RESUMO
INTRODUCTION: Epidermal keratinocytes are increasingly recognized as active participants in the sensory transduction of itch and pain, processes known to involve primary afferent glutamatergic neurons. However the role of keratinocyte glutamate signaling in sensory functioning is not fully understood. Here, we present the observation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid type glutamate receptors (AMPAR) in epidermal keratinocytes. METHODS: Immunohistochemical and in situ hybridization analyses were conducted to assess the expression of AMPAR subunits in epidermal keratinocytes in mouse and human skin samples, and in organotypic cultures of human keratinocytes. In addition, RTPCR further confirmed the expression of GluA4-containing AMPAR in epidermal keratinocytes. RESULTS: We found prominent immunolabeling (IL) for the GluA4 subunit of AMPAR in keratinocytes of glabrous and hairy skin of mouse epidermis, as well as in human epidermal keratinocytes. RTPCR confirmed Gria4 transcript expression in epidermal mouse keratinocytes. In addition, expression of GRIA4 mRNA was confirmed in epidermal human keratinocytes by in situ hybridization. Immunohistochemical studies conducted in human skin biopsies from patients with atopic dermatitis (AD) and postherpetic neuralgia (PHN) demonstrate that keratinocyte expression of GluA4 can be altered under pathological conditions. Moreover, a decrease of GluA4 expression was observed in organotypic cultures of human keratinocytes after direct application of algogenic agents. CONCLUSIONS: We provide evidence that GluA4-containing AMPAR are expressed in epidermal keratinocytes, that human pruritic and painful dermatopathologies have alterations in the keratinocyte expression levels of GluA4-containing AMPAR, and that itch and pain producing substances can directly regulate their production in keratinocytes.
RESUMO
Repeated haloperidol treatment administered to nonhuman primates (NHPs) over several months or even years leads to the gradual appearance of drug-induced dystonic reactions in the orofacial region (mouth opening, tongue protrusion or retraction, bar biting) and in the whole body (writhing of the limbs and trunk, bar grasping). The propensity of antipsychotics to induce dystonia in NHPs is not correlated with their propensity to induce catalepsy in rodents, suggesting that the two types of effects are dissociated and may represent distinct aspects of the extrapyramidal symptoms induced by antipsychotics. In view of the clear homology to clinically observed phenomena, antipsychotic-induced dystonias in antipsychotic-primed NHPs would appear to possess a high degree of translational validity. These NHP phenomena could therefore serve as a useful model for predicting the occurrence of similar abnormal movements with novel substances developed for the treatment of schizophrenia or other psychotic disorders. Moreover, the NHP dystonia model could possibly serve as a biomarker for substances that will eventually cause tardive dyskinesia in patients.
Assuntos
Antipsicóticos/efeitos adversos , Discinesia Induzida por Medicamentos/fisiopatologia , Primatas/fisiologia , Animais , Catalepsia/induzido quimicamente , Catalepsia/fisiopatologia , Modelos Animais de Doenças , Distonia/induzido quimicamente , Distonia/fisiopatologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/fisiopatologia , Agitação Psicomotora/fisiopatologia , RatosRESUMO
A non-selective antihistamine, dimebon, has recently emerged as a potential treatment for Alzheimer's disease and Huntington's disease. Dimebon exerts several effects in addition to its anti-histaminergic effect, and of particular interest is its ability to enhance cognitive function in several models. The mechanism underlying this is unknown though it has been suggested that it may be associated with its anti-cholinergic action. Dimebon has also been reported to be neuroprotective, perhaps as a result of its ability to stabilize mitochondria. We considered that these effects might impact on the well-described age-related impairment in spatial learning and therefore examined the effect of repeated administration of dimebon on performance of young and aged animals in the Morris water maze. Whereas a clear age-related deficit was observed, dimebon failed to exert any effect on performance. Similarly, dimebon exerted no effect on the age-related increase in hippocampal expression of several markers of microglial and astroglial activation. We conclude that, despite its cognitive enhancing effects in some models, dimebon failed to modulate the deficit in spatial learning in aged rats and the evidence suggests that the drug does not possess anti-inflammatory properties.
Assuntos
Gliose/tratamento farmacológico , Indóis/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Envelhecimento , Animais , Cognição/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Indóis/uso terapêutico , Masculino , Ratos , Ratos WistarRESUMO
Alterations in synaptic plasticity and neurocognitive function with age have been well documented in the literature. These changes are accompanied by modifications of neurotransmitter systems in the central nervous system (CNS). The serotonergic system in particular plays an important role in attention, alertness and cognition. Disturbances in serotonergic function have been implicated in differing neurological and neuropsychiatric disorders including depression, psychosis aggression and dementia. The serotonin receptor subtype 5HT6 is distributed within CNS regions relevant to learning and memory, including the striatum, cortex and hippocampus. We examined here the effects of acute and chronic administration of the 5HT6 receptor antagonist SB742457 on performance in a delayed non-matching-to-sample task (DNMS), which was used to identify neurocognitive differences between middle-aged (MA, 13 months) and young adult (YG, 3 months) rats. We found that MA rats have significantly lower performance in the DNMS task compared to YG rats. Acute administration of SB742457 (3 mg/kg/po) significantly improved performance of the MA rats. Chronic administration of SB742457 (3 mg/kg) reversed the age-related deficit of the MA to match their performance to that of YG rats. Furthermore, these improvements were observed for 1 week post-SB742457 treatment cessation. The acute and chronic effects of this treatment suggest that there is both an immediate effect on neurotransmitter action and potentially a longer-term modification of synaptic plasticity. Together these data indicate a role for modulation of the serotonergic system in the development of cognition-enhancing agents.
Assuntos
Envelhecimento , Transtornos Cognitivos/tratamento farmacológico , Proteínas do Tecido Nervoso/antagonistas & inibidores , Nootrópicos/uso terapêutico , Quinolinas/uso terapêutico , Receptores de Serotonina/química , Antagonistas da Serotonina/uso terapêutico , Sulfonas/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Transtornos Cognitivos/metabolismo , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Nootrópicos/administração & dosagem , Quinolinas/administração & dosagem , Ratos , Ratos Wistar , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/administração & dosagem , Sulfonas/administração & dosagem , Transmissão Sináptica/efeitos dos fármacos , Análise e Desempenho de Tarefas , Fatores de TempoRESUMO
Preclinical testing requires rapid and reliable evaluation of the main in vivo effects of novel test substances usually in rodents. Nevertheless, the techniques primarily used up to now involve either automated measurement of motor activity or direct observation of behavioral effects by extensively trained investigators. The advantages of these approaches are respectively high-throughput and comprehensive behavioral assessment. Nevertheless, motor activity is only one aspect of animal behavior and it cannot predict the full neurobehavioral profile of a substance, whereas direct observation is time-consuming. There is thus a need for novel approaches that combine the advantages of both automatic detection and comprehensive behavioral analysis. In the present study, we used the LABORAS™ system to analyze motor and non-motor behavior in rats administered various stimulant substances with or without known psychotomimetic properties or abuse liability (amphetamine, cocaine dizocilpine (MK-801), ketamine, modafinil and nicotine). The data show that LABORAS™ clearly detects the stimulating effects on motor behaviors of amphetamine, cocaine, dizocilpine and ketamine in a dose- and time-dependent manner. Differential effects of these test substances on non-motor behaviors, such as grooming, eating and drinking could also be detected. Nicotine displayed only slight stimulating effects on locomotion, whereas modafinil was virtually without effect on the behaviors evaluated by the system. These data with different stimulant substances suggest that LABORAS™ presents an advantage over classical methods performing automated measurements restricted to locomotion. Furthermore, the procedure is considerably more rapid than behavioral observation procedures. Characterization of the behavioral profile of test substances using LABORAS™ should therefore accelerate preclinical studies. In addition, the multi-faceted parameters measured by LABORAS™ permit a more detailed comparison of the behavioral profiles of novel substances with standard reference substances, thereby providing important indicators for orienting further substance evaluation and supporting drug development.
Assuntos
Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Psicotrópicos/farmacologia , Animais , Automação , Compostos Benzidrílicos/farmacologia , Cocaína/farmacologia , Dextroanfetamina/farmacologia , Maleato de Dizocilpina/farmacologia , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/estatística & dados numéricos , Comportamento Alimentar/efeitos dos fármacos , Asseio Animal/efeitos dos fármacos , Ketamina/farmacologia , Masculino , Modafinila , Atividade Motora/efeitos dos fármacos , Nicotina/farmacologia , Ratos , Ratos WistarRESUMO
Neuroinflammation is a significant and consistent feature of many neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). The greatest risk factor for neurodegenerative disorders is age and a proinflammatory phenotype in the aged brain is believed to contribute to these neurodegenerative conditions. In animal models, neuroinflammatory changes, characterized by increased microglial activation, have been associated with a loss of synaptic plasticity and here we show that treatment of aged rats with the PPARγ agonist, rosiglitazone, modulates the inflammatory changes and restores synaptic function. The evidence presented highlights an important role for astrocytes in inducing inflammatory changes and suggests that the age-related astrogliosis and astrocytosis is responsible for the increase in the proinflammatory cytokine, tumor necrosis factor alpha (TNF-α). Magnetic resonance (MR) imaging revealed an age-related increase in T1 relaxation time and, importantly, treatment of aged rats with rosiglitazone reversed the age-related increases in astrogliosis and astrocytosis, TNF-α concentration and T1 relaxation time. The evidence indicates that the site of action for rosiglitazone is endothelial cells, and suggests that its effect on astrocytes is secondary to its effect on endothelial cells.
Assuntos
Envelhecimento/patologia , Envelhecimento/fisiologia , Astrócitos/patologia , Astrócitos/fisiologia , Células Endoteliais/efeitos dos fármacos , Hipocampo/citologia , Hipoglicemiantes/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Tiazolidinedionas/farmacologia , Animais , Células Cultivadas , Hipocampo/patologia , Hipocampo/fisiopatologia , Mediadores da Inflamação/metabolismo , Imageamento por Ressonância Magnética , Masculino , PPAR gama/agonistas , Ratos , Ratos Wistar , Rosiglitazona , Fator de Necrose Tumoral alfa/metabolismoRESUMO
As an antidiabetic agent, rosiglitazone (ROSI) binds and activates peroxisome proliferator-activator receptor gamma (PPARγ), altering the expression of genes involved in glucose uptake and disposal, ultimately affecting glucose regulation. ROSI might therefore be a potential treatment to ameliorate age-related decline in cognitive function, particularly on an insulin-resistant background, where improvements in peripheral insulin sensitivity and central nervous system (CNS) glucose utilization may facilitate recovery of cognitive function. We therefore examined the amelioration potential of ROSI for neurocognitive deficits resulting from aging in an animal model. Behaviorally, acute and chronic ROSI treatments enhanced acquisition of learning in the water plus maze, a modified version of the Morris water maze task. In parallel, restoration of synaptic plasticity in the dentate gyrus of ROSI-treated middle-aged rats was evident after a single dose intake. Additionally, the spatial receptive fields of hippocampal CA1 place cells were significantly improved by chronic ROSI administration. ROSI treatment reversed basal plasma insulin abnormalities and increased hippocampal glucose transporter (GLUT)-3 expression in middle-aged rats. Taken together, these results suggest that ROSI modulates hippocampal circuitry effectively to promote an improvement in cognitive function, possibly via a glucose transporter-3 mechanism.
Assuntos
Hipocampo/citologia , Hipoglicemiantes/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Neurônios/efeitos dos fármacos , Tiazolidinedionas/farmacologia , Envelhecimento/efeitos dos fármacos , Análise de Variância , Animais , Biofísica , Estimulação Elétrica , Ensaio de Imunoadsorção Enzimática , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 3/genética , Transportador de Glucose Tipo 3/metabolismo , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Rosiglitazona , Fatores de TempoRESUMO
Release of interleukin (IL)-1ß from immunocompetent cells requires formation of the NACHT, LLR and PYD domains-containing protein 3 (NLRP3) inflammasome and caspase 1 activation. Adenosine 5'-triphosphate (ATP), acting on the P2X(7) receptor, is one factor that stimulates inflammasome assembly. We show that a novel specific P2X(7) receptor antagonist, GSK1370319A, inhibits ATP-induced increase in IL-1ß release and caspase 1 activation in lipopolysaccharide (LPS)-primed mixed glia by blocking assembly of the inflammasome in a pannexin 1-dependent manner. GSK1370319A also inhibits ATP-induced subregion-specific neuronal loss in hippocampal organotypic slice cultures, which is dependent on its ability to prevent inflammasome assembly in glia. Significantly, GSK1370319A attenuates age-related deficits in long-term potentiation (LTP) and inhibits the accompanying age-related caspase 1 activity. We conclude that inhibiting P2X(7) receptor-activated NLRP3 inflammasome formation and the consequent IL-1ß release from glia preserve neuronal viability and synaptic activity.
Assuntos
Inflamassomos/metabolismo , Neuroglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Pirrolidinas/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Trifosfato de Adenosina/farmacologia , Animais , Proteínas de Transporte , Células Cultivadas , Técnicas de Cocultura , Conexinas/genética , Conexinas/metabolismo , Inflamassomos/genética , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neuroglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores Citoplasmáticos e Nucleares/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The 5-hydroxytryptamine7 (5-HT7) receptor is a G-protein coupled receptor for serotonin that has been implicated in the pathophysiology of psychiatric and neurological disorders including anxiety, depression and schizophrenia. A number of studies have attempted to evaluate the potential role of the 5-HT7 receptor in schizophrenia by utilising genetic or pharmacological tools but to date these have provided conflicting results. Here we investigate the effect of a selective 5-HT7 receptor antagonist, SB-269970, in in vivo psychosis and cognition models and relate efficacy to brain exposures of the compound. SB-269970 significantly attenuated amphetamine-induced rearing and circling in rats. A similar effect was observed in an N-methyl d-aspartic acid (NMDA) receptor antagonist driven psychosis model, where SB-269970 significantly reversed phencyclidine-induced hyperlocomotion, rearing and circling; although the effect was not as robust as with the 5-HT2a receptor antagonist positive control, MDL100,907. SB-269970 also attenuated a temporal deficit in novel object recognition (NOR), indicative of an improvement in recognition memory. Pharmacokinetic analysis of plasma and brain samples taken after behavioural testing confirmed that efficacy was achieved at doses and pre-treatment times where receptor occupancy was substantial. These findings highlight the anti-psychotic and pro-cognitive potential of 5-HT7 receptor antagonists and warrant further studies to explore their therapeutic potential in schizophrenia.
Assuntos
Cognição/efeitos dos fármacos , Fenóis/farmacologia , Transtornos Psicóticos/tratamento farmacológico , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Sulfonamidas/farmacologia , Anfetamina/antagonistas & inibidores , Anfetamina/farmacologia , Animais , Animais não Endogâmicos , Modelos Animais de Doenças , Fluorbenzenos/farmacologia , Fluorbenzenos/uso terapêutico , Locomoção/efeitos dos fármacos , Masculino , Fenciclidina/antagonistas & inibidores , Fenciclidina/farmacologia , Fenóis/farmacocinética , Fenóis/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos , Antagonistas da Serotonina/farmacocinética , Antagonistas da Serotonina/uso terapêutico , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêuticoRESUMO
Nicotinic acetylcholine receptors mediate fast cholinergic modulation of glutamatergic transmission and synaptic plasticity. Here we investigated the effects of subtype selective activation of the α7 nicotinic acetylcholine receptors on hippocampal transmission and the inhibition of synaptic long-term potentiation by the Alzheimer's disease associated amyloid ß-protein (Aß). The α7 nicotinic acetylcholine receptor agonist "compound A" ((R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl))thiophene-2-carboxamide) induced a rapid-onset persistent enhancement of synaptic transmission in the dentate gyrus in vitro. Consistent with a requirement for activation of α7 nicotinic acetylcholine receptors, the type II α7-selective positive allosteric modulator PheTQS ((3aR, 4S, 9bS)-4-(4-methylphenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) potentiated, and the antagonist methyllycaconitine (MLA) prevented the persistent enhancement. Systemic injection of the agonist also induced a similar MLA-sensitive persistent enhancement of synaptic transmission in the CA1 area in vivo. Remarkably, although compound A did not affect control long-term potentiation (LTP) in vitro, it prevented the inhibition of LTP by Aß1-42 and this effect was inhibited by MLA. These findings strongly indicate that activation of α7 nicotinic acetylcholine receptors is sufficient to persistently enhance hippocampal synaptic transmission and to overcome the inhibition of LTP by Aß.
Assuntos
Peptídeos beta-Amiloides/farmacologia , Hipocampo/citologia , Hipocampo/fisiologia , Potenciação de Longa Duração/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Receptores Nicotínicos/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Animais , Interações Medicamentosas , Hipocampo/efeitos dos fármacos , Técnicas In Vitro , Masculino , Agonistas Nicotínicos/farmacologia , Ratos , Ratos Wistar , Sulfonamidas/química , Sulfonamidas/farmacologia , Tiofenos/química , Tiofenos/farmacologia , Receptor Nicotínico de Acetilcolina alfa7RESUMO
The peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor, thought to play a role in energy metabolism, glucose homeostasis and microglia-mediated neuroinflammation. A novel benzimidazole series of centrally penetrant PPARγ partial agonists has been identified. The optimization of PPARγ activity and in vivo pharmacokinetics leading to the identification of GSK1997132B a potent, metabolically stable and centrally penetrant PPARγ partial agonist, is described.
Assuntos
Benzimidazóis/farmacologia , Descoberta de Drogas , PPAR gama/antagonistas & inibidores , Benzimidazóis/síntese química , Benzimidazóis/química , Relação Dose-Resposta a Droga , Estrutura Molecular , PPAR gama/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Manipulation of diet such as increasing the level of fat or inducing insulin resistance has been shown to exacerbate the pathology in several animal models of neurological disease. Caloric restriction, however, has been demonstrated to extend the life span of many organisms. Reduced calorie consumption appears to increase the resistance of neurons to intracellular and extracellular stress and consequently improves the behavioural phenotype in animal models of neurological diseases, such as Alzheimer's disease. We review the evidence from a variety of mouse models that diet is a risk factor that can significantly contribute to the development of neurological diseases.
Assuntos
Restrição Calórica , Dieta , Modelos Animais de Doenças , Doenças do Sistema Nervoso/fisiopatologia , Animais , Ingestão de Energia , Humanos , CamundongosRESUMO
In a recent clinical study, the thiazolidinedione (TZD) pioglitazone (Actos was reported to preserve cognitive function in patients with mild to moderate Alzheimer's disease and type II diabetes mellitus. TZDs are agonists of the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPARgamma), are peripheral insulin sensitizers, and have recently been reported to increase mitochondrial biogenesis in the central nervous system and dendritic spine density. We report a transcriptional profile of the TZD pioglitazone and the non-TZD PPARgamma agonist GW347845 in primary cortical culture. We observed that pioglitazone, but not GW347845, increased cholesterol biosynthetic and lipogenic gene expression after 6 h, and the expression of the cholesterol efflux transporters Abca1 and Abcg1 after 24 h. Co-treatment of pioglitazone with the PPARgamma antagonist GW9662 did not significantly reduce these effects, suggesting a PPARgamma-independent mechanism. These findings suggest a novel effect of TZDs in neurons that may be of relevance as a novel approach against Alzheimer's disease.
Assuntos
Hipoglicemiantes/farmacologia , Neurônios/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Tiazolidinedionas/farmacologia , Regulação para Cima/efeitos dos fármacos , Animais , Células Cultivadas , Córtex Cerebral/citologia , Colesterol/biossíntese , Colesterol/genética , Embrião de Mamíferos , Inibidores Enzimáticos/farmacologia , Perfilação da Expressão Gênica/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , PPAR gama/antagonistas & inibidores , Pioglitazona , Ratos , Ratos Sprague-Dawley , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Fatores de TempoRESUMO
Chronic inflammation is known to occur in the brains of Alzheimer's Disease (AD) patients, including the presence of activated microglia close to amyloid plaques. We utilised real time autoradiography and immunohistochemistry to investigate microglial activation and the potential anti-inflammatory effects of PPARgamma agonists in the Thy-1 APP695swe/Thy-1 PS-1.M146V (TASTPM) overexpressing transgenic mouse model of AD. An age dependent increase in specific [3H](R)-PK11195 binding to peripheral benzodiazepine receptors (PBR)/translocator protein (18 kDa) (TSPO) was observed in the cortex of TASTPM mice compared to wild type mice, indicative of microglial activation. This was consistent with immunohistochemical data showing age-dependent increases in CD68 immunoreactivity co-localised with amyloid beta (Abeta) deposits. In 10 month old TASTPM mice, pioglitazone (20 mg/kg) and ciglitazone (50 mg/kg) significantly reduced [3H](R)-PK11195 and [3H]DPA-713 binding in cortex and hippocampus, indicative of reduced microglial activation. In AD brain, significant [3H](R)-PK11195 and [3H]DPA-713 binding was observed across all stages of the disease. These results support the use of PBR/TSPO autoradiography in TASTPM mice as a functional readout of microglial activation to assess anti-inflammatory drugs prior to evaluation in AD patients.
Assuntos
Mapeamento Encefálico , Córtex Cerebral/efeitos dos fármacos , PPAR gama/agonistas , Receptores de GABA-A/metabolismo , Receptores de GABA/metabolismo , Acetamidas/metabolismo , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Autorradiografia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Feminino , Humanos , Isoquinolinas/farmacologia , Masculino , Camundongos , Camundongos Transgênicos , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Fragmentos de Peptídeos/metabolismo , Pioglitazona , Presenilina-1/genética , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Pirazóis/metabolismo , Pirimidinas/metabolismo , Tiazolidinedionas/farmacologia , Fatores de TempoRESUMO
Alzheimer's disease (AD) is a devastating neurological condition characterized by a progressive decline in cognitive performance accompanied by behavioral and psychological syndromes, such as depression and psychosis. The neurochemical correlates of these clinical manifestations now appear to involve dysfunctions of multiple neurotransmitter pathways. Because of the extensive serotonergic denervation that has been observed in the AD brain and the important role played by serotonin (5-HT) in both cognition and behavioral control, this neurotransmitter system has become a focus of concerted research efforts to identify new treatments for AD. 5-HT exerts its diverse physiological and pharmacological effects through actions on multiple receptor subtypes. One of the newest members of this family is the 5-HT6 receptor, a subtype localized almost exclusively in the CNS, predominating in brain regions associated with cognition and behavior. With the subsequent development of selective 5-HT6 receptor antagonists, preclinical studies in rodents and primates have elucidated the function of this receptor subtype in more detail. It is increasingly clear that blockade of 5-HT6 receptors leads to an improvement of cognitive performance in a wide variety of learning and memory paradigms and also results in anxiolytic and antidepressant-like activity. These actions are largely underpinned by enhancements of cholinergic, glutamatergic, noradrenergic, and dopaminergic neurotransmission, together with learning-associated neuronal remodeling. A preliminary report that the cognitive enhancing properties of a 5-HT6 receptor antagonist (namely, SB-742457) extends into AD sufferers further highlights the therapeutic promise of this mechanistic approach.
Assuntos
Doença de Alzheimer/complicações , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Receptores de Serotonina/fisiologia , Antagonistas da Serotonina/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Animais , HumanosRESUMO
A beam-walking apparatus has been evaluated for its ability to detect motor impairments in mice acutely treated with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg, s.c., single or double administration). Mice subjected to MPTP lesioning showed deficits in motor performance on the beam-walking task, for up to 6 days post-MPTP administration, as compared to saline-treated controls. In addition, MPTP-treated mice were detected to have a marked depletion in striatal dopamine levels and a concomitant reduction in substantia nigra (SN) tyrosine hydroxylase (TH) immunoreactivity, at 7 days post-MPTP administration, indicative of dopaminergic neuronal loss. Pre-administration of the potent MAO-B inhibitor R-(-)-deprenyl at 3 or 10 mg/kg, 30 min, s.c, significantly inhibited the MPTP-induced reduction in SN TH-immunoreactivity, striatal dopamine depletions and impairments in mouse motor function. The data described in the present study provides further evidence that functional deficits following an acute MPTP dosing schedule in mice can be quantified and are related to nigro-striatal dopamine function.
Assuntos
Encéfalo/fisiopatologia , Dopamina/deficiência , Etologia/instrumentação , Transtornos Neurológicos da Marcha/diagnóstico , Neurofarmacologia/instrumentação , Transtornos Parkinsonianos/diagnóstico , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/efeitos adversos , Animais , Encéfalo/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Corpo Estriado/fisiopatologia , Relação Dose-Resposta a Droga , Etologia/métodos , Transtornos Neurológicos da Marcha/fisiopatologia , Transtornos Neurológicos da Marcha/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidores da Monoaminoxidase/uso terapêutico , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Neurofarmacologia/métodos , Transtornos Parkinsonianos/fisiopatologia , Transtornos Parkinsonianos/prevenção & controle , Valor Preditivo dos Testes , Selegilina/uso terapêutico , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/fisiopatologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
In the light of accumulating evidence for the occurrence of spontaneous cortical spreading depression and peri-infarct depolarizations in the human brain injured by trauma or aneurysmal subarachnoid haemorrhage, we used DC electrode recording and laser speckle imaging to study the relationship between depolarization events and perfusion in the ischaemic, gyrencephalic brain. In 14 adult male cats anaesthetized with chloralose, one cerebral hemisphere was exposed and the middle cerebral artery occluded. Surface cortical perfusion in core and penumbral territories was imaged semiquantitatively at intervals of 13 s for 4 h. Cortical surface DC potential was recorded. Time interval between changes in DC potential and in perfusion was examined, and this comparison was repeated using microelectrodes for DC potential in five similar experiments in a second laboratory. Mean pre-occlusion perfusion was 11707 +/- 4581 units (equivalent to CBF (cerebral blood flow) approximately 40.5 +/- SD 14.4 ml/100 g/min), and fell on occlusion to 5318 +/- 2916 (CBF approximately 17.1 +/- 8.3), 5291 +/- 3407 (CBF approximately 17.0 +/- 10.1), and 6711 +/- 3271 (CBF approximately 22.2 +/- 9.6), quickly recovering to 8704 +/- 4581 (CBF approximately 29.5 +/- 14.4), 9741 +/- 4499 (CBF approximately 33.3 +/- 14.1) and 10 314 +/- 3762 (CBF approximately 35.4 +/- 11.4) on the core, intermediate and outer penumbral gyri, respectively. Mean perfusion later fell secondarily on core and intermediate gyri but, overall, was preserved on the outer (upper level of perfusion) gyrus during the period of observation. Pattern and severity of transient changes in perfusion associated with depolarization events varied with gyral location; falls in perfusion were sometimes profound and irreversible, and followed rather than preceded depolarization. In this model of occlusive stroke, reductions in perfusion linked to peri-infarct depolarization events contribute to secondary deterioration in penumbral areas. The findings suggest that such events play a central rather than a subsidiary role in cerebral infarction in the gyrencephalic brain.
Assuntos
Isquemia Encefálica/fisiopatologia , Córtex Cerebral/fisiopatologia , Circulação Cerebrovascular/fisiologia , Infarto da Artéria Cerebral Média/fisiopatologia , Potenciais de Ação/fisiologia , Animais , Gasometria , Gatos , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Modelos Animais de Doenças , Processamento de Imagem Assistida por Computador/métodos , Masculino , Microcirculação , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo , Vasoconstrição/fisiologiaRESUMO
Rosiglitazone was found to simulate mitochondrial biogenesis in mouse brain in an apolipoprotein (Apo) E isozyme-independent manner. Rosiglitazone induced both mitochondrial DNA (mtDNA) and estrogen-stimulated related receptor alpha (ESRRA) mRNA, a key regulator of mitochondrial biogenesis. Transcriptomics and proteomics analysis suggested the mitochondria produced in the presence of human ApoE3 and E4 were not as metabolically efficient as those in the wild type or ApoE knockout mice. Thus, we propose that PPARgamma agonism induces neuronal mitochondrial biogenesis and improves glucose utilization leading to improved cellular function and provides mechanistic support for the improvement in cognition observed in treatment of Alzheimer's patients with rosiglitazone.
Assuntos
Encéfalo/efeitos dos fármacos , DNA Mitocondrial/genética , Hipoglicemiantes/farmacologia , Mitocôndrias/efeitos dos fármacos , Biogênese de Organelas , RNA Mensageiro/genética , Receptores de Estrogênio/genética , Tiazolidinedionas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Animais , Apolipoproteína E3/metabolismo , Apolipoproteína E4/metabolismo , Apolipoproteínas E/genética , Cognição/efeitos dos fármacos , Lobo Frontal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , PPAR gama/agonistas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rosiglitazona , Tiazolidinedionas/uso terapêutico , Receptor ERRalfa Relacionado ao EstrogênioRESUMO
BACKGROUND: Data indicates anti-oxidant, anti-inflammatory and pro-cognitive properties of noradrenaline and analyses of post-mortem brain of Alzheimer's disease (AD) patients reveal major neuronal loss in the noradrenergic locus coeruleus (LC), the main source of CNS noradrenaline (NA). The LC has projections to brain regions vulnerable to amyloid deposition and lack of LC derived NA could play a role in the progression of neuroinflammation in AD. Previous studies reveal that intraperitoneal (IP) injection of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) can modulate neuroinflammation in amyloid over-expressing mice and in one study, DSP-4 exacerbated existing neurodegeneration. METHODS: TASTPM mice over-express human APP and beta amyloid protein and show age related cognitive decline and neuroinflammation. In the present studies, 5 month old C57/BL6 and TASTPM mice were injected once monthly for 6 months with a low dose of DSP-4 (5 mg kg-1) or vehicle. At 8 and 11 months of age, mice were tested for cognitive ability and brains were examined for amyloid load and neuroinflammation. RESULTS: At 8 months of age there was no difference in LC tyrosine hydroxylase (TH) across all groups and cortical NA levels of TASTPM/DSP-4, WT/Vehicle and WT/DSP-4 were similar. NA levels were lowest in TASTPM/Vehicle. Messenger ribonucleic acid (mRNA) for various inflammatory markers were significantly increased in TASTPM/Vehicle compared with WT/Vehicle and by 8 months of age DSP-4 treatment modified this by reducing the levels of some of these markers in TASTPM. TASTPM/Vehicle showed increased astrocytosis and a significantly larger area of cortical amyloid plaque compared with TASTPM/DSP-4. However, by 11 months, NA levels were lowest in TASTPM/DSP-4 and there was a significant reduction in LC TH of TASTPM/DSP-4 only. Both TASTPM groups had comparable levels of amyloid, microglial activation and astrocytosis and mRNA for inflammatory markers was similar except for interleukin-1 beta which was increased by DSP-4. TASTPM mice were cognitively impaired at 8 and 11 months but DSP-4 did not modify this. CONCLUSION: These data reveal that a low dose of DSP-4 can have varied effects on the modulation of amyloid plaque deposition and neuroinflammation in TASTPM mice dependent on the duration of dosing.
Assuntos
Precursor de Proteína beta-Amiloide/genética , Benzilaminas/administração & dosagem , Mutação , Norepinefrina/biossíntese , Placa Amiloide/efeitos dos fármacos , Presenilina-1/genética , Presenilina-1/metabolismo , Transgenes/efeitos dos fármacos , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Benzilaminas/toxicidade , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Esquema de Medicação , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Norepinefrina/antagonistas & inibidores , Norepinefrina/genética , Placa Amiloide/genética , Placa Amiloide/metabolismo , Presenilina-1/antagonistas & inibidoresRESUMO
The automated behavioural apparatus, LABORAS (Laboratory Animal Behaviour Observation, Registration and Analysis System), has been further validated with respect to the ability of the system to detect behavioural impairments in mice, following various dopaminergic manipulations. Initially data were obtained from mice administered with amphetamine, haloperidol, SCH23390, apomorphine and L-DOPA, with the focus on locomotor and grooming activities. The data recorded by LABORAS on administration of these pharmacological tool compounds, is comparable with published findings using standard LMA systems and conventional observer methods. In addition the home cage behaviour of mice administered with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) using an acute dosing regimen was also investigated. In LABORAS, mice subjected to MPTP lesioning showed deficits in spontaneous motor activity at day 6-7 post-MPTP administration, over a 24 h test period, as compared to saline treated controls. The data captured and analysed using LABORAS, suggests that the automated system is able to detect both pharmacologically and lesion-induced changes in behaviour of mice, reliably and efficiently.