RESUMO
The selenium-binding protein 1 (SELENBP1) has been reported to be up-regulated in the prefrontal cortex (PFC) of schizophrenia patients in postmortem reports. However, no causative link between SELENBP1 and schizophrenia has yet been established. Here, we provide evidence linking the upregulation of SELENBP1 in the PFC of mice with the negative symptoms of schizophrenia. We verified the levels of SELENBP1 transcripts in postmortem PFC brain tissues from patients with schizophrenia and matched healthy controls. We also generated transgenic mice expressing human SELENBP1 (hSELENBP1 Tg) and examined their neuropathological features, intrinsic firing properties of PFC 2/3-layer pyramidal neurons, and frontal cortex (FC) electroencephalographic (EEG) responses to auditory stimuli. Schizophrenia-like behaviors in hSELENBP1 Tg mice and mice expressing Selenbp1 in the FC were assessed. SELENBP1 transcript levels were higher in the brains of patients with schizophrenia than in those of matched healthy controls. The hSELENBP1 Tg mice displayed negative endophenotype behaviors, including heterotopias- and ectopias-like anatomical deformities in upper-layer cortical neurons and social withdrawal, deficits in nesting, and anhedonia-like behavior. Additionally, hSELENBP1 Tg mice exhibited reduced excitabilities of PFC 2/3-layer pyramidal neurons and abnormalities in EEG biomarkers observed in schizophrenia. Furthermore, mice overexpressing Selenbp1 in FC showed deficits in sociability. These results suggest that upregulation of SELENBP1 in the PFC causes asociality, a negative symptom of schizophrenia.
Assuntos
Esquizofrenia , Humanos , Animais , Camundongos , Esquizofrenia/genética , Esquizofrenia/metabolismo , Córtex Pré-Frontal/metabolismo , Células Piramidais/metabolismo , Encéfalo/metabolismo , Camundongos Transgênicos , Proteínas de Ligação a Selênio/genética , Proteínas de Ligação a Selênio/metabolismoRESUMO
The medial prefrontal cortex (mPFC) has been implicated in regulating resistance to the effects of acute uncontrollable stress. We previously showed that mPFC-lesioned animals exhibit impaired object recognition memory after acute exposure to a brief stress that had no effect in normal animals. Here, we used designer receptors exclusively activated by designer drugs to determine how modulating mPFC activity affects recognition-memory performance under stressful conditions. Specifically, animals with chemogenetic excitation or inhibition of the mPFC underwent either a brief ineffective stress (20-min restraint + 20 tail shocks) or a prolonged effective stress (60-min restraint + 60 tail shocks). Subsequent recognition memory tests showed that animals with chemogenetic mPFC inhibition exposed to brief stress showed impairment in an object recognition memory task, whereas those with chemogenetic mPFC excitation exposed to prolonged stress did not. Thus, the present findings the decreased mPFC activity exacerbates acute stress effects on memory function whereas increased mPFC activity counters these stress effects provide evidence that the mPFC bidirectionally modulates stress resistance.
Assuntos
Disfunção Cognitiva , Memória , Córtex Pré-Frontal , Reconhecimento Psicológico , Estresse Fisiológico , Estresse Psicológico , Animais , Masculino , Ratos , Clozapina/análogos & derivados , Clozapina/farmacologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/prevenção & controle , Eletrochoque/psicologia , Memória/efeitos dos fármacos , Memória/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Restrição Física/fisiologia , Estresse Fisiológico/fisiologia , Estresse Psicológico/complicações , Estresse Psicológico/fisiopatologia , Fatores de TempoRESUMO
BACKGROUND: The presence of psychiatric disorders is widely recognized as one of the primary risk factors for suicide. A significant proportion of individuals receiving outpatient psychiatric treatment exhibit varying degrees of suicidal behaviors, which may range from mild suicidal ideations to overt suicide attempts. This study aims to elucidate the transdiagnostic symptom dimensions and associated suicidal features among psychiatric outpatients. METHODS: The study enrolled patients who attended the psychiatry outpatient clinic at a tertiary hospital in South Korea (n = 1, 849, age range = 18-81; 61% women). A data-driven classification methodology was employed, incorporating a broad spectrum of clinical symptoms, to delineate distinctive subgroups among psychiatric outpatients exhibiting suicidality (n = 1189). A reference group of patients without suicidality (n = 660) was included for comparative purposes to ascertain cluster-specific sociodemographic, suicide-related, and psychiatric characteristics. RESULTS: Psychiatric outpatients with suicidality (n = 1189) were subdivided into three distinctive clusters: the low-suicide risk cluster (Cluster 1), the high-suicide risk externalizing cluster (Cluster 2), and the high-suicide risk internalizing cluster (Cluster 3). Relative to the reference group (n = 660), each cluster exhibited distinct attributes pertaining to suicide-related characteristics and clinical symptoms, covering domains such as anxiety, externalizing and internalizing behaviors, and feelings of hopelessness. Cluster 1, identified as the low-suicide risk group, exhibited less frequent suicidal ideation, planning, and multiple attempts. In the high-suicide risk groups, Cluster 2 displayed pronounced externalizing symptoms, whereas Cluster 3 was primarily defined by internalizing and hopelessness symptoms. Bipolar disorders were most common in Cluster 2, while depressive disorders were predominant in Cluster 3. DISCUSSION: Our findings suggest the possibility of differentiating psychiatric outpatients into distinct, clinically relevant subgroups predicated on their suicide risk. This research potentially paves the way for personalizing interventions and preventive strategies that address cluster-specific characteristics, thereby mitigating suicide-related mortality among psychiatric outpatients.
Assuntos
Transtorno Bipolar , Pacientes Ambulatoriais , Humanos , Feminino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Masculino , Tentativa de Suicídio/psicologia , Transtorno Bipolar/psicologia , Transtornos de Ansiedade/psicologia , Ideação Suicida , Fatores de RiscoRESUMO
The transient receptor potential vanilloid 1 (TRPV1) protein is a pain receptor that elicits a hot sensation when an organism eats the capsaicin of red chili peppers. This calcium (Ca2+)-permeable cation channel is mostly expressed in the peripheral nervous system sensory neurons but also in the central nervous system (e.g. hippocampus and cortex). Preclinical studies found that TRPV1 mediates behaviors associated with anxiety and depression. Loss of TRPV1 functionality increases expression of genes related to synaptic plasticity and neurogenesis. Thus, we hypothesized that TRPV1 deficiency may modulate Alzheimer's disease (AD). We generated a triple-transgenic AD mouse model (3xTg-AD+/+) with wild-type (TRPV1+/+), hetero (TRPV1+/-) and knockout (TRPV1-/-) TRPV1 to investigate the role of TRPV1 in AD pathogenesis. We analyzed the animals' memory function, hippocampal Ca2+ levels and amyloid-ß (Aß) and tau pathologies when they were 12 months old. We found that compared with 3xTg-AD-/-/TRPV1+/+ mice, 3xTg-AD+/+/TRPV1+/+ mice had memory impairment and increased levels of hippocampal Ca2+, Aß and total and phosphorylated tau. However, 3xTg-AD+/+/TRPV1-/- mice had better memory function and lower levels of hippocampal Ca2+, Aß, tau and p-tau, compared with 3xTg-AD+/+/TRPV1+/+ mice. Examination of 3xTg-AD-derived primary neuronal cultures revealed that the intracellular Ca2+ chelator BAPTA/AM and the TRPV1 antagonist capsazepine decreased the production of Aß, tau and p-tau. Taken together, these results suggested that TRPV1 deficiency had anti-AD effects and promoted resilience to memory loss. These findings suggest that drugs or food components that modulate TRPV1 could be exploited as therapeutics to prevent or treat AD.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Cálcio/metabolismo , Transtornos da Memória/metabolismo , Canais de Cátion TRPV/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Canais de Cálcio/metabolismo , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Quelantes/farmacologia , Modelos Animais de Doenças , Ácido Egtázico/análogos & derivados , Ácido Egtázico/farmacologia , Hipocampo/metabolismo , Aprendizagem/efeitos dos fármacos , Transtornos da Memória/genética , Camundongos , Camundongos Knockout , Nociceptores/metabolismo , Nociceptores/patologia , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/genética , Proteínas tau/genéticaRESUMO
Post-stroke dementia (PSD) is a major neurodegenerative consequence of stroke. Tauopathy has been reported in diverse neurodegenerative diseases. We investigated the cognitive impairment and pathomechanism associated with tauopathy in a rat model of PSD by modeling acute ischemic stroke and underlying chronic cerebral hypoperfusion (CCH). We performed middle cerebral artery occlusion (MCAO) surgery in rats to mimic acute ischemic stroke, followed by bilateral common carotid artery occlusion (BCCAo) surgery to mimic CCH. We performed behavioral tests and focused on the characterization of tauopathy through histology. Parenchymal infiltration of cerebrospinal fluid (CSF) tracers after intracisternal injection was examined to evaluate glymphatic function. In an animal model of PSD, cognitive impairment was aggravated when BCCAo was combined with MCAO. Tauopathy, manifested by tau hyperphosphorylation, was prominent in the peri-infarct area when CCH was combined. Synergistic accentuation of tauopathy was evident in the white matter. Microtubules in the neuronal axon and myelin sheath showed partial colocalization with the hyperphosphorylated tau, whereas oligodendrocytes showed near-complete colocalization. Parenchymal infiltration of CSF tracers was attenuated in the PSD model. Our experimental results suggest a hypothesis that CCH may aggravate cognitive impairment and tau hyperphosphorylation in a rat model of PSD by interfering with tau clearance through the glymphatic system. Therapeutic strategies to improve the clearance of brain metabolic wastes, including tau, may be a promising approach to prevent PSD after stroke.
Assuntos
Infarto Encefálico , Demência , Acidente Vascular Cerebral , Tauopatias , Animais , Infarto Encefálico/complicações , Infarto Encefálico/metabolismo , Infarto Encefálico/patologia , Infarto Encefálico/fisiopatologia , Demência/etiologia , Demência/metabolismo , Demência/patologia , Demência/fisiopatologia , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto , Ratos , Ratos Wistar , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia , Tauopatias/etiologia , Tauopatias/metabolismo , Tauopatias/patologia , Tauopatias/fisiopatologiaRESUMO
The lateral habenula (LHb) is a small part of the epithalamus that projects to monoamine centers in the brain. Previously, neurotransmission onto the LHb was shown to be abnormally potentiated in animal models of depression. However, synaptic plasticity in this brain area and the effect of stressor exposure on synaptic plasticity of the LHb have not been investigated. Thus, we explored whether the LHb undergoes dynamic changes in synaptic efficacy or not. First, we observed that a moderate LTP occurs in a fraction of LHb neurons obtained from naive Sprague Dawley rats. Interestingly, a single exposure to acute stressors, such as inescapable foot shock or restraint plus tail shock (RTS), significantly enhances the magnitude of LTP in the LHb. We also observed an increased number of LHb neurons expressing phosphorylated cAMP response element-binding protein (pCREB) after exposure to stressors, which may contribute to determine the threshold for LTP induction. LTP induction in the LHb resulted in an additional increase in the number of pCREB-expressing neurons in stress-exposed animals but not in naive control animals. Together, we showed that LHb neurons have heterogeneous propensity for synaptic potentiation at rest; however, a single exposure to stressors greatly facilitates LTP induction in the LHb, suggesting that fundamental alterations in synaptic plasticity in the LHb may occur in animal models of depression or post-traumatic stress disorder.SIGNIFICANCE STATEMENT Stress exposure is known to cause depression in human patients and animal models, although explanations at the cellular level remain to be elaborated. Here, we show that the lateral habenula (LHb) exhibits LTP after a pattern of brief strong stimulation. In addition, we show that stress exposure facilitates LTP in the LHb by lowering the threshold for LTP induction. We observed a selective increase in the number of neurons expressing pCREB in the LHb of animal models of depression. LTP induction results in a further increase in the density of pCREB-expressing neurons only after stress exposure. Our study provides the first evidence that animal models of depression exhibit altered synaptic plasticity of the LHb.
Assuntos
Habenula/fisiopatologia , Potenciação de Longa Duração , Estresse Psicológico/fisiopatologia , Sinapses , Animais , Ansiedade/fisiopatologia , Ansiedade/psicologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Eletrochoque , Técnicas In Vitro , Masculino , Ratos , Ratos Sprague-Dawley , Restrição Física , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Estresse Psicológico/psicologiaRESUMO
Being chased by a predator or a dominant conspecific can induce significant stress. However, only a limited number of laboratory studies have employed chasing by itself as a stressor. In this study, we developed a novel stress paradigm in which rats were chased by a fast-moving object in an inescapable maze. In Experiment 1, defensive behaviors and stress hormone changes induced by chasing stress were measured. During the chasing stress, the chasing-stress group (n = 9) froze and emitted 22-kHz ultrasonic vocalizations (USVs), but the no-chasing control group (n = 10) did not. Plasma corticosterone levels significantly increased following the chasing and were comparable to those of the restraint-stress group (n = 6). In Experiment 2, the long-lasting memory of the chasing event was tested after three weeks. The chasing-stress group (n = 15) showed higher levels of freezing and USV than the no-chasing group (n = 14) when they were presented with the tone associated with the object's chasing action. Subsequently, the rats were subjected to Pavlovian threat conditioning with a tone as a conditioned stimulus and footshock as an unconditioned stimulus. The chasing-stress group showed higher levels of freezing and USV during the conditioning session than the no-chasing group, indicating sensitized defensive reactions in a different threat situation. Taken together, the current results suggest that chasing stress can induce long-lasting memory and sensitization of defensive responses to a new aversive event as well as immediate, significant stress responses.
Assuntos
Comportamento Animal/fisiologia , Corticosterona/sangue , Reação de Congelamento Cataléptica/fisiologia , Memória/fisiologia , Estresse Psicológico/fisiopatologia , Vocalização Animal/fisiologia , Animais , Condicionamento Clássico , Masculino , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/sangueRESUMO
BACKGROUND: Terminalia chebula Retz. (Combretaceae) is a traditional herbal medicine that is widely used in the treatment of diabetes, immunodeficiency diseases, and stomach ulcer in Asia. However, the anti-amnesic effect of T. chebula has not yet been investigated. The present study was designed to determine whether T. chebula extract (TCE) alleviates amnesia induced by scopolamine in mice. We also investigated possible mechanisms associated with cholinergic system and anti-oxidant effects. METHODS: TCE (100 or 200 mg/kg) was orally administered to mice for fourteen days (days 1-14), and scopolamine was intraperitoneally injected to induce memory impairment for seven days (days 8-14). Learning and memory status were evaluated using the Morris water maze. Hippocampal levels of acetylcholine (ACh), acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) were measured ex vivo. Levels of reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA) in the hippocampus were also examined. RESULTS: In the Morris water maze task, TCE treatment reversed scopolamine-induced learning and memory deficits in acquisition and retention. TCE reduced hippocampal AChE activities and increased ChAT and ACh levels in the scopolamine-induced model. Moreover, TCE treatment suppressed scopolamine-induced oxidative damage by ameliorating the increased levels of ROS, NO, and MDA. CONCLUSION: These findings suggest that TCE exerts potent anti-amnesic effects via cholinergic modulation and anti-oxidant activity, thus providing evidence for its potential as a cognitive enhancer for amnesia.
Assuntos
Amnésia/metabolismo , Antioxidantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Escopolamina/efeitos adversos , Terminalia/química , Acetilcolina/análise , Acetilcolina/metabolismo , Acetilcolinesterase/análise , Acetilcolinesterase/metabolismo , Amnésia/induzido quimicamente , Amnésia/prevenção & controle , Animais , Hipocampo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Background: Nasal pretreatment with the neuropeptide oxytocin has been reported to prevent stress-induced impairments in hippocampal synaptic plasticity and spatial memory in rats. However, no study has asked if oxytocin application following a stress experience is effective in rescuing stress-induced impairments. Methods: Synaptic plasticity was measured in hippocampal Schaffer collateral-CA1 synapses of rats subjected to uncontrollable stress; their cognitive function was examined using an object recognition task. Results: Impaired induction of long-lasting, long-term potentiation by uncontrollable stress was rescued, as demonstrated both in rats and hippocampal slices. Intranasal oxytocin after experiencing uncontrollable stress blocked cognitive impairments in stressed rats and in stressed hippocampal slices treated with a perfused bath solution containing oxytocin. Conclusions: These results indicated that posttreatment with oxytocin after experiencing a stressful event can keep synaptic plasticity and cognition function intact, indicating the therapeutic potential of oxytocin for stress-related disorders, including posttraumatic stress disorder.
Assuntos
Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Nootrópicos/farmacologia , Ocitocina/farmacologia , Estresse Psicológico/tratamento farmacológico , Administração Intranasal , Animais , Modelos Animais de Doenças , Hipocampo/fisiopatologia , Potenciação de Longa Duração/fisiologia , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/fisiopatologia , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Estresse Psicológico/fisiopatologia , Técnicas de Cultura de TecidosRESUMO
BACKGROUND AND PURPOSE: Chronic cerebral hypoperfusion can lead to ischemic white matter injury resulting in vascular dementia. To characterize white matter injury in vascular dementia, we investigated disintegration of diverse white matter components using a rat model of chronic cerebral hypoperfusion. METHODS: Chronic cerebral hypoperfusion was modeled in Wistar rats by permanent occlusion of the bilateral common carotid arteries. We performed cognitive behavioral tests, including the water maze task, odor discrimination task, and novel object test; histological investigation of neuroinflammation, oligodendrocytes, myelin basic protein, and nodal or paranodal proteins at the nodes of Ranvier; and serial diffusion tensor imaging. Cilostazol was administered to protect against white matter injury. RESULTS: Diverse cognitive impairments were induced by chronic cerebral hypoperfusion. Disintegration of white matter was characterized by neuroinflammation, loss of oligodendrocytes, attenuation of myelin density, structural derangement at the nodes of Ranvier, and disintegration of white matter tracts. Cilostazol protected against cognitive impairments and white matter disintegration. CONCLUSIONS: White matter injury induced by chronic cerebral hypoperfusion can be characterized by disintegration of diverse white matter components. Cilostazol might be a therapeutic strategy against white matter disintegration in patients with vascular dementia.
Assuntos
Isquemia Encefálica/patologia , Estenose das Carótidas/patologia , Demência Vascular/patologia , Hipocampo/patologia , Leucoencefalopatias/patologia , Substância Branca/patologia , Animais , Comportamento Animal/efeitos dos fármacos , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Estenose das Carótidas/complicações , Estenose das Carótidas/metabolismo , Doença Crônica , Cilostazol , Cognição/efeitos dos fármacos , Demência Vascular/etiologia , Demência Vascular/metabolismo , Imagem de Tensor de Difusão , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inflamação , Leucoencefalopatias/etiologia , Leucoencefalopatias/metabolismo , Proteína Básica da Mielina/efeitos dos fármacos , Proteína Básica da Mielina/metabolismo , Fármacos Neuroprotetores/farmacologia , Testes Neuropsicológicos , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Nós Neurofibrosos/efeitos dos fármacos , Nós Neurofibrosos/metabolismo , Nós Neurofibrosos/patologia , Ratos , Ratos Wistar , Tetrazóis/farmacologia , Substância Branca/efeitos dos fármacos , Substância Branca/metabolismoRESUMO
BACKGROUND: Fructus mume (F. mume) has been used as a traditional treatment for ulcer, cough, and digestive problems for many years in Asian countries. Previous studies have demonstrated that F. mume extracts alleviate cognitive deficits in rats with chronic cerebral hypoperfusion and in mice with scopolamine treatments. The present experiment was conducted to examine the effects of F. mume on cognitive impairments in 5XFAD transgenic mice with five familial Alzheimer's disease (AD) mutations. METHODS: F. mume was administered daily to 5XFAD mice at 12 weeks of age and continued for 90 days. Cognitive function was evaluated using a spatial memory version of the Morris water maze task, the object/location novelty recognition test, and contextual fear conditioning at 24 weeks of age. To elucidate the possible mechanisms underlying the memory improving effects of F. mume in 5XFAD mice, we examined alterations in hippocampal cholinergic function. RESULTS: Vehicle-treated 5XFAD mice exhibited hippocampus-dependent memory impairments compared with non-transgenic littermates, which was reversed in F. mume-treated 5XFAD mice. In addition, reduced hippocampal choline acetyltransferase (ChAT) levels in 5XFAD mice were reversed by F. mume treatment, indicating that F. mume enhances the effects of cholinergic neuronal function. CONCLUSIONS: F. mume may have therapeutic effects on cognitive impairments in AD.
Assuntos
Transtornos Cognitivos/tratamento farmacológico , Plantas Medicinais , Prunus , Doença de Alzheimer , Animais , Colina O-Acetiltransferase/metabolismo , Feminino , Frutas/química , Hipocampo/enzimologia , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos TransgênicosRESUMO
BACKGROUND: Ginseng (Panax ginseng C.A. Meyer) has been used as a traditional herb in the treatment of many medical disorders. Ginsenosides, which are triterpene derivatives that contain sugar moieties, are the main pharmacological ingredients in ginseng. This study was designed to investigate the effect of ginsenoside Rg3-enriched ginseng extract (Rg3GE) on scopolamine-induced memory impairment in mice. METHODS: Rg3GE (50 and 100 mg/kg) were administered to C57BL/6 mice by oral gavage for 14 days (days 1-14). Memory impairment was induced by scopolamine (1 mg/kg, intraperitoneal injection) for 6 days (days 914). The Morris water maze test was used to assess hippocampus-dependent spatial memory. The effects of scopolamine with or without Rg3GE on acetylcholinesterase and nuclear factor-κB (NF-κB) in the hippocampus were also examined. RESULTS: Mice with scopolamine treatment alone showed impairments in the acquisition and retention of spatial memory. Mice that received Rg3GE and scopolamine showed no scopolamine-induced impairment in the acquisition of spatial memory. Oral administration of Rg3GE suppressed the scopolamine-mediated increase in acetylcholinesterase activity and stimulation of the NF-κB pathway (i.e., phosphorylation of p65) in the hippocampus. CONCLUSION: These findings suggest that Rg3GE may stabilize scopolamine-induced memory deficits through the inhibition of acetylcholinesterase activity and NF-κB signaling in the hippocampus.
Assuntos
Ginsenosídeos/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Panax , Extratos Vegetais/uso terapêutico , Animais , Deficiências da Aprendizagem/induzido quimicamente , Deficiências da Aprendizagem/tratamento farmacológico , Masculino , Transtornos da Memória/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , EscopolaminaRESUMO
Lysophosphatidic acid (LPA) is one of the well-characterized, ubiquitous phospholipid molecules. LPA exerts its effect by activating G protein-coupled receptors known as LPA receptors (LPARs). So far, LPAR signaling has been critically implicated during early development stages, including the regulation of synapse formation and the morphology of cortical and hippocampal neurons. In adult brains, LPARs seem to participate in cognitive as well as emotional learning and memory. Recent studies using LPAR1-deficient mice reported impaired performances in a number of behavioral tasks, including the hippocampus-dependent spatial memory and fear conditioning tests. Nevertheless, the effect of LPAR activation in the synaptic transmission of central synapses after the completion of embryonic development has not been investigated. In this study, we took advantage of a novel extracellular agonist for LPARs called gintonin to activate LPARs in adult brain systems. Gintonin, a recently identified active ingredient in ginseng, has been shown to activate LPARs and mobilize Ca(2+) in an artificial cell system. We found that the activation of LPARs by application of gintonin acutely enhanced both excitatory and inhibitory transmission in central synapses, albeit through tentatively distinct mechanisms. Gintonin-mediated LPAR activation primarily resulted in synaptic enhancement and an increase in neuronal excitability in a phospholipase C-dependent manner. Our findings suggest that LPARs are able to directly potentiate synaptic transmission in central synapses when stimulated exogenously. Therefore, LPARs could serve as a useful target to modulate synaptic activity under pathological conditions, including neurodegenerative diseases.
Assuntos
Encéfalo/metabolismo , Potenciais Pós-Sinápticos Excitadores , Potenciais Pós-Sinápticos Inibidores , Extratos Vegetais/farmacologia , Receptores de Ácidos Lisofosfatídicos/metabolismo , Sinapses/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Cálcio/metabolismo , Masculino , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley , Receptores de Ácidos Lisofosfatídicos/agonistas , Sinapses/efeitos dos fármacos , Sinapses/fisiologia , Fosfolipases Tipo C/metabolismoRESUMO
Many patients with diabetes are at increased risk of cognitive dysfunction and dementia. Diabetes mellitus is a vascular risk factor that may increase the risk of dementia through its associations with vascular dementia. We tested whether cognitive impairment could be exacerbated in combined injury using a rat model of chronic cerebral hypoperfusion with diabetes. We also determined whether a potent inhibitor of type III phosphodiesterase could prevent the cognitive decline caused by this combined injury. We used Otsuka Long-Evans Tokushima Fatty (OLETF) rats as a model of type II diabetes (T2DM) and Long-Evans Tokushima Otsuka (LETO) rats as a control. Chronic cerebral hypoperfusion was modeled by permanent bilateral common carotid artery occlusion (BCCAO). At 24weeks, the non-diabetic and T2DM rats were randomly assigned into groups for the following experiments: analysis I (1) sham non-diabetic rats (n=8); (2) hypoperfused non-diabetic rats (n=9); (3) sham T2DM rats (n=8); (4) hypoperfused T2DM rats (n=9); analysis II- (1) sham T2DM rats without treatment (n=8); (2) cilostazol-treated T2DM rats (n=8); (3) hypoperfused T2DM rats (n=9); and (4) hypoperfused T2DM rats and cilostazol treatment (n=9). The rats were orally administered cilostazol (50mg/kg) or vehicle once a day for 2weeks after 24weeks. Rats performed Morris water maze tasks, and neuronal cell death and neuroinflammation were investigated via Western blots and histological investigation. Spatial memory impairment was exacerbated synergistically in the hypoperfused T2DM group compared with the hypoperfused non-diabetic group and sham T2DBM group (P<0.05). Compared with the control group, neuronal cell death was increased in the hippocampus of the hypoperfused T2DM group. Cilostazol, a PDE-3 inhibitor, improved the memory impairments through inhibition of neuronal cell death, activation of CREB phosphorylation and BDNF expression in the hypoperfused T2DM group. Our experimental results support the hypothesis that there are deleterious interactions between chronic cerebral hypoperfusion and T2DM. That is, metabolic diseases such as diabetes may exacerbate cognitive impairment in a rat model of vascular dementia. We also suggest that surprisingly, the phosphodiesterase III inhibitor, cilostazol may be useful for the treatment of cognitive impairment in diabetes mellitus-induced dementia. In conclusion, diabetes can aggravate cognitive dysfunction in vascular dementia, and PDE-3 inhibitors, such as cilostazol, may form the basis of a novel therapeutic strategy for diabetes-associated cognitive impairment or vascular dementia.
Assuntos
Doenças das Artérias Carótidas/complicações , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Diabetes Mellitus Tipo 2/complicações , Fármacos Neuroprotetores/uso terapêutico , Tetrazóis/uso terapêutico , Animais , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação a CREB/metabolismo , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Cilostazol , Modelos Animais de Doenças , Seguimentos , Marcação In Situ das Extremidades Cortadas , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Ratos Long-Evans , Tempo de Reação/efeitos dos fármacosRESUMO
BACKGROUND: Fructus mume (F. mume) has been used as a traditional medicine for many years in Asian countries. The present study was designed to determine the effect of a 70% ethanol extract of F. mume on white matter and hippocampal damage induced by chronic cerebral hypoperfusion. METHODS: Permanent bilateral common carotid artery occlusion (BCCAo) was performed on male Wistar rats to induce chronic cerebral hypoperfusion. Daily oral administration of F. mume (200 mg/kg) was initiated 21 days after BCCAo and continued for 42 days. The experimental groups in this study were divided into three groups: a sham-operated group, a BCCAo group, and a BCCAo group that was administered with the F. mume extract. The activation of glial cells, including microglia and astrocytes, and the levels of myelin basic protein (MBP), inflammatory mediators, Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and p38 mitogen-activated protein kinase (MAPK) phosphorylation were measured in brains from rats subjected to chronic BCCAo. RESULTS: Our results revealed that F. mume alleviates the reduction in MBP expression caused by chronic BCCAo in the white matter and the hippocampus and significantly attenuates microglial and astrocytic activation induced by chronic BCCAo in the optic tract of white matter. In addition, F. mume treatment reduced the increased expression of cyclooxygenase-2 (COX-2), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6), as well as the activation of TLR4/MyD88 and p38 MAPK signaling, in the hippocampus of rats subjected to chronic BCCAo. CONCLUSION: Taken together, our findings demonstrate that brain injury induced by chronic BCCAo is ameliorated by the anti-inflammatory effects of F. mume via inhibition of MBP degradation, microglial and astrocytic activation, increased inflammatory mediator expression, and activated intracellular signalings, including TLR4 and p38 MAPK, implying that F. mume is potentially an effective therapeutics for the treatment of vascular dementia.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Demência Vascular/metabolismo , Inflamação/prevenção & controle , Prunus , Receptor 4 Toll-Like/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Encéfalo/citologia , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Citocinas/metabolismo , Demência Vascular/prevenção & controle , Regulação para Baixo , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Proteína Básica da Mielina/metabolismo , Fosforilação/efeitos dos fármacos , Fitoterapia , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Substância Branca/efeitos dos fármacos , Substância Branca/metabolismoRESUMO
BACKGROUND: Salvia miltiorrhiza (SM), an herbal plant, is traditionally used in the treatment of cardiovascular and cerebrovascular diseases in Asian countries. SM has multiple biological effects including anti-inflammatory activity. The present study is aimed at investigating the effects of SM extract in rats with chronic cerebral hypoperfusion. METHODS: Chronic cerebral hypoperfusion was induced in male Wistar rats by permanent bilateral common carotid artery occlusion (BCCAo). The rats were divided into 3 groups: sham-control, BCCAo treated with vehicle, and BCCAo treated with SM extract. Vehicle or SM extract (200 mg/kg) were administered daily by oral gavage beginning on day 21 after BCCAo and continuing to day 42. Immunohistochemical analyses were used to measure Iba-1-positive microglia and myelin basic protein (MBP) in white matter and hippocampal tissue. In addition, the expression levels of proinflammatory cytokines, including TNF-α, IL-1ß, and IL-6, and the toll-like receptor (TLR) pathway in the hippocampus, were analyzed by western blot. RESULTS: Administration of SM extract attenuated the activation of microglial cells in the white matter and hippocampus after BCCAo. SM extract also prevented neuroinflammation after BCCAo by reducing hippocampal levels of TNF-α, IL-1ß, and IL-6, and increasing the reduced levels of MBP in the white matter and hippocampus. Further, the administration of SM extract alleviated the up-regulation of hippocampal TLR4 and myeloid differentiation primary response gene 88 (MyD88) in rats with chronic BCCAo. CONCLUSIONS: Our findings suggest that SM may be a promising therapeutic candidate in vascular dementia because of its protective effects against damage to the white matter and hippocampus after BCCAo.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Hipocampo/efeitos dos fármacos , Substâncias Protetoras/administração & dosagem , Salvia miltiorrhiza/química , Substância Branca/efeitos dos fármacos , Animais , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Hipocampo/lesões , Hipocampo/metabolismo , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Perfusão , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Substância Branca/lesões , Substância Branca/metabolismoRESUMO
Sulforaphane, an organosulfur compound present in cruciferous vegetables, has been shown to exert neuroprotective effects in experimental in vitro and in vivo models of neurodegeneration. To determine whether sulforaphane can preserve cognitive function, we examined its effects on scopolamine-induced memory impairment in mice using the Morris water maze test. Sulforaphane (10 or 50mg/kg) was administered to C57BL/6 mice by oral gavage for 14 days (days 1-14), and memory impairment was induced by intraperitoneal injection of scopolamine (1mg/kg) for 7 days (days 8-14). Mice that received scopolamine alone showed impaired learning and memory retention and considerably decreased cholinergic system reactivity in the hippocampus and frontal cortex, as indicated by a decreased acetylcholine (ACh) level and an increased acetylcholinesterase (AChE) activity. Sulforaphane significantly attenuated the scopolamine-induced memory impairment and improved cholinergic system reactivity, as indicated by an increased ACh level, decreased AChE activity, and increased choline acetyltransferase (ChAT) expression in the hippocampus and frontal cortex. These effects of sulforaphane on cholinergic system reactivity were confirmed in vitro. Sulforaphane (10 or 20µM) increased the ACh level, decreased the AChE activity, and increased ChAT expression in scopolamine-treated primary cortical neurons. These observations suggest that sulforaphane might exert a significant neuroprotective effect on cholinergic deficit and cognitive impairment.
Assuntos
Isotiocianatos/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Acetilcolina/metabolismo , Acetilcolinesterase/metabolismo , Animais , Células Cultivadas , Colina O-Acetiltransferase/metabolismo , Feminino , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Isotiocianatos/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Escopolamina , SulfóxidosRESUMO
Associating a neutral conditioned stimulus (CS) with the absence of a biologically significant unconditioned stimulus (US) confers conditioned inhibitory properties upon the CS, referred to as conditioned inhibition. Conditioned inhibition and conditioned excitation, an association of a CS with the presence of the US, are fundamental components of associative learning. While the neural substrates of conditioned excitation are well established, those of conditioned inhibition remain poorly understood. Recent research has shed light on the lateral habenula (LHb) engagement in conditioned inhibition, along with the midbrain dopaminergic neurons. This article reviews behavioral tasks conducted to assess conditioned inhibition and how experimental LHb manipulations affect performance in these tasks. These results underscore the critical role of the LHb in conditioned inhibition. Intriguingly, stress increases LHb reactivity and impairs performances in tasks consisting of a component of conditioned inhibition in animals. Dysfunction of the LHb is observed in patients with depression. The ability of an organism to perform conditioned inhibition is closely linked to altered neuronal activity in the LHb, which has implications for mental disorders. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Assuntos
Condicionamento Clássico , Depressão , Habenula , Habenula/fisiologia , Animais , Depressão/fisiopatologia , Condicionamento Clássico/fisiologia , Inibição Psicológica , Humanos , Neurônios Dopaminérgicos/fisiologia , Aprendizagem por Associação/fisiologiaRESUMO
BACKGROUND: The cardiotonic pill (CP) is a herbal medicine composed of Salvia miltiorrhiza (SM), Panax notoginseng (PN), and Dryobalanops aromatica Gaertner (DAG) that is widely used to treat cardiovascular diseases. The present experiment was conducted to examine the effects of CP on white matter and hippocampal damage induced by chronic cerebral hypoperfusion. METHODS: Chronic cerebral hypoperfusion was induced in male Wistar rats by permanent bilateral common carotid artery occlusion (BCCAo). Daily oral administration of CP (200 mg/kg) began 21 days after BCCAo and continued for 42 days. The levels of microglial activation and myelin basic protein (MBP) were measured in the white matter and hippocampus of rats with chronic BCCAo, and the expression levels of mitogen-activated protein kinases (MAPKs) and inflammatory markers such as cyclooxygenase-2, interleukin-1ß, and interleukin-6 were examined. RESULTS: MBP expression was reduced in the white matter and hippocampal regions of rats that received BCCAo. In contrast, reduced levels of MBP were not observed in BCCAo rats given CP treatments. The administration of CP alleviated microglial activation, the alteration of ERK and p38 MAPK signaling, and inflammatory mediator expression in rats with chronic BCCAo. CONCLUSION: These results suggest that CP may have protective effects against chronic BCCAo-induced white matter and hippocampal damage by inhibiting inflammatory processes including microglial activation and proinflammatory mediator expression, and downreguating the hyperphosphorylation of ERK and p38 MAPK signaling.
Assuntos
Cardiotônicos/farmacologia , Estenose das Carótidas/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Análise de Variância , Animais , Estenose das Carótidas/metabolismo , Estenose das Carótidas/fisiopatologia , Ciclo-Oxigenase 2/metabolismo , Dipterocarpaceae , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Microglia/efeitos dos fármacos , Proteína Básica da Mielina/metabolismo , Panax notoginseng , Fosforilação/efeitos dos fármacos , Ratos , Ratos Wistar , Salvia miltiorrhizaRESUMO
Recent studies have indicated that the lateral habenula (LHb) mediates the association of a conditioned stimulus (CS) with the absence of an unconditioned stimulus (US). We generated a CS-no US association using an explicit unpaired training procedure and evaluated the conditioned inhibitory properties using the modified version of the retardation-of-acquisition procedure, one of the procedures for assessing conditioned inhibition. First, rats in the unpaired group received explicit unpaired light (CS) and food (US) presentations, followed by light-food pairings. Rats in the comparison group received paired training alone. The rats in the two groups showed increased food-cup responses to light over paired training. However, rats in the unpaired group showed a slower acquisition of light and food excitatory conditioning than those in the comparison group. Light acquired conditioned inhibitory properties through explicitly unpaired training, as evidenced by its slowness. Second, we examined the effects of the LHb lesions on the decremental effects of unpaired learning on subsequent excitatory learning. Sham-operated rats exhibited decremental effects of unpaired learning on subsequent excitatory learning, while rats with LHb neurotoxic lesions did not. Third, we tested whether preexposure to the same number of lights presented in the unpaired training retarded the acquisition of subsequent excitatory conditioning. Preexposure to light did not significantly retard the acquisition of subsequent excitatory associations, with no LHb lesion effects. These findings indicate that LHb is critically involved in the association between CS and the absence of US.