RESUMO
PURPOSE: The neuroprotective actions of the ovarian hormone 17ß-estradiol (E2) against different brain lesions have been constantly confirmed in a variety of models including kainic acid (KA) lesions. Similarly, the pituitary hormone prolactin (PRL), traditionally associated with lactogenesis, has recently been linked to a large diversity of functions, including neurogenesis, neuroprotection, and cognitive processes. While the mechanisms of actions of E2 as regards its neuroprotective and behavioral effects have been extensively explored, the molecular mechanisms of PRL related to these roles remain under investigation. The current study aimed to investigate whether the simultaneous administration of PRL and a low dose of E2 prevents the KA-induced cognitive deficit and if this action is associated with changes in hippocampal neuronal density. METHODS: Ovariectomized (OVX) rats were treated with saline, PRL, and/or E2 in the presence or absence of KA. Neuroprotection was assessed by Nissl staining and neuron counting. Memory was evaluated with the novel object recognition test (NOR). RESULTS: On their own, both PRL and E2 prevented short- and long-term memory deficits in lesioned animals and exerted neuroprotection against KA-induced excitotoxicity in the hippocampus. Interestingly, the combined hormonal treatment was superior to either of the treatments administered alone as regards improving both memory and neuronal survival. CONCLUSION: Taken together, these results point to a synergic effect of E2 and PRL in the hippocampus to produce their behavioral, proliferative, and neuroprotective effects.
Assuntos
Estradiol , Hipocampo , Ácido Caínico , Transtornos da Memória , Fármacos Neuroprotetores , Ovariectomia , Prolactina , Animais , Ácido Caínico/farmacologia , Estradiol/farmacologia , Feminino , Prolactina/farmacologia , Fármacos Neuroprotetores/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/metabolismo , Ratos , Transtornos da Memória/prevenção & controle , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/induzido quimicamente , Ratos Wistar , Sinergismo Farmacológico , Neurônios/efeitos dos fármacos , Neurônios/patologiaRESUMO
Schizophrenia is a serious neuropsychiatric disorder characterized by the presence of positive symptoms (hallucinations, delusions, and disorganization of thought and language), negative symptoms (abulia, alogia, and affective flattening), and cognitive impairment (attention deficit, impaired declarative memory, and deficits in social cognition). Dopaminergic hyperactivity seems to explain the positive symptoms, but it does not completely clarify the appearance of negative and cognitive clinical manifestations. Preclinical data have demonstrated that acute and subchronic treatment with NMDA receptor antagonists such as ketamine (KET) represents a useful model that resembles the schizophrenia symptomatology, including cognitive impairment. This latter has been explained as a hypofunction of NMDA receptors located on the GABA parvalbumin-positive interneurons (near to the cortical pyramidal cells), thus generating an imbalance between the inhibitory and excitatory activity in the corticomesolimbic circuits. The use of behavioral models to explore alterations in different domains of memory is vital to learn more about the neurobiological changes that underlie schizophrenia. Thus, to better understand the neurophysiological mechanisms involved in cognitive impairment related to schizophrenia, the purpose of this review is to analyze the most recent findings regarding the effect of KET administration on these processes.
Assuntos
Disfunção Cognitiva , Ketamina , Esquizofrenia , Humanos , Ketamina/farmacologia , Esquizofrenia/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Receptores de N-Metil-D-AspartatoRESUMO
Schizophrenia is a serious mental disorder that affects 1% of the world's population. Although various therapeutic tools have been developed since the appearance of the first generation of antipsychotics, the effect of these agents does not manage to attenuate a significant part of psychotic symptoms. Ketamine is an anesthetic agent able to produce psychotic-like symptoms through the antagonism of the glutamatergic N-methyl-d-aspartic acid (NMDA) receptors (NMDARs). This drug has been widely used to study new pharmacological tools with potential antipsychotic properties. On the contrary, it is known that the 5-HT6 receptor agonist and antagonist drugs induce procognitive, anxiolytic and antidepressant effects in different preclinical models. Therefore, the aim of this study was to evaluate the behavioral actions of the 5-HT6 receptors' agonist E-6837 and the antagonist SB-271046, in ICR-CD1 mice previously treated with a subchronic ketamine scheme (10 mg/kg i.p. daily for 5 days). Results showed that repeated administration of ketamine induced recognition memory deficit, anxiogenic effects, obsessive-compulsive behaviors and stereotyped movements. The acute administration of both 5-HT6 agents reversed the memory deficit and induced a decrease in anxiety, whereas SB-271046 administration produced a decrease in climbing behavior. The injection of either of these 5-HT6 drugs had no effect in the light-dark test. Surprisingly, when these drugs were injected together with ketamine, anxiogenic actions were produced. Current findings suggest that both agonist and antagonist 5-HT6 drugs play an important role in modulating psychotic-like symptoms induced by the subchronic blockade of NMDAR.
Assuntos
Antipsicóticos , Ketamina , Esquizofrenia , Animais , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Humanos , Indóis , Ketamina/farmacologia , Transtornos da Memória/tratamento farmacológico , Camundongos , Camundongos Endogâmicos ICR , Receptores de N-Metil-D-Aspartato , Esquizofrenia/tratamento farmacológico , Sulfonamidas , TiofenosRESUMO
Ketamine is an anesthetic agent that antagonizes N-methyl-d-aspartate receptors, inducing psychotic-like symptoms in healthy humans and animals. This agent has been used as a pharmacological tool for studying biochemical and physiological mechanisms underlying the clinical manifestations of schizophrenia. The main goal of this study was to evaluate the effect of repeated injections of ketamine (5 and 10 mg/kg, i.p., daily for 5 days) on recognition memory and neuronal morphology in ICR-CD1 mice. This treatment induced recognition memory impairment in the novel object recognition test and a decrease in dendritic spines density in both dorsal striatum and CA1-hippocampus. Sholl analysis showed that both ketamine doses decrease the dendritic arborization in ventromedial prefrontal cortex, dorsal striatum, and CA1-hippocampus. Finally, dendritic spines morphology was modified by both doses; that is, an increase of the filipodia-type spines (10 mg/kg) and a reduction of the mushroom-type spines (5 and 10 mg/kg) was observed in the ventromedial prefrontal cortex. In the dorsal striatum, the low dose of ketamine induced an increase in long thin spines and a decrease of mushroom spines. Interestingly, in CA1-hippocampus, there was an increase in the mushrooms type spines (5 mg/kg). Current findings suggest that the subchronic blockade of N-methyl-d-aspartate receptor changes the neuronal plasticity of several brain regions putatively related to recognition memory impairment.
Assuntos
Antagonistas de Aminoácidos Excitatórios/toxicidade , Ketamina/toxicidade , Transtornos da Memória/induzido quimicamente , Reconhecimento Psicológico/efeitos dos fármacos , Animais , Corpo Estriado/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Hipocampo/efeitos dos fármacos , Ketamina/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos ICR , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
Quercetin has been identified as a promising compound with a neuroprotective potential against age-related neurodegenerative diseases such as Alzheimer's disease (AD). Nevertheless, the clinical application of quercetin is hampered by its low oral bioavailability. The aim of this work was to evaluate the capability of nanoencapsulated quercetin in zein nanoparticles (NPQ), that significantly improves the oral absorption and bioavailability of the flavonoid, as potential oral treatment for AD. For this purpose, SAMP8 mice were orally treated for two months with either NPQ (25mg/kg every 48h) or a solution of quercetin (Q; 25mg/kg daily). NPQ displayed a size of 260nm and a payload of about 70µg/mg. For Q, no significant effects were observed in animals. On the contrary, the oral administration of NPQ improved the cognition and memory impairments characteristics of SAMP8 mice. These observations appeared to be related with a decreased expression of the hippocampal astrocyte marker GFAP. Furthermore, significant levels of quercetin were quantified in the brain of mice treated with nanoparticles. These findings highlight the potential of zein nanoparticles to promote the oral absorption of quercetin as well as the therapeutic potential of this flavonoid in AD pathogenesis.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Portadores de Fármacos/química , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Quercetina/uso terapêutico , 2-Hidroxipropil-beta-Ciclodextrina , Administração Oral , Doença de Alzheimer/psicologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacocinética , Tamanho da Partícula , Quercetina/administração & dosagem , Quercetina/farmacocinética , Teste de Desempenho do Rota-Rod , Zeína/química , beta-Ciclodextrinas/químicaRESUMO
Diversos antagonistas del receptor N-metil-D-aspartato (RNMDA) como la fenciclidina o la ketamina estudiados en roedores han permitido inducir alteraciones cognitivas similares a las observadas en la esquizofrenia. Casualmente, uno de los receptores a serotonina, el 5-HT6, ha cobrado interés en la búsqueda de nuevos fármacos con propiedades procognitivas. Con la finalidad de comprender mejor la interacción de ambos receptores (NMDA y 5-HT6) en la regulación cognitiva se realizó una revisión exhaustiva en la literatura. Varios estudios con esquemas agudos o subcrónicos de los antagonistas NMDA en roedores fueron evaluados en distintas pruebas, en donde se encontró deterioro cognitivo. Fue común que el esquema agudo de diversos fármacos serotoninérgicos 5-HT6 revirtiera el deterioro cognitivo inducido por la administración previa de los antagonistas del RNMDA. Por el contrario y sorprendentemente, la inyección aguda y combinada tanto de los antagonistas NMDA como de los fármacos serotoninérgicos 5-HT6 lograron fortalecer la memoria. El esquema subcrónico de los antagonistas NMDA representa el modelo más integrador para el estudio de las alteraciones cognitivas asociadas a la esquizofrenia. Aunque el deterioro y el efecto procognitivo mediados por estos receptores pudieran ser explicados mediante la regulación conjunta que ejercen ambos receptores sobre la liberación de distintos neurotransmisores como el glutamato, es una situación compleja que se requiere continuar investigando para fundamentar mejor estas ideas (AU)
Diverse antagonists of the NMDA receptor studied in rodents, such as phencyclidine or ketamine, have enabled researchers to induce cognitive changes similar to those found in schizophrenia. Interestingly, one of the serotonin receptors, 5-HT6, has attracted much attention for the development of new drugs with pro-cognitive properties. With the aim of better understanding the interaction of both NMDA and 5-HT6 in cognitive regulation, an exhaustive review of the literature was carried out. Various studies have found cognitive impairment, evaluated in rodents using different tests, after applying acute or sub-chronic schemes of NMDA antagonists. An acute scheme of applying different serotogenic 5-HT6 receptors has often reversed the cognitive impairment induced by the previous administration of NMDA antagonists. Surprisingly, an acute injection of a combination of suboptimal doses of NMDA and 5-HT6 antagonists resulted in strengthening memory. The sub-chronic scheme of NMDA antagonists represents the most reliable model for the study of cognitive changes associated with schizophrenia. Cognitive impairment, as well as a pro-cognitive effect mediated by NMDA and 5-HT6, may be explained by a joint regulation of these receptors to modulate the release of distinct neurotransmitters, such as glutamate. This represents a complex interaction that requires ongoing research to clarify the mechanisms at play (AU)