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

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

RATIONALE: Individuals with opioid use disorders often relapse into drug-seeking behavior after recalling memories linked to the drug use experience. Improving extinction efficacy has been used as a strategy to treat substance use disorders and suppress relapse. Although N-methyl-D-aspartate receptor (NMDAr) agonists facilitate acquisition, consolidation, and extinction, no study has addressed whether spermidine (SPD), a natural polyamine ligand of the NMDA receptor, facilitates the extinction and reinstatement of morphine-induced conditioned place preference (CPP). OBJECTIVES AND METHODS: The aim of the present study was to investigate the effect of SPD, an NMDAr agonist, on the extinction and reinstatement of morphine-induced CPP in mice. Adult male albino Swiss mice received saline (0.9% NaCl) or morphine (5 mg/kg) intraperitoneally (i.p.) and were respectively confined to a black or a white compartment for 30 min for four consecutive days for CPP induction. SPD (10-30 mg/kg, i.p.) or ifenprodil (NMDAr antagonist, 0.1-1 mg/kg, i.p.) were injected 15 min before extinction training. RESULTS: SPD and ifenprodil facilitated the extinction of morphine-induced CPP. SPD treatment during the extinction period impaired reinstatement induced by a priming dose of morphine (1.25 mg/kg). Ifenprodil (0.1 mg/kg) prevented the facilitatory effect of spermidine on the extinction of morphine-induced CPP but did not prevent reinstatement induced by morphine. CONCLUSIONS: These results suggest that SPD facilitated the extinction of morphine-induced CPP by modulating the polyamine binding site of the NMDA receptor. Our findings reveal important effects of SPD and ifenprodil on the re-exposure-induced decrease in morphine-induced CPP, which may be promising for developing novel pharmacological strategies to treat opioid use disorder.

Asunto(s)

Condicionamiento Clásico/efectos de los fármacos , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Extinción Psicológica/efectos de los fármacos , Morfina/efectos adversos , Receptores de N-Metil-D-Aspartato/agonistas , Espermidina/uso terapéutico , Animales , Condicionamiento Clásico/fisiología , Comportamiento de Búsqueda de Drogas/fisiología , Extinción Psicológica/fisiología , Masculino , Ratones , Morfina/farmacología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , N-Metilaspartato/farmacología , Trastornos Relacionados con Opioides/tratamiento farmacológico , Trastornos Relacionados con Opioides/psicología , Receptores de N-Metil-D-Aspartato/metabolismo , Espermidina/farmacología

RESUMEN

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease. The present study investigated the effects of 50 and 100 mg/kg berberine (BRB) on recognition memory, oxidative stress, and purinergic neurotransmission, in a model of sporadic dementia of the Alzheimer's type induced by intracerebroventricular (ICV) injection of streptozotocin (STZ) in rats. Rats were submitted to ICV-STZ 3 mg/kg or saline, and 3 days later, were started on a treatment of BRB or saline for 21 days. The results demonstrated that BRB was effective in protecting against memory impairment, increased reactive oxygen species, and the subsequent increase in protein and lipid oxidation in the cerebral cortex and hippocampus, as well as δ-aminolevulinate dehydratase inhibition in the cerebral cortex. Moreover, the decrease in total thiols, and the reduced glutathione and glutathione S-transferase activity in the cerebral cortex and hippocampus of ICV-STZ rats, was prevented by BRB treatment. Besides an antioxidant effect, BRB treatment was capable of preventing decreases in ecto-nucleoside triphosphate diphosphohydrolase (NTPDase), 5'-nucleotidase (EC-5'-Nt), and adenosine deaminase (ADA) activities in synaptosomes of the cerebral cortex and hippocampus. Thus, our data suggest that BRB exerts a neuroprotective effect on recognition memory, as well as on oxidative stress and oxidative stress-related damage, such as dysfunction of the purinergic system. This suggests that BRB may act as a promising multipotent agent for the treatment of AD.

Asunto(s)

Berberina/farmacología , Encéfalo/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Reconocimiento en Psicología/efectos de los fármacos , 5'-Nucleotidasa/efectos de los fármacos , 5'-Nucleotidasa/metabolismo , Adenosina Desaminasa/efectos de los fármacos , Adenosina Desaminasa/metabolismo , Enfermedad de Alzheimer/psicología , Animales , Antibióticos Antineoplásicos/toxicidad , Antioxidantes , Encéfalo/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Modelos Animales de Enfermedad , Glutatión , Glutatión Transferasa/efectos de los fármacos , Glutatión Transferasa/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Inyecciones Intraventriculares , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Trastornos de la Memoria/inducido químicamente , Oxidación-Reducción/efectos de los fármacos , Pirofosfatasas/efectos de los fármacos , Pirofosfatasas/metabolismo , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Estreptozocina/toxicidad , Sinaptosomas/efectos de los fármacos , Sinaptosomas/enzimología

RESUMEN

In some chronic disorders, as in arthritis, the inflammatory pain persists beyond the inflammation control becoming pathological. Its treatment shows limited efficacy and adverse effects which compromises patients' quality of life. Mansoa alliacea, known as 'cipo alho', is popularly used as analgesic and others species of this genus show anti-inflammatory actions. We investigated the anti-inflammatory and antinociceptive potential of M. alliacea extract in an inflammatory pain model which presents inflammatory characteristics similar to those caused by arthritis, through of the intraplantar injection of complete Freund's adjuvant (CFA) in mice. The extract chromatographic analysis revealed the presence of ρ-coumaric, ferulic and chlorogenic acids, luteolin, and apigenin. The treatment with M. alliacea prevented and reversed the CFA-induced mechanical allodynia with maximum inhibition (Imax) of 100% and 90 ±â€¯10%, respectively. The co-administration of M. alliacea extract plus morphine enhanced the anti-allodynic effect with Imax of 100%. The M. alliacea extract also reverted the CFA-induced thermal hyperalgesia with Imax of 3.6 times greater compared to the vehicle and reduced the thermal threshold under physiological conditions. However, M. alliacea extract did not reduce the CFA-induced edema and myeloperoxidase activity. Additionally, non-selective and δ-selective opioid receptor antagonists, but not κ-opioid, prevented extract anti-allodynic effect with Imax of 98 ±â€¯2% and 93 ±â€¯2%, respectively. Moreover, M. alliacea extract did not induce adverse effects commonly caused by opioids and other analgesic drugs, at least in the tested pharmacological doses after the acute treatment. M. alliacea extract presents antinociceptive activity in an inflammatory pain model, which presents inflammatory characteristics similar to those arthritis-induced, without causing adverse effects in tested pharmacological doses. These effects seem to be mediated mainly via δ-opioid receptors.

Asunto(s)

Analgésicos Opioides/farmacología , Analgésicos/farmacología , Hiperalgesia/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Extractos Vegetales/farmacología , Animales , Enfermedad Crónica , Dolor Crónico/tratamiento farmacológico , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Morfina/uso terapéutico

RESUMEN

Lipopolysaccharide (LPS) has been long known to promote neuroinflammation and learning and memory deficits. Since spermine, one of the main natural polyamines in the central nervous system, protects from LPS-induced memory deficit by a mechanism that comprises GluN2B receptors, the aim of the present study was to determine whether brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB) receptor and cAMP response element binding (CREB) are involved in this protective effect of spermine. Adult male Swiss albino mice received, immediately after training in the novel object recognition task, saline or LPS (250 µg/kg, i.p.); 5 min later they received saline or spermine (0.3 mg/kg, i.p.) and, when specified, 5 min thereafter saline or the TrkB receptor antagonist ANA-12 (0.5 mg/kg, i.p.) in different flanks. Animals were tested 24 h after training. Spermine protected from LPS-induced memory deficit and this protective effect was reversed by ANA-12. In a subset of animals BDNF, CREB and phospho-CREB immunoreactivity was determined in the hippocampi and cerebral cortex 4 h after spermine injection. Spermine reversed the decrease of mature BDNF levels induced by LPS in both hippocampus and cerebral cortex. Spermine increased phospho-CREB content and phospho-CREB/total CREB ratio in the cerebral cortex of LPS-treated mice. The results support that the protective effect of spermine on LPS-induced memory deficits depends on TrkB receptor activation and is accompanied by restoration of mature BDNF levels in hippocampus and cerebral cortex, as well as increased CREB phosphorylation in the cerebral cortex.

Asunto(s)

Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hipocampo/efectos de los fármacos , Glicoproteínas de Membrana/metabolismo , Trastornos de la Memoria/metabolismo , Fármacos Neuroprotectores/farmacología , Proteínas Tirosina Quinasas/metabolismo , Espermina/farmacología , Animales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Hipocampo/metabolismo , Lipopolisacáridos , Masculino , Trastornos de la Memoria/inducido químicamente , Ratones , Fosforilación/efectos de los fármacos , Transducción de Señal/efectos de los fármacos

RESUMEN

OBJECTIVE: Here we investigated the impact of chronic high-intensity interval training (HIIT) and caffeine consumption on the activities of Na+-K+-ATPase and enzymes of the antioxidant system, as well as anxiolytic-like behaviour in the rat brain. METHODS: Animals were divided into groups: control, caffeine (4 mg/kg), caffeine (8 mg/kg), HIIT, HIIT plus caffeine (4 mg/kg) and HIIT plus caffeine (8 mg/kg). Rats were trained three times per week for 6 weeks, and caffeine was administered 30 minutes before training. We assessed the anxiolytic-like behaviour, Na+-K+-ATPase, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities, levels of reduced glutathione (GSH) and thiobarbituric acid reactive substances (TBARS) in the brain. RESULTS AND DISCUSSION: HIIT-induced anxiolytic-like behaviour increased Na+-K+-ATPase and GPx activities and TBARS levels, altered the activities of SOD and CAT in different brain regions, and decreased GSH levels. Caffeine, however, elicited anxiogenic-like behaviour and blocked HIIT effects. The combination of caffeine and HIIT prevented the increase in SOD activity in the cerebral cortex and GPx activity in three brain regions. Our results show that caffeine promoted anxiogenic behaviour and prevented HIIT-induced changes in the antioxidant system and Na+-K+-ATPase activities.

Asunto(s)

Ansiolíticos/uso terapéutico , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Cafeína/uso terapéutico , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Animales , Antioxidantes/metabolismo , Catalasa/metabolismo , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo

RESUMEN

Putrescine, spermidine and spermine are organic cations implicated in learning, memory consolidation, reconsolidation and neurogenesis. These physiological processes are closely related, and convincing evidence indicates that neurogenesis is implicated both, in the establishment and maintenance of remote contextual fear memory. Although brain-derived neurotrophic factor (BDNF) is a key mediator involved in both neurogenesis and memory consolidation, effects of spermidine on persistence of memory after reactivation (reconsolidation) and possible involvement of BDNF have not been investigated. Here, we investigated whether the intrahippocampal infusion of spermidine improves the persistence of reconsolidated contextual fear conditioning memory in rats and whether these possible changes depend on BDNF/TrkB signaling in the hippocampus. The infusion of spermidine immediately and 12h post-reactivation improved fear memory of the animals tested seven but not two days after reactivation. The facilitatory effect of spermidine on the persistence of reconsolidated memory was blocked by the TrkB inhibitor ANA-12 (73.6pmol/site) and accompanied by mature BDNF level increase in the hippocampus, indicating that it depends on the BDNF/TrkB pathway. We also investigated whether spermidine alters BDNF levels and neural progenitor cell differentiation in vitro. Spermidine increased BDNF levels in vitro, facilitating neuritogenesis and neural migration. Spermidine-induced neuritogenesis in vitro was also blocked by ANA-12 (10µM). Since spermidine increases BDNF levels and facilitates neural differentiation in vitro, similar mechanisms may be involved in spermidine-induced facilitation of the persistence of reconsolidated memory.

Asunto(s)

Factor Neurotrófico Derivado del Encéfalo/metabolismo , Miedo/efectos de los fármacos , Hipocampo/efectos de los fármacos , Consolidación de la Memoria/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Espermidina/farmacología , Animales , Azepinas/farmacología , Benzamidas/farmacología , Movimiento Celular/efectos de los fármacos , Condicionamiento Clásico/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Ratas , Ratas Wistar , Receptor trkB/antagonistas & inhibidores

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

This study investigated the protective effect of curcumin on memory loss and on the alteration of acetylcholinesterase and ectonucleotidases activities in rats exposed chronically to cadmium (Cd). Rats received Cd (1 mg/kg) and curcumin (30, 60, or 90 mg/kg) by oral gavage 5 days a week for 3 months. The animals were divided into eight groups: vehicle (saline/oil), saline/curcumin 30 mg/kg, saline/curcumin 60 mg/kg, saline/curcumin 90 mg/kg, Cd/oil, Cd/curcumin 30 mg/kg, Cd/curcumin 60 mg/kg, and Cd/curcumin 90 mg/kg. Curcumin prevented the decrease in the step-down latency induced by Cd. In cerebral cortex synaptosomes, Cd-exposed rats showed an increase in acetylcholinesterase and NTPDase (ATP and ADP as substrates) activities and a decrease in the 5'-nucleotidase activity. Curcumin was not able to prevent the effect of Cd on acetylcholinesterase activity, but it prevented the effects caused by Cd on NTPDase (ATP and ADP as substrate) and 5'-nucleotidase activities. Increased acetylcholinesterase activity was observed in different brain structures, whole blood and lymphocytes of the Cd-treated group. In addition, Cd increased lipid peroxidation in different brain structures. Higher doses of curcumin were more effective in preventing these effects. These findings show that curcumin prevented the Cd-mediated memory impairment, demonstrating that this compound has a neuroprotective role and is capable of modulating acetylcholinesterase, NTPDase, and 5'-nucleotidase activities. Finally, it highlights the possibility of using curcumin as an adjuvant against toxicological conditions involving Cd exposure. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 70-83, 2017.

Asunto(s)

Intoxicación por Cadmio/fisiopatología , Curcumina/uso terapéutico , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/prevención & control , Sistema Nervioso Parasimpático/efectos de los fármacos , Receptores Purinérgicos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Reacción de Prevención/efectos de los fármacos , Intoxicación por Cadmio/enzimología , Curcumina/administración & dosificación , Relación Dosis-Respuesta a Droga , Electrochoque , Peroxidación de Lípido/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Wistar , Sinaptosomas/efectos de los fármacos , Sinaptosomas/enzimología

RESUMEN

The present study aimed to investigate the effects of berberine (BRB) on spatial and learning memory, anxiety, acetylcholinesterase activity and cell death in an experimental model of intracerebroventricular streptozotocin (ICV-STZ) induced sporadic Alzheimer's-like dementia. Sixty male Wistar rats were randomly divided into six groups: control (CTR), BRB 50mg/kg (BRB 50), BRB 100mg/kg (BRB 100), streptozotocin (STZ), streptozotocin plus BRB 50mg/kg (STZ+BRB 50), and streptozotocin plus BRB 100mg/kg (STZ+BRB 100). Rats were injected with ICV-STZ (3mg/kg) or saline, and daily oral BRB treatment began on day 4 for a period of 21days. Behavioral tests were carried out on day 17, and rats were euthanized on day 24. Cell death analysis and determination of acetylcholinesterase activity was performed on the cerebral cortex and hippocampus of the brain. Administration of BRB prevented the memory loss, anxiogenic behavior, increased acetylcholinesterase activity and cell death induced by ICV-STZ. This may be explained, in part, by a protective effect of BRB on ameliorating the progression of neurodegenerative diseases, including Alzheimer's disease, and the results of this study provide a better understanding of the effect of BRB on the brain. Thus, BRB may act as a potential neuroprotective agent.

Asunto(s)

Enfermedad de Alzheimer/complicaciones , Ansiedad/tratamiento farmacológico , Berberina/uso terapéutico , Trastornos de la Memoria/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/patología , Animales , Antibióticos Antineoplásicos/administración & dosificación , Ansiedad/etiología , Peso Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Muerte Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , L-Lactato Deshidrogenasa/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/etiología , Ratas , Ratas Wistar , Estreptozocina/administración & dosificación , Sinaptosomas/efectos de los fármacos , Sinaptosomas/ultraestructura

RESUMEN

The present study investigated the protective effect of quercetin (Querc) on memory, anxiety-like behavior and impairment of ectonucleotidases and acetylcholinesterase (AChE) activities in brain of streptozotocin-induced diabetic rats (STZ-diabetes). The type 1 diabetes mellitus was induced by an intraperitoneal injection of 70mg/kg of streptozotocin (STZ), diluted in 0.1M sodium-citrate buffer (pH 4.5). Querc was dissolved in 25% ethanol and administered by gavage at the doses of 5, 25 and 50mg/kg once a day during 40days. The animals were distributed in eight groups of ten animals as follows: vehicle, Querc 5mg/kg, Querc 25mg/kg, Querc 50mg/kg, diabetes, diabetes plus Querc 5mg/kg, diabetes plus Querc 25mg/kg and diabetes plus Querc 50mg/kg. Querc was able to prevent the impairment of memory and the anxiogenic-like behavior induced by STZ-diabetes. In addition, Querc prevents the decrease in the NTPDase and increase in the adenosine deaminase (ADA) activities in SN from cerebral cortex of STZ-diabetes. STZ-diabetes increased the AChE activity in SN from cerebral cortex and hippocampus. Querc 50mg/kg was more effective to prevent the increase in AChE activity in the brain of STZ-diabetes. Querc also prevented an increase in the malondialdehyde levels in all the brain structures. In conclusion, the present findings showed that Querc could prevent the impairment of the enzymes that regulate the purinergic and cholinergic extracellular signaling and improve the memory and anxiety-like behavior induced by STZ-diabetes.

Asunto(s)

5'-Nucleotidasa/metabolismo , Acetilcolinesterasa/metabolismo , Adenosina Desaminasa/metabolismo , Ansiedad/prevención & control , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Trastornos de la Memoria/prevención & control , Memoria/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Quercetina/farmacología , Animales , Ansiedad/inducido químicamente , Ansiedad/enzimología , Ansiedad/psicología , Encéfalo/enzimología , Encéfalo/fisiopatología , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/enzimología , Diabetes Mellitus Experimental/psicología , Diabetes Mellitus Tipo 1/inducido químicamente , Diabetes Mellitus Tipo 1/enzimología , Diabetes Mellitus Tipo 1/psicología , Relación Dosis-Respuesta a Droga , Proteínas Ligadas a GPI/metabolismo , Masculino , Malondialdehído/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/enzimología , Trastornos de la Memoria/psicología , Actividad Motora/efectos de los fármacos , Ratas Wistar , Estreptozocina

RESUMEN

The aim of this study was to evaluate the effect of subcutaneous administration of diphenyl diselenide (PhSe)2 on animal behavior and activities of acetylcholinesterase (AChE), adenylate kinase (AK), and creatine kinase (CK) in the brain of mice infected by Toxoplasma gondii. In addition, thiobarbituric acid reactive species (TBARS) levels and glutathione (GR, GPx and GST) activity were also evaluated. For the study, 40 female mice were divided into four groups of 10 animals each: group A (uninfected and untreated), group B (uninfected and treated with (PhSe)2), group C (infected and untreated) and group D (infected and treated with (PhSe)2). The mice were inoculated with 50 cysts of the ME49 strain of T. gondii. After infection the animals of the groups B and D were treated on days 1 and 20 post-infection (PI) with 5.0 µmol/kg of (PhSe)2 subcutaneously. Behavioral tests were conducted on days 29 PI to assess memory loss (object recognition), anxiety (elevated plus maze), locomotor and exploratory activity (Open Field) and it was found out that infected and untreated animals (group C) had developed anxiety and memory impairment, and the (PhSe)2 treatment did not reverse these behavioral changes on infected animals treated with (PhSe)2 (group D). The results showed an increase on AChE activity (P < 0.01) in the brain of infected and untreated animals (group C) compared to the uninfected and untreated animals (group A). The AK and CK activities decreased in infected and untreated animals (group C) compared to the uninfected and untreated animals (group A) (P < 0.01), however the (PhSe)2 treatment did not reverse these alterations. Infected and untreated animals (group C) showed increased TBARS levels and GR activity, and decreased GPx and GST activities when compared to uninfected and untreated animals (group A). Infected animals treated with (PhSe)2 (group D) decreased TBARS levels and GR activity, while increased GST activity when compared to infected and untreated animals (group C). It was concluded that (PhSe)2 showed antioxidant activity, but the dose used had no anti-inflammatory effect and failed to reverse the behavioral changes caused by the parasite.

Asunto(s)

Conducta Animal/efectos de los fármacos , Derivados del Benceno/uso terapéutico , Encéfalo/efectos de los fármacos , Compuestos de Organoselenio/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Toxoplasmosis Animal/tratamiento farmacológico , Acetilcolinesterasa/metabolismo , Adenilato Quinasa/metabolismo , Animales , Derivados del Benceno/administración & dosificación , Derivados del Benceno/farmacología , Encéfalo/enzimología , Encéfalo/patología , Creatina Quinasa/metabolismo , Femenino , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/metabolismo , Glutatión Transferasa/metabolismo , Inyecciones Subcutáneas , Ratones , Compuestos de Organoselenio/administración & dosificación , Compuestos de Organoselenio/farmacología , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Toxoplasmosis Animal/fisiopatología

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

Spermidine (SPD) is an endogenous aliphatic amine that modulates GluN2B-containing NMDA receptors and improves memory. Recent evidence suggests that systemic SPD improves the persistence of the long term memory of fear. However, the role of hippocampal polyamines and its binding sites in the persistence of fear memory is to be determined, as well as its putative underlying mechanisms. This study investigated whether the intrahippocampal (i.h.) infusion of spermidine or arcaine, modulators of polyamine binding site at GluN2B-containing NMDA receptors, alters the persistence of the memory of contextual fear conditioning task in rats. We also investigated whether protein synthesis and cAMP dependent protein kinase (PKA) play a role in SPD-induced improvement of the fear memory persistence. While 12h post-training infusion of spermidine facilitated, arcaine and the inhibitor of protein synthesis (anisomycin) impaired the memory of fear assessed 7days after training. The infusion of arcaine, anisomycin or a selective PKA inhibitor (H-89), at doses that have no effect on memory per se, prevented the SPD-induced improvement of memory persistence. H-89 prevented the stimulatory effect of SPD on phospho-PKA/total-PKA ratio. These results suggests that the improvement of fear memory persistence induced by spermidine involves GluN2B-containing NMDA receptors, PKA pathway and protein synthesis in rats.

Asunto(s)

Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Miedo/fisiología , Hipocampo/efectos de los fármacos , Memoria a Largo Plazo/efectos de los fármacos , Nootrópicos/farmacología , Poliaminas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de la Síntesis de la Proteína/farmacología , Espermidina/farmacología , Animales , Anisomicina/administración & dosificación , Anisomicina/farmacología , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Biguanidas/administración & dosificación , Biguanidas/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Isoquinolinas/administración & dosificación , Isoquinolinas/farmacología , Masculino , Nootrópicos/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de la Síntesis de la Proteína/administración & dosificación , Ratas , Ratas Wistar , Espermidina/administración & dosificación , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacología

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Scutia buxifolia is a tree native to South America and is used as a cardiotonic agent; however, this property has not been associated with a clear mechanism or a specific compound. AIM OF THE STUDY: Given the importance of Na(+),K(+)-ATPase as a drug target in the treatment of heart failure, this study aimed to investigate the possible inhibitory effect of S. buxifolia crude extract and fractions (dichloromethane, ethyl acetate, and butanolic fractions), and identified compounds with effects on the activity of Na(+),K(+)-ATPase in vitro. MATERIALS AND METHODS: First, we characterized the crude extract and fractions by high-performance liquid chromatography, and then monitored their effects on the activity of Na(+),K(+)-ATPase obtained from heart muscle and brain membranes of adult male Wistar rats. RESULTS: We identified gallic acid, chlorogenic acid, caffeic acid, rutin, quercitrin, quercetin, and ursolic acid in S. buxifolia stem bark and leaves; quercitrin and ursolic acid were the main compounds in the ethyl acetate and dichloromethane fractions from leaves and stem bark. The crude extract (3 and 30mg/ml), and the ethyl acetate and dichloromethane fractions (0.1 and 1mg/ml) of both the stem bark and leaves inhibited Na(+),K(+)-ATPase activity in heart and brain samples. We found that, of the identified compounds, only ursolic acid (0.1mg/ml) was able to diminish Na(+), K(+)-ATPase activity in heart and brain samples. CONCLUSIONS: These data indicated that the cardiotonic effects of S. buxifolia may be due to the inhibition of Na(+),K(+)-ATPase activity in heart muscle, supporting the popular use of this plant as a treatment for heart failure.

Asunto(s)

Miocardio/enzimología , Extractos Vegetales/farmacología , Rhamnaceae/química , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Triterpenos/farmacología , Animales , Encéfalo/metabolismo , Corazón/efectos de los fármacos , Masculino , Membranas/efectos de los fármacos , Membranas/enzimología , Corteza de la Planta/química , Hojas de la Planta/química , Tallos de la Planta/química , Ratas , Ratas Wistar , Solventes , Ácido Ursólico

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

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