation. Furthermore, both opioid antagonists caused a significant decrease in the mean incidence of aversive behavioral responses induced by microinjections of bicuculline in the deep layers of the superior colliculus (DLSC) and in dorsal aspects of the periaqueductal gray matter (DPAG), as compared with controls. These findings suggest an opioid modulation of the GABAergic inhibitory inputs controlling the aversive behavior elicited by midbrain tectum stimulation. In fact, immunohistochemical evidence suggests that the dorsal mesencephalon is rich in beta-endorphin-containing neurons and fibers with varicosities. Iontophoretical microinjections of the neurotracer biodextran in the substantia nigra, pars reticulata (SNpr), show nigro-tectal pathways connecting SNpr with the same neural substrate of the DPAG rich in neuronal cells immunoreactive for opioid peptides. Labeled neurons of the DLSC and periaqueductal gray matter send inputs with varsicosities to ipsi- and contralateral DPAG and ipsilateral SNpr. These findings, in addition to the psychopharmacological evidence for the interaction between opioid and GABAergic mechanisms, offer a neuroanatomical basis of a possible presynaptic opioid inhibition of GABAergic nigro-tectal neurons modulating the fear in aversive structures of the cranial mesencephalon, in a short link, and maybe through a major neural circuit, also in GABA-containing perikarya of nigro-tectal neurons.
Asunto(s)
Agresión/fisiología , Miedo/fisiología , Vías Nerviosas/fisiología , Sustancia Gris Periacueductal/fisiología , Receptores de GABA/fisiología , Receptores Opioides/fisiología , Colículos Superiores/fisiología , Agresión/efectos de los fármacos , Animales , Bicuculina/farmacología , Estimulación Eléctrica , Miedo/efectos de los fármacos , Antagonistas del GABA/farmacología , Inmunohistoquímica , Masculino , Mesencéfalo/efectos de los fármacos , Mesencéfalo/fisiología , Microinyecciones , Naloxona/farmacología , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Vías Nerviosas/anatomía & histología , Vías Nerviosas/efectos de los fármacos , Neuronas/efectos de los fármacos , Sustancia Gris Periacueductal/anatomía & histología , Sustancia Gris Periacueductal/efectos de los fármacos , Ratas , Ratas Wistar , Receptores de GABA/efectos de los fármacos , Receptores Opioides/efectos de los fármacos , Estimulación Química , Colículos Superiores/anatomía & histología , Colículos Superiores/efectos de los fármacosRESUMEN
Neurological dysfunction is common in patients with maple syrup urine disease (MSUD). However, the mechanisms underlying the pathophysiology of this disorder are poorly known. In the present study we investigated the effect of intrastriatal administration of the alpha-keto acids accumulating in MSUD on the behavior of adult rats. After cannula placing, rats received unilateral intrastriatal injections of alpha-ketoisocaproic acid (KIC, 8 micromol), alpha-ketoisovaleric acid (KIV, 8 micromol), alpha-keto-beta-methylvaleric acid (KMV, 6 micromol) or NaCl. KIV elicited clonic convulsions in a dose-response manner, whereas KIC and KMV did not induce seizure-like behavior. Convulsions provoked by KIV were prevented by intrastriatal preadministration of muscimol (46 pmol) and MK-801 (3 nmol), but not by the preadministration of DNQX (8 nmol). These results indicate that among the keto acids that accumulate in MSUD, KIV is the only metabolite capable of causing convulsions in the present animal model and indicates that KIV is an important excitatory metabolite. Moreover, the participation of GABAergic and glutamatergic NMDA mechanisms in the KIV-induced convulsant behavior is suggested, since KIV-induced convulsions are attenuated by muscimol and MK-801. The authors suggest that KIV may play an important role in the convulsions observed in MSUD, and highlight its relevance to the understanding of the pathophysiology of the neurological dysfunction of MSUD patients.
Asunto(s)
Cuerpo Estriado/metabolismo , Cetoácidos/efectos adversos , Enfermedad de la Orina de Jarabe de Arce/metabolismo , Convulsiones/inducido químicamente , Animales , Cuerpo Estriado/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Agonistas del GABA/farmacología , Agonistas del GABA/uso terapéutico , Hemiterpenos , Masculino , Ratas , Ratas Wistar , Receptores de GABA/efectos de los fármacos , Receptores de GABA/metabolismo , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsiones/tratamiento farmacológicoRESUMEN
INTRODUCTION: Antisense targeting refers to the use of synthetic short lengths of single stranded DNA, or RNA with base sequences complementary to a specific gene or its mRNA. Commonly, synthetic oligonucleotides are designed to hybridize to specific mRNA and thus preventing its translation in a specific protein. DEVELOPMENT: The use of this technology as research tool is well known since two decades ago, but it has been in the last few years, when it has been proposed as a promising tool for the development of a new generation of drugs with high specificity, relative ease of production and low rate of toxicity. Antisense therapeutics is currently being evaluated in clinical trials for cancer, inflammation, and viral diseases. In the field of Neuropharmacology, it has become in a very valuable tool to block the expression of specific genes in vitro as well in the living brain. In this article, we review the contributions of this technology in the field of the Neurosciences, and also give an overview concerning the advances of the antisense strategy in the design of possible new treatments for certain neurological disorders. Other clinically relevant information regarding molecular biology, pharmacokinetics, mechanism of action, and side effects of antisense oligonucleotides has been collected and summarized. CONCLUSIONS: In the neuropharmacological area is the Neurooncology the most intensively researched; nevertheless, the lack of oligos that cross the blood-brain barrier in sufficient amount continues being one of the main difficulties for the successful application of this technique on the central nervous system.
Asunto(s)
Sistema Nervioso Central/efectos de los fármacos , Oligodesoxirribonucleótidos Antisentido/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Neoplasias Encefálicas/tratamiento farmacológico , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Oligodesoxirribonucleótidos Antisentido/efectos adversos , Oligodesoxirribonucleótidos Antisentido/farmacocinética , Receptores Dopaminérgicos/efectos de los fármacos , Receptores de GABA/efectos de los fármacos , Receptores de Neuropéptido Y/efectos de los fármacosRESUMEN
The pathophysiology of convulsive and non-convulsive epilepsies is discussed in its primary generalised forms. Focal, clinical and experimental epilepsies, with emphasis placed on the temporal lobe epilepsies (TLE) and their pathophysiologies are also reviewed. Neurotransmitters and neuromodulators and between them, the second messenger systems are considered in the generation, maintenance or inhibition of the epileptic discharge. Action mechanisms of the more classic antiepileptic drugs are briefly summarized along with the therapeutic strategies that might achieve the final control of abnormal discharges, including genetic control as a promising alternative in the current state of research. We emphasized the study of all type of glutamate and GABA receptors and their relation with mRNA editing in the brain. Some of the genetic studies which have been so fruitful during the last ten years and which have brought new insights regarding the understanding of epileptic syndromes are summarized in this article.
Asunto(s)
Epilepsia Generalizada/fisiopatología , Epilepsia del Lóbulo Temporal/fisiopatología , Receptores de GABA/fisiología , Transducción de Señal/fisiología , Animales , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Epilepsia Generalizada/tratamiento farmacológico , Epilepsia Generalizada/genética , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Epilepsia del Lóbulo Temporal/genética , Epilepsia Tónico-Clónica/tratamiento farmacológico , Epilepsia Tónico-Clónica/genética , Epilepsia Tónico-Clónica/fisiopatología , Humanos , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Receptores de GABA/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
The inferior colliculus is involved in conveying auditory information of an aversive nature to higher cortical structures. Gradual increases in the electrical stimulation of this structure produce progressive aversive responses from vigilance, through freezing, until escape. Recently, we have shown that microinjections of NMDA into the inferior colliculus mimic these aversive effects and that the neural substrates responsible for learned escape behavior in the inferior colliculus are regulated by GABA-benzodiazepine mechanisms. In the present study, we extend these observations showing that unlearned aversive responses are also depressed by muscimol and midazolam, both GABA-benzodiazepine agonists, and that microinjection of glutamate, an excitatory amino acid, into the inferior colliculus can trigger freezing responses. Electrical stimulation of the inferior colliculus of rats placed inside an open field allowed the determination of thresholds for the aversive responses, alertness, freezing and escape. Systemic administration (3 and 5.6 mg/kg) as well as microinjections into the inferior colliculus of the anxiolytic compound midazolam (10, 20 and 40 nmol) caused increases in threshold for these aversive responses. Similar results were obtained following microinjections of the GABA-A agonist muscimol (0.1, 1 and 5 nmol) into this brainstem structure. Microinjections of low doses of glutamate (5 nmol), presumed to activate mainly AMPA/kainate receptors, into the ventrolateral division of the central nucleus of the inferior colliculus of rats placed inside a circular arena induced aversive reactions, characterized by freezing responses. However, higher doses of glutamate caused no apparent effects. GDEE, an AMPA/kainate receptor antagonist, inhibited, whereas AP7, a NMDA receptor antagonist, did not influence these responses. It is suggested that GABA-benzodiazepine processes modulate the expression of defensive reactions in the inferior colliculus and that activation of fast-acting excitatory amino acid receptors in this midbrain region can trigger the initial steps of the defense reaction without eliciting the motor explosive behavior usually seen following the activation of NMDA receptors.