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1.
Learn Mem ; 23(1): 21-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26670183

RESUMO

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.


Assuntos
Memória/efeitos dos fármacos , Proteínas Quinases/metabolismo , Espermidina/farmacologia , Análise de Variância , Animais , Anisomicina/farmacologia , Biguanidas/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Medo/efeitos dos fármacos , Medo/fisiologia , Hipocampo/efeitos dos fármacos , Indóis/farmacologia , Masculino , Maleimidas/farmacologia , Inibidores da Síntese de Proteínas/farmacologia , Ratos , Ratos Wistar
2.
Pharmacol Res ; 112: 99-118, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27015893

RESUMO

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.


Assuntos
Aprendizagem , Memória , Espermidina/química , Espermina/química , Animais , Sítios de Ligação , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/fisiopatologia , Humanos , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Putrescina/química , Putrescina/metabolismo , Ratos , Espermidina/metabolismo , Espermina/metabolismo
3.
J Neuroinflammation ; 12: 3, 2015 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-25573647

RESUMO

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.


Assuntos
Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Espermina/uso terapêutico , Análise de Variância , Animais , Citocinas/metabolismo , Discriminação Psicológica/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Antagonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Piperidinas/farmacologia , Reconhecimento Psicológico/efeitos dos fármacos
4.
Pharmacol Biochem Behav ; 240: 173774, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38648866

RESUMO

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.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Proteínas Quinases Dependentes de AMP Cíclico , Memória , Ratos Wistar , Transdução de Sinais , Espermidina , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Ratos , Espermidina/farmacologia , Masculino , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Memória/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Fosforilação/efeitos dos fármacos , Sulfonamidas/farmacologia , Benzilaminas/farmacologia , Benzilaminas/administração & dosagem , Aprendizagem da Esquiva/efeitos dos fármacos , Proteína Quinase C/metabolismo , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados
5.
Neurobiol Learn Mem ; 104: 9-15, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23632063

RESUMO

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.


Assuntos
Biguanidas/farmacologia , Medo , Memória/efeitos dos fármacos , Memória/fisiologia , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Espermidina/farmacologia , Animais , Condicionamento Psicológico/efeitos dos fármacos , Medo/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar
6.
Neurobiol Learn Mem ; 100: 98-107, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23261855

RESUMO

Cigarette smoke-exposure promotes neurobiological changes associated with neurocognitive abnormalities. Curcumin, a natural polyphenol, have shown to be able to prevent cigarette smoke-induced cognitive impairment. Here, we investigated possible mechanisms involved in curcumin protection against cigarette smoke-induced cognitive impairment and, due to its poor bioavailability, we investigated the potential of using curcumin-loaded lipid-core nanocapsules (C-LNC) suspension. Rats were treated with curcumin and cigarette smoke, once a day, 5 days each week, for 30 days. Animals were divided into ten groups: I, control (vehicle/corn oil); II, curcumin 12.5mg/kg; III, curcumin 25mg/kg; IV, curcumin 50mg/kg; V, C-LNC 4 mg/kg; VI, tobacco exposed; VII, curcumin 12.5mg/kg along with tobacco exposure; VIII, curcumin 25mg/kg along with tobacco exposure; IX, curcumin 50mg/kg along with tobacco exposure; X, C-LNC 4 mg/kg along with tobacco exposure. Cigarette smoke-exposure impaired object recognition memory (P<0.001), indicated by the low recognition index, increased biomarkers of oxidative/nitrosative stress such as TBARS (P<0.05) and NOx (P<0.01), decreased antioxidant defenses such as NPSH content (P<0.01) and SOD activity (P<0.01) and inhibited the activities of enzymes involved in ion homeostasis such as Na(+),K(+)-ATPase and Ca(2+)-ATPase. Both curcumin formulations (free and nanoencapsulated) prevented the memory impairment, the redox imbalance and the alterations observed in the ATPases activities. Maintenance of ion homeostasis and redox balance is involved in the protective mechanism of curcumin against tobacco-induced cognitive impairment. Our results suggest that curcumin is a potential therapeutic agent for neurocognition and that C-LNC may be an alternative to its poor bioavailability.


Assuntos
Transtornos Cognitivos/prevenção & controle , Curcumina/farmacologia , Memória/efeitos dos fármacos , Nicotiana/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Fumaça/efeitos adversos , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/metabolismo , Glutationa Peroxidase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Memória/fisiologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Oxirredução , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/metabolismo , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
7.
Neurobiol Learn Mem ; 97(3): 294-300, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22390858

RESUMO

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.


Assuntos
Amnésia/metabolismo , Aprendizagem por Associação/efeitos dos fármacos , Biguanidas/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Medo/efeitos dos fármacos , Receptores Opioides mu/metabolismo , Amnésia/induzido quimicamente , Animais , Aprendizagem por Associação/fisiologia , Condicionamento Psicológico/fisiologia , Medo/fisiologia , Reação de Congelamento Cataléptica/efeitos dos fármacos , Reação de Congelamento Cataléptica/fisiologia , Masculino , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Ratos , Ratos Wistar
8.
Inflamm Res ; 61(2): 103-12, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22057902

RESUMO

OBJECTIVE AND DESIGN: To investigate whether N-acetylcysteine (NAC) alters baker's-yeast-induced fever and inflammation. MATERIAL OR SUBJECTS: Male Wistar rats (26-28 days old) injected with baker's yeast (135 mg/kg, intraperitoneal) or prostaglandin E(2) (300 ng/100 µL, intrathecal). TREATMENT: Rats were injected with NAC (500 mg/kg, subcutaneous, or 50 µg/100 µL, intrathecal) 1 h before, or 2 h after, pyrogen injection. METHODS: Rectal temperature changes induced by baker's yeast, PGE(2) and NAC were followed up over time. Four hours after baker's yeast injection, total leukocytes, protein, interleukin (IL)-1ß, tumor necrosis factor (TNF)-α and nonprotein thiol content were assessed in peritoneal lavage and hypothalamus. RESULTS: Systemic administration of NAC decreased leukocytes, protein, IL-1ß and TNF-α levels in peritoneal lavage, and decreased IL-1ß levels in the hypothalamus. The central administration of NAC prevented baker's-yeast-induced fever, but did not alter the febrile response elicited by prostaglandin E(2). CONCLUSION: These results suggest an anti-inflammatory and antipyretic role for NAC in yeast-induced peritonitis.


Assuntos
Acetilcisteína/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Antipiréticos/uso terapêutico , Febre/tratamento farmacológico , Sequestradores de Radicais Livres/farmacologia , Peritonite/tratamento farmacológico , Saccharomyces cerevisiae/efeitos dos fármacos , Acetilcisteína/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antipiréticos/farmacologia , Dinoprostona/farmacologia , Febre/microbiologia , Hipotálamo/química , Hipotálamo/metabolismo , Interleucina-1beta/análise , Contagem de Leucócitos , Masculino , Lavagem Peritoneal , Peritonite/metabolismo , Peritonite/microbiologia , Proteínas/análise , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/análise
9.
Cell Biochem Funct ; 30(4): 347-53, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22359364

RESUMO

The aim of this study was to investigate the effect of the aqueous extract (AE) of Achyrocline satureioides on serum lipid profile, liver oxidative profile and Na(+),K(+)-ATPase activity of rats submitted to a hyperlipidic diet. The animals were divided into four groups: control (C), AE 10% (A(10)), hyperlipidic (H) and hyperlipidic/AE 10% (HA(10)). In serum, we measured the levels of total cholesterol (TC), high-density lipoprotein, very-low-density lipoprotein, low-density lipoprotein (LDL) and triglyceride (TG). In liver homogenates, we measured the thiobarbituric acid reactive substances, the carbonyl proteins, the non-protein thiols (NPSHs) and the activity of superoxide dismutase, catalase (CAT) and Na(+),K(+)-ATPase. We observed a significant increase in the TC and LDL levels in the H group. A. satureioides prevented these effects, decreased the TG levels in the HA(10) group and increased the NPSH levels in the A(10) and HA(10) groups. The H group showed an increase in the carbonyl protein level and a decrease in CAT and Na(+),K(+)-ATPase activities. With the use of this model, results show that increased levels of lipids are related to a redox imbalance in the liver, which is also related to the inhibition of Na(+),K(+)-ATPase activity, and that chronic administration of the AE of A. satureioides is capable of changing this profile.


Assuntos
Achyrocline/química , Anticolesterolemiantes/farmacologia , Extratos Vegetais/farmacologia , Animais , Catalase/metabolismo , Colesterol/sangue , Dieta Hiperlipídica , Ativação Enzimática/efeitos dos fármacos , Lipídeos/sangue , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Masculino , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , ATPase Trocadora de Sódio-Potássio/metabolismo , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/análise , Triglicerídeos/sangue
10.
Neurobiol Learn Mem ; 96(2): 324-32, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21708277

RESUMO

Spermidine (SPD) is an endogenous polyamine that modulates N-methyl-D-aspartate (NMDA) receptor function, and has been reported to facilitate memory formation. In the current study we determined whether or not the PKA/CREB signaling pathway is involved in SPD-induced facilitation of memory of inhibitory avoidance task in adult rats. The post-training administration of the cAMP-dependent protein kinase (PKA) inhibitor, N-[2-bromocinnamylamino)ethyl]-5-isoquinoline sulfonamide [H-89, 0.5 ρmol intrahippocampal (ih)] or the antagonist of the NMDA receptor polyamine-binding site (arcaine, 0.02 nmol ih) with SPD (0.2 nmol ih) prevented memory improvement induced by SPD. Intrahippocampal administration of SPD (0.2 nmol) facilitated PKA and cAMP response element-binding protein (CREB) phosphorylation in the hippocampus 180 min, but not 30 min, after administration, and increased translocation of the catalytic subunit of PKA into the nucleus. Arcaine (0.02 nmol) and H-89 (0.5 ρmol) prevented the stimulatory effect of SPD on PKA and CREB phosphorylation. These results suggest that memory enhancement induced by the ih administration of SPD involves the PKA/CREB pathways in rats.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Hipocampo/metabolismo , Memória/fisiologia , Transdução de Sinais/fisiologia , Espermidina/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Biguanidas/farmacologia , Hipocampo/efeitos dos fármacos , Memória/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos
11.
Neurobiol Learn Mem ; 93(4): 589-95, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20206278

RESUMO

Polyamines, such as spermidine and spermine, have been reported to improve memory retention through the activation of N-methyl-d-aspartate receptors (NMDAr). However whether polyamine agonists and antagonists alter extinction remains unclear. In the current study, we investigated whether spermidine and polyamine antagonists that selectively block the NR2B subunit at the NMDAr alter the extinction of contextual conditioned fear in male Wistar rats. The bilateral intra-hippocampal administration of exogenous spermidine (2 nmol/site) immediately after, but not 6h after extinction training, facilitated the extinction of fear conditioning. The injection of the NMDAr antagonists arcaine (0.2 nmol/site), ifenprodil (20 nmol/site) and traxoprodil (0.2 nmol/site), disrupted fear extinction and, at doses that had no effect per se, reversed the facilitatory effect of spermidine on fear extinction. These results suggest that exogenous and endogenous polyamines facilitate the extinction of contextual conditioned fear through activation of NR2B subunit-containing NMDAr in the hippocampus. Since extinction-based exposure therapy is widely used as treatment for a number of anxiety-related disorders, including phobias and post-traumatic stress, the currently reported facilitation of extinction by polyaminergic agents suggest these compounds as putative candidates for drug development.


Assuntos
Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Nootrópicos/farmacologia , Espermidina/farmacologia , Animais , Biguanidas/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Reação de Congelamento Cataléptica , Masculino , Testes Neuropsicológicos , Piperidinas/farmacologia , Poliaminas/farmacologia , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo
12.
Inflamm Res ; 59(3): 189-96, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19730987

RESUMO

OBJECTIVE: To investigate the effect of diacerein, an anti-inflammatory drug, on body temperature and protocols of fever induction in male Wistar rats. METHODS: The effect of diacerein (5.0 mg/kg, s.c.) on rectal temperature (T (R)) changes induced by Baker's yeast (0.135 g/kg, i.p.) and PGE(2) (10 ng/animal, i.t.) was evaluated. T (R) changes were recorded over time. The leukocyte count and TNF-alpha and IL-1beta content were evaluated in the peritoneal fluid by means of optical microscopy and enzyme immunoassay (ELISA kits), respectively. RESULTS: The administration of diacerein to febrile animals attenuated Baker's yeast-induced fever but did not alter prostaglandin E(2)-induced fever. Diacerein prevented the development of Baker's yeast-induced fever and significantly attenuated the increase in peritoneal leukocytes and decreased IL-1beta and TNF-alpha levels in peritoneal fluid. CONCLUSIONS: These data suggest that diacerein partially protects against Baker's yeast-induced fever and peritoneal leukocyte migration, and indicate that this effect appears to be due to inhibition of release of cytokines (such as TNF-alpha and IL-1beta).


Assuntos
Antraquinonas/farmacologia , Anti-Inflamatórios/farmacologia , Líquido Ascítico/metabolismo , Febre/prevenção & controle , Interleucina-1beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Temperatura Corporal/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Dinoprostona/efeitos adversos , Modelos Animais de Doenças , Febre/induzido quimicamente , Leucócitos/citologia , Leucócitos/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Saccharomyces cerevisiae
13.
Brain Res Bull ; 164: 208-213, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32858125

RESUMO

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.


Assuntos
Condicionamento Psicológico/efeitos dos fármacos , Consolidação da Memória/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Espermidina/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Medo/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Ratos , Ratos Wistar , Receptor trkB/metabolismo
14.
J Nat Prod ; 72(4): 608-12, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19231884

RESUMO

The analgesic potential of six 14-membered-ring cyclopeptide alkaloids, namely, franganine (1), discarine B (2), scutianines B (3), C (4), and D (5), and adouetine X (6), have been investigated. Among the compounds tested, only franganine (1) and adouetine X (6) produced antinociceptive effects in a mouse model of acute pain, without inducing undesirable side effects. Furthermore, compound 6 also exhibited a pronounced analgesic effect in a chronic neuropathic pain model in mice. It has been found that adouetine X (6) can decrease the activities of Ca(2+)-ATPase and Na(+)/K(+)-ATPase in vitro. Thus, the present findings have demonstrated that adouetine X (6) is a promising analgesic agent.


Assuntos
Alcaloides/farmacologia , Analgésicos/isolamento & purificação , Analgésicos/farmacologia , ATPases Transportadoras de Cálcio/antagonistas & inibidores , Malvaceae/química , Peptídeos Cíclicos/isolamento & purificação , Peptídeos Cíclicos/farmacologia , Plantas Medicinais/química , Rhamnaceae/química , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Alcaloides/química , Analgésicos/química , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Estrutura Molecular , Peptídeos Cíclicos/química
15.
Neurochem Int ; 122: 157-169, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30496767

RESUMO

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.


Assuntos
Analgésicos Opioides/farmacologia , Analgésicos/farmacologia , Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Doença Crônica , Dor Crônica/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Morfina/uso terapêutico
16.
J Hypertens ; 37(1): 135-143, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30507864

RESUMO

: Background: Central nervous system function has been emerging as an approach to understand hypertension-mediated memory dysfunction, and chronic exercise is able to modulate the purinergic system. METHOD: Herein, we investigated the effect of chronic swimming training on the purinergic system in cortex and hippocampus of L-NAME-induced hypertensive rats. Male Wistar rats were divided into four groups: Control, Exercise, L-NAME and Exercise L-NAME. Inhibitory avoidance test was used to assess memory status. NTPDase, CD73 and adenosine deaminase activities and expression, and P2 receptors expression were analyzed. Data were analyzed using two-way ANOVA and Kruskal-Wallis tests, considering P less than 0.05. RESULTS: Physical exercise reduced the blood pressure and prevented memory impairment induced by L-NAME model of hypertension. L-NAME treatment promoted an increase in NTPDase1, NTPDase3 and CD73 expression and activity in the cortex. A2A expression is increased in hippocampus and cortex in the hypertension group and exercise prevented this overexpression. CONCLUSION: These changes suggest that hypertension increases adenosine generation, which acts through A2A receptors, and exercise prevents these effects. These data may indicate a possible mechanism by which exercise may prevent memory impairment induced by L-NAME.


Assuntos
5'-Nucleotidase/metabolismo , Antígenos CD/metabolismo , Apirase/metabolismo , Hipertensão/fisiopatologia , Memória/fisiologia , Condicionamento Físico Animal/fisiologia , Animais , Córtex Cerebral/química , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , NG-Nitroarginina Metil Éster/metabolismo , Ratos , Receptor A2A de Adenosina/metabolismo , Natação/fisiologia
17.
Psychopharmacology (Berl) ; 236(2): 641-655, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30377748

RESUMO

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.


Assuntos
Berberina/farmacologia , Encéfalo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Reconhecimento Psicológico/efeitos dos fármacos , 5'-Nucleotidase/efeitos dos fármacos , 5'-Nucleotidase/metabolismo , Adenosina Desaminase/efeitos dos fármacos , Adenosina Desaminase/metabolismo , Doença de Alzheimer/psicologia , Animais , Antibióticos Antineoplásicos/toxicidade , Antioxidantes , Encéfalo/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Glutationa , Glutationa Transferase/efeitos dos fármacos , Glutationa Transferase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Injeções Intraventriculares , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Oxirredução/efeitos dos fármacos , Pirofosfatases/efeitos dos fármacos , Pirofosfatases/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Estreptozocina/toxicidade , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/enzimologia
18.
Psychopharmacology (Berl) ; 201(3): 405-11, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18758754

RESUMO

RATIONALE: The polyamines putrescine, spermidine, and spermine are a group of aliphatic amines that may act as physiological modulators of the N-methyl-D-aspartate (NMDA) receptor, a glutamate receptor implicated in memory formation and consolidation. Arcaine is a competitive antagonist of the polyamine binding site at the NMDA receptor, the post-training administration of which impairs memory of various tasks. OBJECTIVES: In this study, we investigated whether the administration of arcaine and MK-801 alters the memory of the step-down inhibitory avoidance task, and whether the effects of these NMDA antagonists involve state-dependency mechanisms, in adult male Wistar rats. RESULTS: The administration of arcaine (30 mg/kg, i.p.) or MK-801 (0.03 mg/kg, i.p.) immediately after training impaired inhibitory avoidance performance at testing. Arcaine- and MK-801-induced performance impairment was reversed by the administration of arcaine (30 mg/kg, i.p.) and MK-801 (0.03 mg/kg, i.p.), respectively, 30 min before testing. Response transfer also occurred if arcaine substituted MK-801 at testing, and vice-versa. CONCLUSION: These results suggest that arcaine and MK-801 induce state-dependent recall and that, probably due to their ability to decrease NMDA receptor function, one drug can substitute for the other at testing, demonstrating a cross-state dependency between arcaine and MK-801.


Assuntos
Biguanidas/farmacologia , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Rememoração Mental/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Comportamento Animal , Biguanidas/química , Soluções Tampão , Maleato de Dizocilpina/química , Relação Dose-Resposta a Droga , Esquema de Medicação , Antagonistas de Aminoácidos Excitatórios/química , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Injeções Intraperitoneais , Masculino , Rememoração Mental/fisiologia , Fosfatos , Poliaminas/química , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/fisiologia , Fatores de Tempo , Transferência de Experiência/efeitos dos fármacos , Transferência de Experiência/fisiologia
19.
Behav Brain Res ; 187(1): 200-4, 2008 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-17950476

RESUMO

Achievements made over the last years have highlighted the important role of creatine in health and disease. However, studies of its effect on cognition function have been limited. In the present study, we investigated the effect of creatine on early consolidation of the spatial learning in rats. Statistical analysis showed that intrahippocampal administration of creatine (2.5 and 7.5 nmol/hippocampus) (post-training) decreased the latency for scape and mean number of errors in Barnes maze test. The involvement of polyamine binding site at NMDA receptor in creatine-induced spatial learning enhancement was investigated by co-administration of arcaine (0.02 nmol/hippocampus) or spermidine (0.02 nmol/hippocampus) with creatine (2.5 nmol/hippocampus) (post-training). Statistical analysis revealed that creatine-induced spatial learning enhancement was reverted by co-administration of arcaine (0.02 nmol/hippocampus) and intensified by spermidine (0.02 nmol/hippocampus). These results provide evidence that creatine not only seem to be involved in energy metabolism but may also play an important role in early consolidation of spatial learning in hippocampus which participation of polyamines binding site at the NMDA receptor.


Assuntos
Creatina/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Poliaminas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Percepção Espacial/efeitos dos fármacos , Animais , Biguanidas/farmacologia , Sítios de Ligação , Creatina/administração & dosagem , Creatina/antagonistas & inibidores , Hipocampo/fisiologia , Masculino , Microinjeções , Ratos , Espermidina/farmacologia , Estimulação Química
20.
Brain Res ; 1198: 107-14, 2008 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-18243165

RESUMO

Polyamines are aliphatic amines containing nucleophilic centers that are found in all eukaryotic cells, including brain cells. These compounds determine neuroprotection in experimental models of cerebral ischemia and neurotoxicity. In the current study we investigated the protective effects of spermine, an agonist of the polyamine binding site at the N-methyl-d-aspartate receptor, against the behavioral and neurochemical alterations induced by quinolinic acid. The unilateral intrastriatal injection of quinolinic acid (180 nmol/site into the dorsal striatum) induced stereotypical motor asymmetries, assessed by the open field and elevated body swing tests. Spermine modulated quinolinic acid-induced rotational behavior biphasically. While the previous intrastriatal administration of spermine at the dose of 0.1 nmol/site increased, the administration of spermine at the dose of 10 nmol/site reduced quinolinic acid-induced rotational behavior. Spermine (10 nmol/site) also decreased the contralateral swing behavior induced by quinolinic acid. Furthermore, the effect of 10 nmol of spermine was counteracted by the co-administration of arcaine (10 nmol), a selective antagonist of the polyamine binding site at the N-methyl-d-aspartate receptor. In addition, spermine (10 nmol) protected against quinolinic acid-induced protein carbonylation in the rat striatum, further suggesting an antioxidant role for this polyamine. These results provide evidence that the behavioral and biochemical alterations induced by quinolinic acid are attenuated or prevented by spermine through its interaction with N-methyl-d-aspartate receptor and/or its antioxidant function.


Assuntos
Antioxidantes/metabolismo , Química Encefálica/fisiologia , Corpo Estriado/metabolismo , Estresse Oxidativo/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Espermina/metabolismo , Animais , Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Biguanidas/farmacologia , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/fisiologia , Ligação Competitiva/efeitos dos fármacos , Ligação Competitiva/fisiologia , Química Encefálica/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Ácidos Quinolínicos/antagonistas & inibidores , Ácidos Quinolínicos/farmacologia , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Espermina/farmacologia
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