RESUMEN

Memory consolidation is associated with the regulation of protein kinases, which impact synaptic functions and promote synaptogenesis. The administration of spermidine (SPD) has been shown to modulate major protein kinases associated with memory improvement, including the Ca2+-dependent protein kinase (PKC) and cAMP-dependent protein kinase (PKA), key players in the cAMP response element-binding protein (CREB) activation. Nevertheless, the initial mechanism underlying SPD-mediated memory consolidation remains unknown, as we hypothesize a potential involvement of the memory consolidation precursor, Ca2+/calmodulin-dependent protein kinase II-α (CaMKIIα), in this process. Based on this, our study aimed to investigate potential interactions among PKC, PKA, and CREB activation, mediated by CaMKIIα activation, in order to elucidate the SPD memory consolidation pathway. Our findings suggest that the post-training administration of the CaMKII inhibitor, KN-62 (0.25 nmol, intrahippocampal), prevented the memory enhancement induced by SPD (0.2 nmol, intrahippocampal) in the inhibitory avoidance task. Through western immunoblotting, we observed that phosphorylation of CaMKIIα in the hippocampus was facilitated 15 min after intrahippocampal SPD administration, resulting in the activation of PKA and CREB, 180 min after infusion, suggesting a possible sequential mechanism, since SPD with KN-62 infusion leads to a downregulation in CaMKIIα/PKA/CREB pathway. However, KN-62 does not alter the memory-facilitating effect of SPD on PKC, possibly demonstrating a parallel cascade in memory acquisition via PKA, without modulating CAMKIIα. These results suggest that memory enhancement induced by SPD administration involves crosstalk between CaMKIIα and PKA/CREB, with no PKC interaction.

Asunto(s)

Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Proteínas Quinasas Dependientes de AMP Cíclico , Memoria , Ratas Wistar , Transducción de Señal , Espermidina , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Ratas , Espermidina/farmacología , Masculino , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Memoria/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Fosforilación/efectos de los fármacos , Sulfonamidas/farmacología , Bencilaminas/farmacología , Bencilaminas/administración & dosificación , Reacción de Prevención/efectos de los fármacos , Proteína Quinasa C/metabolismo , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados

RESUMEN

Proteins involved in the Alzheimer's disease (AD), such as amyloid precursor protein (APP) and presenilin-1 (PS1), play critical roles in early development of the central nervous system (CNS), as well as in innate immune and glial cell responses. Familial AD is associated with the presence of APPswe and PS1dE9 mutations. However, it is still unknown whether these mutations cause deficits in CNS development of carriers. We studied genome-wide gene expression profiles of differentiated neural progenitor cells (NPCs) from wild-type and APPswe/PS1dE9 mouse embryo telencephalon. The occurrence of strong innate immune and glial cell responses in APPswe/PS1dE9 neurospheres mainly involves microglial activation, inflammatory mediators and chemokines. APPswe/PS1dE9 neurospheres augmented up to 100-fold CCL12, CCL5, CCL3, C3, CX3CR1, TLR2 and TNF-alpha expression levels, when compared to WT neurospheres. Expression levels of the glia cell marker GFAP and microglia marker Iba-1 were up to 20-fold upregulated in APPswe/PS1dE9 neurospheres. The secretome of differentiated APPswe/PS1dE9 NPCs revealed enhanced chemoattraction of peripheral blood mononuclear cells. When evaluating the inferred protein interaction networks constructed from the array data, an improvement in astrocyte differentiation in APPswe/PS1dE9 neurospheres was evident in view of increased GFAP expression. Transgenic NPCs differentiated into neural phenotypes presented expression patterns of cytokine, glial cells, and inflammatory mediators characteristic of APPswe/PS1dE9 adult animals. Consequently, the neurogenic niche obtained from differentiation of embryonic APPswe/PS1dE9 neurospheres spontaneously presents several alterations observed in adult AD brains. Finally, our data strengthen pathophysiological hypotheses that propose an early neurodevelopmental origin for familial AD.

Asunto(s)

Enfermedad de Alzheimer , Ratones , Animales , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/metabolismo , Leucocitos Mononucleares/metabolismo , Ratones Transgénicos , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Neuroglía/metabolismo , Diferenciación Celular/genética , Mediadores de Inflamación , Inmunidad Innata/genética

RESUMEN

Spermidine (SPD) is an endogenous polyamine that plays a facilitatory role in memory acquisition and consolidation. Memory consolidation occurs immediately after learning and again around 3-6 hours later. Current evidence indicates that the polyamine binding site at the NMDA receptor (NMDAr) mediates the effects of SPD on memory. While NMDAr activation increases brain-derived neurotrophic factor (BDNF) release, no study has investigated whether BDNF-activated signaling pathways, such as the phosphatidylinositol 3-kinase (PI3K)/Akt pathway play a role in SPD-induced improvement of memory consolidation. Therefore, the aim of the current study was to evaluate whether the TrkB receptor and the PI3K/Akt pathway are involved in the facilitatory effect of SPD on memory consolidation. Male Wistar rats were trained in the contextual conditioned fear task. SPD, ANA-12 (TrkB antagonist), and LY294002 (PI3K inhibitor) were administered immediately after training. The animals were tested 24 h after training. We found that SPD improved fear memory consolidation and that both ANA-12 and LY294002 prevented the facilitatory effect of SPD on memory. These results suggest that SPD-induced improvement of memory consolidation involves the activation of the TrkB receptor and PI3K/Akt pathway.

Asunto(s)

Condicionamiento Psicológico/efectos de los fármacos , Consolidación de la Memoria/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Espermidina/farmacología , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Miedo/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Ratas , Ratas Wistar , Receptor trkB/metabolismo

RESUMEN

Nectandra grandiflora Ness (Lauraceae) essential oil (EO) main constituent, the sesquiterpenoid (+)-dehydrofukinone (DHF), has sedative and anticonvulsant effects through GABAergic mechanisms. Other DHF-related sesquiterpenoids have been identified in the EO, such as, dehydrofukinone epoxide (DFX), eremophil-11-en-10-ol (ERM) and selin-11-en-4-α-ol (SEL). However, the neuronal effects of these compounds in mammals remain unknown. Therefore, the aim of this study was to evaluate the anxiolytic potential of the N. grandiflora EO and the isolated compounds in in mice. For this purpose, mice were administered orally with vehicle, 10, 30 or 100 mg/kg EO, DHF, DFX, ERM or SEL or 1 mg/kg diazepam. Locomotion and ethological parameters in the open field (OF) and elevated plus maze (EPM) were recorded. We also examined the effect of DFX, ERM and SEL on the membrane potential and calcium influx in synaptosomes, and the presence of the compounds in the cortical tissue using gas chromatography. EOs and isolated compounds reduced anxiety-related parameters in the EPM (open arms time and entries, end activity, head dipping) and OF (center time and entries, total rearing, unprotected rearing, sniffing, grooming) without alter ambulation or induce sedation. Flumazenil (2 mg/kg, i.p.) altered the anxiolytic-like effect of all treatments and vanished the DFX, ERM and SEL-induced changes in membrane potential. However, FMZ did not blocked the DFX-, ERM- and SEL-induced inhibition of calcium influx. Therefore, our results suggest that N. grandiflora EO and isolated compounds induced anxiolytic-like effect in mice due to positive modulation of GABAa receptors and/or inhibition of neuronal calcium influx.

Asunto(s)

Ansiedad/tratamiento farmacológico , GABAérgicos/farmacología , Lauraceae/química , Aceites Volátiles/farmacología , Aceites de Plantas/farmacología , Sesquiterpenos/farmacología , Animales , Conducta Animal , GABAérgicos/química , Masculino , Ratones , Estructura Molecular , Actividad Motora , Aceites Volátiles/química , Aceites de Plantas/química , Análisis de Componente Principal , Sesquiterpenos/química

RESUMEN

An analytical method utilizing liquid chromatography coupled to mass spectrometry with electrospray ionization has been developed for the identification of prostaglandins (PGs) in cerebral tissues. The five compounds identified (thromboxane B2, prostaglandin E2, prostaglandin D2, 6-keto-prostaglandin F1 alpha and prostaglandin F2 alpha) are cellular mediators of inflammation and are involved in a variety of physiological and pathological processes by acting on membrane receptors on the surfaces of target cells. The parameters of the electrospray ionization interface were optimized to obtain the highest possible sensitivity for all compounds studied. The limits of detection ranged from 0.25 to 1.09 µg L-1, and the limits of quantification ranged from 0.83 to 3.64 µg L-1. The method was validated and applied to samples of brain tissue from five mice. The sample concentrations of the four prostaglandins quantified ranged from 375 ȵg L-1for prostaglandin E2 to 6602 µg L-1 for prostaglandin D2. An advantage of this work that should be emphasized is the fast response of the method, which allows to obtaining the lipid profile after a 3 min chromatographic run.

Asunto(s)

Cerebro/química , Prostaglandinas/análisis , Animales , Cromatografía Líquida de Alta Presión , Ratones , Estructura Molecular , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en Tándem

RESUMEN

(+)-Dehydrofukinone (DHF), isolated from Nectandra grandiflora (Lauraceae) essential oil, induces sedation and anesthesia by modulation of GABAa receptors. However, no study has addressed whether DHF modulates other cellular events involved in the control of cellular excitability, such as seizure behavior. Therefore, the aim of the present study was to investigate the effect of DHF on cellular excitability and seizure behavior in mice. For this purpose, we used isolated nerve terminals (synaptosomes) to examine the effect of DHF on the plasma membrane potential, the involvement of GABAa receptors and the downstream activation of Ca2+ mobilization. Finally, we performed an in vivo assay in order to verify whether DHF could impact on seizures induced by pentylenetetrazole (PTZ) in mice. The results showed that DHF induced a GABA-dependent sustained hyperpolarization, sensitive to flumazenil and absent in low-[Cl-] medium. Additionally, (1-100µM) DHF decreased KCl-evoked calcium mobilization over time in a concentration-dependent manner and this effect was prevented by flumazenil. DHF increased the latency to myoclonic jerks (10mg/kg), delayed the onset of generalized tonic-clonic seizures (10, 30 and 100mg/kg), and these effects were also blocked by the pretreatment with flumazenil. Our data indicate that DHF has anticonvulsant properties and the molecular target underlying this effect is likely to be the facilitation of GABAergic neuronal inhibition. The present study highlights the therapeutic potential of the natural compound DHF as a suppressor of neuronal excitability.

Asunto(s)

Moduladores del GABA/farmacología , Potenciales de la Membrana/efectos de los fármacos , Receptores de GABA-A/metabolismo , Convulsiones/tratamiento farmacológico , Sesquiterpenos/farmacología , Animales , Anticonvulsivantes/farmacología , Femenino , Flumazenil/farmacología , Ratones , Pentilenotetrazol , Convulsiones/inducido químicamente

RESUMEN

Epilepsy is a common and devastating neurological disease affecting more than 50 million people worldwide. Accumulating experimental and clinical evidence suggests that inflammatory pathways contribute to the development of seizures in various forms of epilepsy. In this context, while the activation of the PGE2 EP2 receptor causes early neuroprotective and late neurotoxic effects, the role of EP2 receptor in seizures remains unclear. We investigated whether the systemic administration of the highly selective EP2 agonist ONO-AE1-259-01 prevented acute pentylenetetrazole (PTZ)- and pilocarpine-induced seizures. The effect of ONO-AE1-259-01 on cell death in the hippocampal formation of adult male mice seven days after pilocarpine-induced status epilepticus (SE) was also evaluated. ONO-AE1-259-01 (10µg/kg, s.c.) attenuated PTZ- and pilocarpine-induced seizures, evidenced by the increased latency to seizures, decreased number and duration of seizures episodes and decreased mean amplitude of electrographic seizures. ONO-AE1-259-01 and pilocarpine alone significantly increased the number of pyknotic cells per se in all hippocampal subfields. The EP2 agonist also additively increased pilocarpine-induced pyknosis in the pyramidal cell layer of CA1 but reduced pilocarpine-induced pyknosis in the granule cell layer of the dentate gyrus (DG). Although the systemic administration of ONO-AE1-259-01 caused a significant anticonvulsant effect in our assays, this EP2 agonist caused extensive cell death. These findings limit the likelihood of EP2 receptor agonists being considered as novel potential anticonvulsant drugs.

Asunto(s)

Anticonvulsivantes/uso terapéutico , Dinoprostona/análogos & derivados , Hipocampo/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Convulsiones/tratamiento farmacológico , Estado Epiléptico/tratamiento farmacológico , Animales , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/efectos adversos , Dinoprostona/administración & dosificación , Dinoprostona/efectos adversos , Dinoprostona/uso terapéutico , Masculino , Ratones , Neuronas/efectos de los fármacos , Pentilenotetrazol , Pilocarpina , Convulsiones/inducido químicamente , Estado Epiléptico/inducido químicamente

RESUMEN

Seizures increase prostaglandin and cytokine levels in the brain. However, it remains to be determined whether cyclooxygenase-2 (COX-2) derived metabolites play a role in seizure-induced cytokine increase in the brain and whether anticonvulsant activity is shared by all COX-2 inhibitors. In this study we investigated whether three different COX-2 inhibitors alter pentylenetetrazol (PTZ)-induced seizures and increase of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) levels in the hippocampus and cerebral cortex of mice. Adult male albino Swiss mice received nimesulide, celecoxib or etoricoxib (0.2, 2 or 20mg/kg in 0.1% carboxymethylcellulose (CMC) in 5% Tween 80, p.o.). Sixty minutes thereafter the animals were injected with PTZ (50mg/kg, i.p.) and the latency to myoclonic jerks and to generalized tonic-clonic seizures were recorded. Twenty minutes after PTZ injection animals were killed and cytokine levels were measured. PTZ increased cytokine levels in the cerebral cortex and hippocampus. While celecoxib and nimesulide attenuated PTZ -induced increase of proinflammatory cytokines in the cerebral cortex, etoricoxib did not. Nimesulide was the only COX-2 inhibitors that attenuated PTZ-induced seizures. This effect coincided with an increase of IL-10 levels in the cerebral cortex and hippocampus, constituting circumstantial evidence that IL-10 increase may be involved in the anticonvulsant effect of nimesulide.

Asunto(s)

Corteza Cerebral/efectos de los fármacos , Inhibidores de la Ciclooxigenasa 2/farmacología , Citocinas/metabolismo , Hipocampo/efectos de los fármacos , Pentilenotetrazol/efectos adversos , Convulsiones/tratamiento farmacológico , Convulsiones/metabolismo , Animales , Corteza Cerebral/metabolismo , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Hipocampo/metabolismo , Inflamación/metabolismo , Masculino , Ratones , Convulsiones/inducido químicamente

RESUMEN

N-methyl-D-aspartate (NMDA) receptor antagonists block morphine-induced conditioned place preference (CPP). Although polyamines are endogenous modulators of the NMDA receptor, it is not known whether polyaminergic agents induce CPP or modulate morphine-induced CPP. Here, we examined whether polyamine ligands modify morphine CPP acquisition, consolidation, and expression. Adult male albino Swiss mice received saline (0.9 % NaCl, intraperitoneally (i.p.)) or morphine (5 mg/kg, i.p.) and were respectively confined to a black or a white compartment for 30 min for four consecutive days for CPP induction. The effect of arcaine (3 mg/kg, i.p.) or spermidine (30 mg/kg, i.p.), respectively, an antagonist and an agonist of the polyamine-binding site at the NMDA receptor, on the acquisition, consolidation, and expression of morphine CPP was studied. In those experiments designed to investigate whether spermidine prevented or reversed the effect of arcaine, spermidine (30 mg/kg, i.p.) was administered 15 min before or 15 min after arcaine, respectively. Arcaine and spermidine did not induce CPP or aversion per se. Arcaine (3 mg/kg, i.p.) impaired the acquisition, consolidation, and expression of morphine CPP. Spermidine prevented the impairing effect of arcaine on the acquisition of morphine CPP but not the impairing effect of arcaine on consolidation or expression of morphine CPP. These results suggest that arcaine may impair morphine CPP acquisition by modulating the polyamine-binding site at the NMDA receptor. However, the arcaine-induced impairment of consolidation and expression of morphine CPP seems to involve other mechanisms.

Asunto(s)

Analgésicos Opioides/administración & dosificación , Condicionamiento Clásico/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Morfina/administración & dosificación , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Recompensa , Animales , Condicionamiento Clásico/fisiología , Relación Dosis-Respuesta a Droga , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Ratones , Receptores de N-Metil-D-Aspartato/fisiología

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Vitex megapotamica (Spreng) Moldenke has been used in South American folk medicine to treat inflammatory diseases. However, the effects of V. megapotamica on animal models of nociception and depression have not been evaluated. AIM OF THE STUDY: This study investigated whether the crude leaf extract of V. megapotamica exhibits antinociceptive and antidepressant-like effects in a Freund's adjuvant-induced chronic inflammation and depression model. MATERIALS AND METHODS: Chronic inflammation was induced in rats by the intraplantar administration of complete Freund's adjuvant (CFA; 100µl). The effect of oral crude extract of V. megapotamica (VmE; 3-30mg/kg, p.o.) on nociception (thermal hyperalgesia, mechanical allodynia and arthritis score), inflammation (edema, myeloperoxidase activity), immobility (forced swimming test), locomotor activity (open field), gastrointestinal transit, hyperalgesia and naloxone-precipitated morphine withdrawal syndrome was evaluated. Naloxone (0.4mg/kg, i.p.) was used to investigate the involvement of opioid system in the currently described effects of VmE. RESULTS: Crude extract caused antinociceptive/antidepressant-like effects in the CFA-induced chronic inflammation model, which was prevented by naloxone. The VmE extract (10mg/kg, p.o.) did not alter the locomotor activity, gastrointestinal function and inflammatory parameters and did not cause hyperalgesia. CONCLUSION: V. megapotamica induces opioid-dependent antinociception and antidepressant-like effect, without anti-inflammatory activity. The results support the use of VmE as analgesic and antidepressant.

Asunto(s)

Analgésicos/farmacología , Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Depresión/prevención & control , Hiperalgesia/prevención & control , Actividad Motora/efectos de los fármacos , Nocicepción/efectos de los fármacos , Extractos Vegetales/farmacología , Vitex/química , Administración Oral , Analgésicos/administración & dosificación , Analgésicos/aislamiento & purificación , Animales , Antidepresivos/administración & dosificación , Antidepresivos/aislamiento & purificación , Depresión/etiología , Depresión/psicología , Modelos Animales de Enfermedad , Adyuvante de Freund , Hiperalgesia/etiología , Hiperalgesia/fisiopatología , Inflamación/inducido químicamente , Masculino , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Umbral del Dolor/efectos de los fármacos , Fitoterapia , Extractos Vegetales/administración & dosificación , Extractos Vegetales/aislamiento & purificación , Hojas de la Planta/química , Plantas Medicinales , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos , Natación , Factores de Tiempo

RESUMEN

Spermine and spermidine are natural polyamines that are produced mainly via decarboxylation of l-ornithine and the sequential transfer of aminopropyl groups from S-adenosylmethionine to putrescine by spermidine synthase and spermine synthase. Spermine and spermidine interact with intracellular and extracellular acidic residues of different nature, including nucleic acids, phospholipids, acidic proteins, carboxyl- and sulfate-containing polysaccharides. Therefore, multiple actions have been suggested for these polycations, including modulation of the activity of ionic channels, protein synthesis, protein kinases, and cell proliferation/death, within others. In this review we summarize these neurochemical/neurophysiological/morphological findings, particularly those that have been implicated in the improving and deleterious effects of spermine and spermidine on learning and memory of naïve animals in shock-motivated and nonshock-motivated tasks, from a historical perspective. The interaction with the opioid system, the facilitation and disruption of morphine-induced reward and the effect of polyamines and putative polyamine antagonists on animal models of cognitive diseases, such as Alzheimer's, Huntington, acute neuroinflammation and brain trauma are also reviewed and discussed. The increased production of polyamines in Alzheimer's disease and the biphasic nature of the effects of polyamines on memory and on the NMDA receptor are also considered. In light of the current literature on polyamines, which include the description of an inborn error of the metabolism characterized by mild-to moderate mental retardation and polyamine metabolism alterations in suicide completers, we can anticipate that polyamine targets may be important for the development of novel strategies and approaches for understanding the etiopathogenesis of important central disorders and their pharmacological treatment.

Asunto(s)

Aprendizaje , Memoria , Espermidina/química , Espermina/química , Animales , Sitios de Unión , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/fisiopatología , Humanos , Aprendizaje/efectos de los fármacos , Memoria/efectos de los fármacos , Putrescina/química , Putrescina/metabolismo , Ratas , Espermidina/metabolismo , Espermina/metabolismo

RESUMEN

In this study, we determined whether the calcium-dependent protein kinase (PKC) signaling pathway is involved in the improvement of fear memory reconsolidation induced by the intrahippocampal administration of spermidine in rats. Male Wistar rats were trained in a fear conditioning apparatus using a 0.4-mA footshock as an unconditioned stimulus. Twenty-four hours after training, animals were re-exposed to the apparatus in the absence of shock (reactivation session). Immediately after the reactivation session, spermidine (2-200 pmol/site), the PKC inhibitor 3-[1-(dimethylaminopropyl)indol-3-yl]-4-(indol-3-yl) maleimide hydrochloride (GF 109203X, 0.3-30 pg/site), the antagonist of the polyamine-binding site at the NMDA receptor, arcaine (0.2-200 pmol/site), or the PKC activator phorbol 12-myristate 13-acetate (PMA, 0.02-2 nmol/site) was injected. While the post-reactivation administration of spermidine (20 and 200 pmol/site) and PMA (2 nmol/site) improved memory reconsolidation, GF 109203X (1, 10, and 30 pg/site) and arcaine (200 pmol/site) impaired it. GF 109203X (0.3 pg/site) impaired memory reconsolidation in the presence of spermidine (200 pmol/site). PMA (0.2 nmol/site) prevented the arcaine (200 pmol/site)-induced impairment of memory reconsolidation. Anisomycin (2 µg/site) also impaired memory reconsolidation in the presence of spermidine (200 pmol/site). Drugs had no effect when they were administered in the absence of reactivation. These results suggest that the spermidine-induced enhancement of memory reconsolidation involves PKC activation.

Asunto(s)

Memoria/efectos de los fármacos , Proteínas Quinasas/metabolismo , Espermidina/farmacología , Análisis de Varianza , Animales , Anisomicina/farmacología , Biguanidas/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Miedo/efectos de los fármacos , Miedo/fisiología , Hipocampo/efectos de los fármacos , Indoles/farmacología , Masculino , Maleimidas/farmacología , Inhibidores de la Síntesis de la Proteína/farmacología , Ratas , Ratas Wistar

RESUMEN

Although leukotrienes have been implicated in seizures, no study has systematically investigated whether the blockade of CysLT1 receptors synergistically increases the anticonvulsant action of classic antiepileptics. In this study, behavioral and electroencephalographic methods, as well as isobolographic analysis, are used to show that the CysLT1 inverse agonist montelukast synergistically increases the anticonvulsant action of phenobarbital against pentylenetetrazole-induced seizures. Moreover, it is shown that LTD4 reverses the effect of montelukast. The experimentally derived ED50mix value for a fixed-ratio combination (1:1 proportion) of montelukast plus phenobarbital was 0.06±0.02 µmol, whereas the additively calculated ED50add value was 0.49±0.03 µmol. The calculated interaction index was 0.12, indicating a synergistic interaction. The association of montelukast significantly decreased the antiseizure ED50 for phenobarbital (0.74 and 0.04 µmol in the absence and presence of montelukast, respectively) and, consequently, phenobarbital-induced sedation at equieffective doses. The demonstration of a strong synergism between montelukast and phenobarbital is particularly relevant because both drugs are already used in the clinics, foreseeing an immediate translational application for epileptic patients who have drug-resistant seizures.

Asunto(s)

Acetatos/farmacología , Anticonvulsivantes/farmacología , Antagonistas de Leucotrieno/farmacología , Fenobarbital/farmacología , Quinolinas/farmacología , Animales , Convulsivantes , Ciclopropanos , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Electroencefalografía/efectos de los fármacos , Femenino , Ratones , Actividad Motora/efectos de los fármacos , Pentilenotetrazol , Convulsiones/inducido químicamente , Convulsiones/prevención & control , Sulfuros

RESUMEN

BACKGROUND: Lipopolysaccharide (LPS) induces neuroinflammation and memory deficit. Since polyamines improve memory in various cognitive tasks, we hypothesized that spermine administration reverses LPS-induced memory deficits in an object recognition task in mice. The involvement of the polyamine binding site at the N-methyl-D-aspartate (NMDA) receptor and cytokine production in the promnesic effect of spermine were investigated. METHODS: Adult male mice were injected with LPS (250 µg/kg, intraperitoneally) and spermine (0.3 to 1 mg/kg, intraperitoneally) or ifenprodil (0.3 to 10 mg/kg, intraperitoneally), or both, and their memory function was evaluated using a novel object recognition task. In addition, cortical and hippocampal cytokines levels were measured by ELISA four hours after LPS injection. RESULTS: Spermine increased but ifenprodil decreased the recognition index in the novel object recognition task. Spermine, at doses that did not alter memory (0.3 mg/kg, intraperitoneally), reversed the cognitive impairment induced by LPS. Ifenprodil (0.3 mg/kg, intraperitoneally) reversed the protective effect of spermine against LPS-induced memory deficits. However, spermine failed to reverse the LPS-induced increase of cortical and hippocampal cytokine levels. CONCLUSIONS: Spermine protects against LPS-induced memory deficits in mice by a mechanism that involves GluN2B receptors.

Asunto(s)

Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Espermina/uso terapéutico , Análisis de Varianza , Animales , Citocinas/metabolismo , Discriminación en Psicología/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Antagonistas de Aminoácidos Excitadores/farmacología , Conducta Exploratoria/efectos de los fármacos , Lipopolisacáridos/toxicidad , Masculino , Ratones , Piperidinas/farmacología , Reconocimiento en Psicología/efectos de los fármacos

RESUMEN

RATIONALE: Current evidence suggests that pharmacological manipulation around 12 h after training alters the persistence of long-term memory. However, no study has addressed whether opioids modulate the persistence of fear. The current study examined whether morphine alters the persistence of the memory of contextual fear conditioning. METHODS: Male adult Wistar rats were injected with saline (NaCl 0.9 %, intraperitoneally (i.p.)) or morphine (3 and/or 10 mg/kg, i.p.) 6, 9, 12, or 24 h post-training and tested 2 or 7 days after training, when freezing responses were assessed. The involvement of state dependence and opioid receptors in the effect of morphine was investigated by respectively injecting naloxone (1 mg/kg, i.p.) 30 min before morphine, and morphine (10 mg/kg, i.p.) 30 min before testing. RESULTS: Morphine (10 mg/kg, i.p., 12 h post-training) did not alter freezing to context in animals tested 2 days after training but impaired freezing to context when testing was carried out 7 or 14 days after training. Morphine (10 mg/kg, i.p.) administration 6, 9, or 24 h post-training did not alter freezing measured 2 or 7 days after training. Pre-test morphine improved recall but did not alter the deleterious effect of 12 h post-training morphine. The deleterious effect of morphine was prevented by naloxone, indicating that opioid receptors are involved in this effect. CONCLUSIONS: Our findings indicate an inhibitory role for opioid receptors in memory persistence. This is relevant from both the experimental and clinical point of views, since it may have implications for the prevention of post-traumatic stress disorder (PTSD).

Asunto(s)

Analgésicos Opioides/farmacología , Miedo/efectos de los fármacos , Memoria a Largo Plazo/efectos de los fármacos , Morfina/farmacología , Animales , Relación Dosis-Respuesta a Droga , Miedo/fisiología , Miedo/psicología , Masculino , Memoria a Largo Plazo/fisiología , Recuerdo Mental/efectos de los fármacos , Recuerdo Mental/fisiología , Ratas , Ratas Wistar , Receptores Opioides/agonistas , Receptores Opioides/fisiología

RESUMEN

Antipsychotics may cause tardive dyskinesia in humans and orofacial dyskinesia in rodents. Although the dopaminergic system has been implicated in these movement disorders, which involve the basal ganglia, their underlying pathomechanisms remain unclear. CB1 cannabinoid receptors are highly expressed in the basal ganglia, and a potential role for endocannabinoids in the control of basal ganglia-related movement disorders has been proposed. Therefore, this study investigated whether CB1 receptors are involved in haloperidol-induced orofacial dyskinesia in rats. Adult male rats were treated for four weeks with haloperidol decanoate (38mg/kg, intramuscularly - i.m.). The effect of anandamide (6nmol, intracerebroventricularly - i.c.v.) and/or the CB1 receptor antagonist SR141716A (30µg, i.c.v.) on haloperidol-induced vacuous chewing movements (VCMs) was assessed 28days after the start of the haloperidol treatment. Anandamide reversed haloperidol-induced VCMs; SR141716A (30µg, i.c.v.) did not alter haloperidol-induced VCM per se but prevented the effect of anandamide on VCM in rats. These results suggest that CB1 receptors may prevent haloperidol-induced VCMs in rats, implicating CB1 receptor-mediated cannabinoid signaling in orofacial dyskinesia.

Asunto(s)

Antipsicóticos/efectos adversos , Ácidos Araquidónicos/farmacología , Agonistas de Receptores de Cannabinoides/farmacología , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Endocannabinoides/farmacología , Haloperidol/análogos & derivados , Alcamidas Poliinsaturadas/farmacología , Receptor Cannabinoide CB1/metabolismo , Animales , Antagonistas de Receptores de Cannabinoides/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Discinesia Inducida por Medicamentos/fisiopatología , Haloperidol/efectos adversos , Masculino , Masticación/efectos de los fármacos , Masticación/fisiología , Movimiento/efectos de los fármacos , Movimiento/fisiología , Piperidinas/farmacología , Pirazoles/farmacología , Ratas Wistar , Rimonabant , Resultado del Tratamiento

RESUMEN

AIMS: Alpha-melanocyte stimulating hormone (α-MSH) is a pro-opiomelanocortin (POMC)-derived peptide involved in different neurological functions that also exerts anti-inflammatory effects, including in the central nervous system (CNS). Although inflammation has been implicated in seizures and epilepsy, no study has systematically investigated whether α-MSH modifies seizures. Therefore, in the current study we determined whether α-MSH alters pentylenetetrazol (PTZ)- and pilocarpine-induced seizures. MAIN METHODS: Adult male Swiss mice were injected with α-MSH (1.66, 5 or 15 µg/3 µL, intracerebroventricular (i.c.v.)) or systemic (0.1, 0.3 or 1 mg/kg, intraperitoneally (i.p.)). Five to sixty minutes after the injection of the peptide, animals were injected with PTZ (60 mg/kg, i.p.) or pilocarpine (370 mg/kg, i.p.). Latency to myoclonic jerks and tonic-clonic seizures, number of seizure episodes, total time spent seizing and seizure intensity, assessed by the Racine and Meurs scales were recorded. Interleukin 1 beta (IL-1ß) levels in the hippocampus were measured by a commercial enzyme-linked immunoabsorbent assay (ELISA). KEY FINDINGS: Neither intracerebroventricular (1.66, 5 or 15 µg/3 µL, i.c.v.) nor systemic (0.1, 0.3 or 1 mg/kg, i.p.) administration of α-MSH altered PTZ- and pilocarpine-induced seizures. IL-1ß levels in the hippocampi were not altered by α-MSH, PTZ or pilocarpine. SIGNIFICANCE: Although inflammation has been implicated in seizures and epilepsy and α-MSH is a potent anti-inflammatory peptide, our results do not support a role for α-MSH in seizure control.

Asunto(s)

Antiinflamatorios/farmacología , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , alfa-MSH/farmacología , Animales , Hipocampo/efectos de los fármacos , Hipocampo/inmunología , Interleucina-1beta/análisis , Interleucina-1beta/inmunología , Masculino , Ratones , Pentilenotetrazol , Pilocarpina

RESUMEN

When consolidated memories are reactivated, they become labile and, to persist, must undergo a new stabilization process called reconsolidation. During reactivation, memory is susceptible to pharmacological interventions that may improve or impair it. Spermidine (SPD) is an endogenous polyamine that physiologically modulates the N-methyl-d-aspartate (NMDA) receptor in mammals by binding on the polyamine-binding site at the NMDA receptor. While polyamine agonists and antagonists of the polyamine binding site on the NMDA receptor respectively improve and impair early consolidation, it has not been defined whether these agents alter memory reconsolidation. Male Wistar rats were trained in a fear conditioning apparatus using a 0.4 mA footshock as unconditioned stimulus. Twenty four hours after training, animals were re-exposed to the apparatus in the absence of shock (reactivation session). Immediately after the reactivation session, SPD (1-30 mg/kg, i.p.) or the antagonist of the polyamine-binding site at the NMDA receptor, arcaine (0.1-10 mg/kg, i.p.), were injected, and the animals were tested in the same apparatus 24 h later. Freezing scores at testing were considered a measure of memory. While SPD (3 and 10mg/kg) improved, arcaine (1 and 10 mg/kg) impaired memory reconsolidation. These drugs had no effect on memory if they were administered in the absence of reactivation, or 6h after reactivation session. Arcaine (0.1 mg/kg, i.p.) prevented SPD (3 mg/kg)-induced improvement of memory reconsolidation. Accordingly, SPD (1 mg/kg) prevented arcaine (10 mg/kg)-induced impairment of memory reconsolidation. The amnesic effect of arcaine was not reversed by arcaine administration prior to test, ruling out state dependence in this effect. These results suggest that systemic administration of polyamine binding site ligands modulate memory reconsolidation.

Asunto(s)

Biguanidas/farmacología , Miedo , Memoria/efectos de los fármacos , Memoria/fisiología , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Espermidina/farmacología , Animales , Condicionamiento Psicológico/efectos de los fármacos , Miedo/efectos de los fármacos , Masculino , Ratas , Ratas Wistar

RESUMEN

Methylmalonic acidemias are inherited metabolic disorders characterized by methylmalonate (MMA) accumulation and neurological dysfunction, including seizures. Dietary fatty acids are known as an important energy source and reduce seizure activity in selected acute animal models. This study investigated whether chronic treatment with fish oil or with oleic acid attenuates MMA-induced seizures and whether maintenance of Na(+),K(+)-ATPase activity was involved in such an effect. Adult male Wistar rats were given fish oil (85 mg/kg), oleic acid (85 mg/kg) or vehicle (0.42% aqueous Cremophor EL™, 4 mL/kg/body weight/day), p.o., for 75 days. On the 73th day a cannula was implanted in the right lateral ventricle with electrodes over the parietal cortex for EEG recording. On the 76th day the animals were injected with NaCl (2.5 µmol/2.5 µL, i.c.v.), or with MMA (2.5 µmol/2.5 µL, i.c.v.), and seizure activity was measured by electroencephagraphic (EEG) recording with concomitant behavior monitoring. The effect of prostaglandin E2 (PGE2) on Na(+),K(+)-ATPase activity of slices of cerebral cortex from NaCl-injected animals was determined. Fish oil increased the latency to MMA-induced tonic-clonic seizures, reduced the mean amplitude of ictal EEG recordings, and prevented PGE2-induced decrease of Na(+),K(+)-ATPase activity in cortical slices in vitro. Oleic acid decreased mean amplitude of ictal EEG recordings. The results support that fish oil decreases MMA-induced seizures. The decreased sensitivity of Na(+),K(+)-ATPase to the inhibitory effect of PGE2 in fish oil-treated animals may be related to the currently reported anticonvulsant activity.

Asunto(s)

Anticonvulsivantes/uso terapéutico , Aceites de Pescado/uso terapéutico , Ácido Metilmalónico/toxicidad , Convulsiones/inducido químicamente , Convulsiones/prevención & control , Animales , Electroencefalografía/métodos , Masculino , Distribución Aleatoria , Ratas , Ratas Wistar , Convulsiones/fisiopatología

RESUMEN

Previous exposure to the training context disrupts glutamatergic N-methyl-d-aspartate receptor (NMDAr) antagonist-induced amnesia, indicating that novelty is necessary for such an amnestic effect. While there are reports that novelty-related release of opioids cause amnesia, no study has addressed whether the amnestic effect of NMDAr antagonists involve opioid mechanisms. In this study we investigated whether pharmacological manipulation of the opioid system immediately after context pre-exposure alters the amnestic effect of arcaine, a NMDAr antagonist. Adult male Wistar rats were habituated (pre-exposed) to a fear conditioning training apparatus or to a different context (open field). Immediately after pre-exposure, animals were injected with saline or naloxone (0.5 mg/kg, i.p.) or anti-beta-endorphin antibody (1:500, i.c.v.). Forty eight hours after pre-exposure session, all animals were subjected to fear conditioning acquisition protocol and saline or arcaine (30 mg/kg, i.p.) was administered immediately after training. Testing was carried out 24 h later, and freezing responses due to re-exposure to the training apparatus were recorded. Pre-exposure to the training apparatus prevented the impairment of memory induced by post-training arcaine. Administration of naloxone or anti-beta-endorphin antibody, immediately after pre-exposure to the training apparatus, reinstated the amnesic effect of post-training arcaine. The results suggest that endogenous opioid mechanisms are involved in the pre-exposure-induced loss of the amnestic effect of arcaine.

Asunto(s)

Amnesia/metabolismo , Aprendizaje por Asociación/efectos de los fármacos , Biguanidas/farmacología , Condicionamiento Psicológico/efectos de los fármacos , Miedo/efectos de los fármacos , Receptores Opioides mu/metabolismo , Amnesia/inducido químicamente , Animales , Aprendizaje por Asociación/fisiología , Condicionamiento Psicológico/fisiología , Miedo/fisiología , Reacción Cataléptica de Congelación/efectos de los fármacos , Reacción Cataléptica de Congelación/fisiología , Masculino , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Ratas , Ratas Wistar