RESUMO
N-methyl-D-aspartate (NMDA) receptor hypofunctionality is a well-studied hypothesis for schizophrenia pathophysiology, and daily dosing of the NMDA receptor co-agonist, D-serine, in clinical trials has shown positive effects in patients. Therefore, inhibition of D-amino acid oxidase (DAAO) has the potential to be a new therapeutic approach for the treatment of schizophrenia. TAK-831 (luvadaxistat), a novel, highly potent inhibitor of DAAO, significantly increases D-serine levels in the rodent brain, plasma, and cerebrospinal fluid. This study shows luvadaxistat to be efficacious in animal tests of cognition and in a translational animal model for cognitive impairment in schizophrenia. This is demonstrated when luvadaxistat is dosed alone and in conjunction with a typical antipsychotic. When dosed chronically, there is a suggestion of change in synaptic plasticity as seen by a leftward shift in the maximum efficacious dose in several studies. This is suggestive of enhanced activation of NMDA receptors in the brain and confirmed by modulation of long-term potentiation after chronic dosing. DAAO is highly expressed in the cerebellum, an area of increasing interest for schizophrenia, and luvadaxistat was shown to be efficacious in a cerebellar-dependent associative learning task. While luvadaxistat ameliorated the deficit seen in sociability in two different negative symptom tests of social interaction, it failed to show an effect in endpoints of negative symptoms in clinical trials. These results suggest that luvadaxistat potentially could be used to improve cognitive impairment in patients with schizophrenia, which is not well addressed with current antipsychotic medications.
Assuntos
Antipsicóticos , Esquizofrenia , Animais , Oxirredutases , Roedores , Esquizofrenia/tratamento farmacológico , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Inibidores Enzimáticos/farmacologia , Cognição , Serina/farmacologia , Aminoácidos , Receptores de N-Metil-D-AspartatoRESUMO
Narcolepsy type 1 (NT1) is a sleep disorder caused by a loss of orexinergic neurons. Narcolepsy type 2 (NT2) is heterogeneous; affected individuals typically have normal orexin levels. Following evaluation in mice, the effects of the orexin 2 receptor (OX2R)-selective agonist danavorexton were evaluated in single- and multiple-rising-dose studies in healthy adults, and in individuals with NT1 and NT2. In orexin/ataxin-3 narcolepsy mice, danavorexton reduced sleep/wakefulness fragmentation and cataplexy-like episodes during the active phase. In humans, danavorexton administered intravenously was well tolerated and was associated with marked improvements in sleep latency in both NT1 and NT2. In individuals with NT1, danavorexton dose-dependently increased sleep latency in the Maintenance of Wakefulness Test, up to the ceiling effect of 40 min, in both the single- and multiple-rising-dose studies. These findings indicate that OX2Rs remain functional despite long-term orexin loss in NT1. OX2R-selective agonists are a promising treatment for both NT1 and NT2.
Assuntos
Estimulantes do Sistema Nervoso Central , Narcolepsia , Receptores de Orexina , Adulto , Animais , Ataxina-3/genética , Ataxina-3/metabolismo , Cataplexia/tratamento farmacológico , Cataplexia/genética , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Modelos Animais de Doenças , Humanos , Camundongos , Narcolepsia/tratamento farmacológico , Narcolepsia/genética , Neurônios/metabolismo , Receptores de Orexina/agonistas , Receptores de Orexina/genética , Receptores de Orexina/metabolismo , Receptores de Orexina/uso terapêutico , Orexinas/genética , Orexinas/metabolismo , Fenótipo , Vigília/efeitos dos fármacos , Vigília/genéticaRESUMO
Chimeric antigen receptor (CAR)-expressing T cells now offer an effective treatment option for people with previously refractory B cell malignancies and are under development for a wide range of other tumours. However, neurological toxicity is a common complication of CAR-T cell therapy, seen in over 50% of recipients in some cohorts. Since 2018, the term immune effector cell-associated neurotoxicity syndrome (ICANS) has been used to describe and grade neurotoxicity seen after CAR-T cells and other similar therapies. ICANS following CAR-T therapy is usually self-limiting but can necessitate admission to the intensive care unit and is rarely fatal. As CAR-T therapies enter routine clinical practice, it is important for neurologists to be aware of the nature of neurological complications. Here, we summarise the clinical manifestations, mechanisms, investigations and recommended treatment of CAR-T-related neurotoxicity, focusing on the licensed CD19 products.
Assuntos
Doenças do Sistema Nervoso , Síndromes Neurotóxicas , Receptores de Antígenos Quiméricos , Antígenos CD19 , Humanos , Imunoterapia Adotiva , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/terapia , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/terapiaRESUMO
The paucity of novel drugs for neuropsychiatric indications contrasts with the remarkable recent advances in neuroscience research. We have identified 5 challenges the field needs to address and recommend potential solutions. First, we need to drive discovery efforts based on human data. Second, we need to think more carefully about animal models, embracing them as tools to test pathophysiological alterations. Third, we need to develop strategies to select more homogenous groups of patients in our clinical trials. Fourth, we need to develop and validate translational biomarkers, which can be used for pharmacodynamic assessments as well as for patient selection. Fifth, we need to adopt more reliable and objective measures to capture clinical efficacy. The tools that will allow these solutions to be implemented may already be in place but not routinely adopted or are still being developed. Overall, a change in mindset to adopt science- and data-driven paths is needed.
Assuntos
Descoberta de Drogas , Psicotrópicos , Animais , Biomarcadores , Descoberta de Drogas/métodos , Humanos , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/metabolismo , Neurociências/métodos , Psicotrópicos/farmacocinética , Psicotrópicos/farmacologia , Psicotrópicos/uso terapêutico , Pesquisa Translacional Biomédica/métodosRESUMO
Induced pluripotent stem (iPS) cells offer the exciting opportunity for modeling neurological disorders in vitro in the context of a human genetic background. While significant progress has been made in advancing the use of iPS cell-based disease models, there remains an unmet need to characterize the electrophysiological profile of individual neurons with sufficient throughput to enable statistically robust assessment of disease phenotypes and pharmacological modulation. Here, we describe the Optopatch platform technology that utilizes optogenetics to both stimulate and record action potentials (APs) from human iPS cell-derived excitatory neurons with similar information content to manual patch clamp electrophysiology, but with ~ 3 orders of magnitude greater throughput. Cortical excitatory neurons were produced using the NGN2 transcriptional programming approach and cultured in the presence of rodent glial cells. Characterization of the neuronal preparations using immunocytochemistry and qRT-PCR assays reveals an enrichment of neuronal and glutamatergic markers as well as select ion channels. We demonstrate the scale of our intrinsic cellular excitability assay using pharmacological assessment with select ion channel modulators quinidine and retigabine, by measuring changes in both spike timing and waveform properties. The Optopatch platform in human iPS cell-derived cortical excitatory neurons has the potential for detailed phenotype and pharmacology evaluation, which can serve as the basis of cellular disease model exploration for drug discovery and phenotypic screening efforts.
Assuntos
Diferenciação Celular/fisiologia , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Neurais/citologia , Neurônios/citologia , Potenciais de Ação/fisiologia , Células Cultivadas , Fenômenos Eletrofisiológicos/fisiologia , Humanos , Optogenética/métodosRESUMO
Approximately one-quarter of patients with mitochondrial disease experience epilepsy. Their epilepsy is often severe and resistant towards conventional antiepileptic drugs. Despite the severity of this epilepsy, there are currently no animal models available to provide a mechanistic understanding of mitochondrial epilepsy. We conducted neuropathological studies on patients with mitochondrial epilepsy and found the involvement of the astrocytic compartment. As a proof of concept, we developed a novel brain slice model of mitochondrial epilepsy by the application of an astrocytic-specific aconitase inhibitor, fluorocitrate, concomitant with mitochondrial respiratory inhibitors, rotenone and potassium cyanide. The model was robust and exhibited both face and predictive validity. We then used the model to assess the role that astrocytes play in seizure generation and demonstrated the involvement of the GABA-glutamate-glutamine cycle. Notably, glutamine appears to be an important intermediary molecule between the neuronal and astrocytic compartment in the regulation of GABAergic inhibitory tone. Finally, we found that a deficiency in glutamine synthetase is an important pathogenic process for seizure generation in both the brain slice model and the human neuropathological study. Our study describes the first model for mitochondrial epilepsy and provides a mechanistic insight into how astrocytes drive seizure generation in mitochondrial epilepsy.
Assuntos
Astrócitos/patologia , Astrócitos/fisiologia , Epilepsia do Lobo Temporal/patologia , Mitocôndrias/patologia , Doenças Mitocondriais/patologia , Convulsões/patologia , Adulto , Idoso , Animais , Epilepsia do Lobo Temporal/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Convulsões/metabolismo , Adulto JovemRESUMO
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by the degeneration of upper and lower motor neurons. Defects in axonal transport have been observed pre-symptomatically in the SOD1G93A mouse model of ALS, and have been proposed to play a role in motor neuron degeneration as well as in other pathologies of the nervous system, such as Alzheimer's disease and hereditary neuropathies. In this study, we screen a library of small-molecule kinase inhibitors towards the identification of pharmacological enhancers of the axonal retrograde transport of signalling endosomes, which might be used to normalise the rate of this process in diseased neurons. Inhibitors of p38 mitogen-activated protein kinases (p38 MAPK) were identified in this screen and were found to correct deficits in axonal retrograde transport of signalling endosomes in cultured primary SOD1G93A motor neurons. In vitro knockdown experiments revealed that the alpha isoform of p38 MAPK (p38 MAPKα) was the sole isoform responsible for SOD1G93A-induced transport deficits. Furthermore, we found that acute treatment with p38 MAPKα inhibitors restored the physiological rate of axonal retrograde transport in vivo in early symptomatic SOD1G93A mice. Our findings demonstrate the pathogenic effect of p38 MAPKα on axonal retrograde transport and identify a potential therapeutic strategy for ALS.
Assuntos
Esclerose Lateral Amiotrófica/enzimologia , Esclerose Lateral Amiotrófica/patologia , Transporte Axonal , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Acetilcarnitina/farmacologia , Animais , Transporte Axonal/efeitos dos fármacos , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Membro Posterior/efeitos dos fármacos , Membro Posterior/fisiopatologia , Imidazóis/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/metabolismo , Músculos/efeitos dos fármacos , Músculos/fisiopatologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Quinazolinonas/farmacologia , Receptores de Fator de Crescimento Neural/metabolismo , Superóxido Dismutase/metabolismo , Toxina Tetânica/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND: We investigated a family that presented with an infantile-onset chorea-predominant movement disorder, negative for NKX2-1, ADCY5, and PDE10A mutations. METHODS: Phenotypic characterization and trio whole-exome sequencing was carried out in the family. RESULTS: We identified a homozygous mutation affecting the GAF-B domain of the 3',5'-cyclic nucleotide phosphodiesterase PDE2A gene (c.1439A>G; p.Asp480Gly) as the candidate novel genetic cause of chorea in the proband. PDE2A hydrolyzes cyclic adenosine/guanosine monophosphate and is highly expressed in striatal medium spiny neurons. We functionally characterized the p.Asp480Gly mutation and found that it severely decreases the enzymatic activity of PDE2A. In addition, we showed equivalent expression in human and mouse striatum of PDE2A and its homolog gene, PDE10A. CONCLUSIONS: We identified a loss-of-function homozygous mutation in PDE2A associated to early-onset chorea. Our findings possibly strengthen the role of cyclic adenosine monophosphate and cyclic guanosine monophosphate metabolism in striatal medium spiny neurons as a crucial pathophysiological mechanism in hyperkinetic movement disorders. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Assuntos
Coreia/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/genética , Mutação/genética , Animais , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Saúde da Família , Testes Genéticos , Humanos , Masculino , Diester Fosfórico Hidrolases/genética , Diester Fosfórico Hidrolases/metabolismo , RNA Mensageiro/metabolismoRESUMO
Chorea is a hyperkinetic movement disorder resulting from dysfunction of striatal medium spiny neurons (MSNs), which form the main output projections from the basal ganglia. Here, we used whole-exome sequencing to unravel the underlying genetic cause in three unrelated individuals with a very similar and unique clinical presentation of childhood-onset chorea and characteristic brain MRI showing symmetrical bilateral striatal lesions. All individuals were identified to carry a de novo heterozygous mutation in PDE10A (c.898T>C [p.Phe300Leu] in two individuals and c.1000T>C [p.Phe334Leu] in one individual), encoding a phosphodiesterase highly and selectively present in MSNs. PDE10A contributes to the regulation of the intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both substitutions affect highly conserved amino acids located in the regulatory GAF-B domain, which, by binding to cAMP, stimulates the activity of the PDE10A catalytic domain. In silico modeling showed that the altered residues are located deep in the binding pocket, where they are likely to alter cAMP binding properties. In vitro functional studies showed that neither substitution affects the basal PDE10A activity, but they severely disrupt the stimulatory effect mediated by cAMP binding to the GAF-B domain. The identification of PDE10A mutations as a cause of chorea further motivates the study of cAMP signaling in MSNs and highlights the crucial role of striatal cAMP signaling in the regulation of basal ganglia circuitry. Pharmacological modulation of this pathway could offer promising etiologically targeted treatments for chorea and other hyperkinetic movement disorders.
Assuntos
Coreia/genética , Corpo Estriado/patologia , Mutação , Diester Fosfórico Hidrolases/genética , Sequência de Aminoácidos , Animais , Criança , Coreia/diagnóstico , Corpo Estriado/metabolismo , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Camundongos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Conformação Proteica , Alinhamento de Sequência , Transdução de Sinais , Adulto JovemRESUMO
Increasingly in the realm of neurological disorders, particularly those involving neurodegeneration, mitochondrial dysfunction is emerging at the core of their pathogenic processes. Most of these diseases still lack effective treatment and are hampered by a shortfall in the development of novel medicines. Clearly new targets that translate well to the clinic are required. Physiological parameters in the form of neuronal network activity are increasingly being used as a therapeutic screening approach in drug development and disorders with mitochondrial dysfunction generally display neuronal network activity disturbance. However research directly linking the disturbances in neuronal network activity with mitochondrial dysfunction is only just starting to emerge. This review will summarize the breadth of knowledge linking neuronal network activity to mitochondrial dysfunction in neurodegenerative diseases and suggest potential avenues for exploration in respect to future drug development.
Assuntos
Mitocôndrias/fisiologia , Doenças Mitocondriais/fisiopatologia , Rede Nervosa/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Neurônios/fisiologia , Animais , Humanos , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Rede Nervosa/efeitos dos fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Neurônios/efeitos dos fármacosRESUMO
AIMS: The NADPH oxidase (NOX) family of enzymes catalyzes the formation of reactive oxygen species (ROS). NOX enzymes not only have a key role in a variety of physiological processes but also contribute to oxidative stress in certain disease states. To date, while numerous small molecule inhibitors have been reported (in particular for NOX2), none have demonstrated inhibitory activity in vivo. As such, there is a need for the identification of improved NOX inhibitors to enable further evaluation of the biological functions of NOX enzymes in vivo as well as the therapeutic potential of NOX inhibition. In this study, both the in vitro and in vivo pharmacological profiles of GSK2795039, a novel NOX2 inhibitor, were characterized in comparison with other published NOX inhibitors. RESULTS: GSK2795039 inhibited both the formation of ROS and the utilization of the enzyme substrates, NADPH and oxygen, in a variety of semirecombinant cell-free and cell-based NOX2 assays. It inhibited NOX2 in an NADPH competitive manner and was selective over other NOX isoforms, xanthine oxidase, and endothelial nitric oxide synthase enzymes. Following systemic administration in mice, GSK2795039 abolished the production of ROS by activated NOX2 enzyme in a paw inflammation model. Furthermore, GSK2795039 showed activity in a murine model of acute pancreatitis, reducing the levels of serum amylase triggered by systemic injection of cerulein. INNOVATION AND CONCLUSIONS: GSK2795039 is a novel NOX2 inhibitor that is the first small molecule to demonstrate inhibition of the NOX2 enzyme in vivo.
Assuntos
Aminopiridinas/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Glicoproteínas de Membrana/metabolismo , NADPH Oxidases/metabolismo , Sulfonamidas/farmacologia , Aminopiridinas/química , Animais , Células Cultivadas , Inibidores Enzimáticos/uso terapêutico , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Camundongos Endogâmicos C57BL , NADPH Oxidase 2 , NADPH Oxidases/antagonistas & inibidores , Pancreatite/tratamento farmacológico , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Sulfonamidas/químicaRESUMO
Small molecule phosphodiesterase (PDE) 4 inhibitors have long been known to show therapeutic benefit in various preclinical models of psychiatric and neurologic diseases because of their ability to elevate cAMP in various cell types of the central nervous system. Despite the registration of the first PDE4 inhibitor, roflumilast, for the treatment of chronic obstructive pulmonary disease, the therapeutic potential of PDE4 inhibitors in neurologic diseases has never been fulfilled in the clinic due to severe dose-limiting side effects such as nausea and vomiting. In this study, we describe the detailed pharmacological characterization of GSK356278 [5-(5-((2,4-dimethylthiazol-5-yl)methyl)-1,3,4-oxadiazol-2-yl)-1-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine], a potent, selective, and brain-penetrant PDE4 inhibitor that shows a superior therapeutic index to both rolipram and roflumilast in various preclinical species and has potential for further development in the clinic for the treatment of psychiatric and neurologic diseases. GSK356278 inhibited PDE4B enzyme activity with a pIC50 of 8.8 and bound to the high-affinity rolipram binding site with a pIC50 of 8.6. In preclinical models, the therapeutic index as defined in a rodent lung inflammation model versus rat pica feeding was >150 compared with 0.5 and 6.4 for rolipram and roflumilast, respectively. In a model of anxiety in common marmosets, the therapeutic index for GSK356278 was >10 versus <1 for rolipram. We also demonstrate that GSK356278 enhances performance in a model of executive function in cynomolgus macaques with no adverse effects, a therapeutic profile that supports further evaluation of GSK356278 in a clinical setting.
Assuntos
Córtex Cerebral/enzimologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/efeitos dos fármacos , Nootrópicos/farmacologia , Oxidiazóis/farmacologia , Inibidores da Fosfodiesterase 4/efeitos adversos , Inibidores da Fosfodiesterase 4/farmacologia , Tiazóis/farmacologia , Aminopiridinas/farmacologia , Animais , Ansiolíticos/efeitos adversos , Ansiolíticos/farmacocinética , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Benzamidas/farmacologia , Callithrix , Córtex Cerebral/efeitos dos fármacos , Ciclopropanos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Furões , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Isoenzimas/antagonistas & inibidores , Macaca fascicularis , Masculino , Nootrópicos/efeitos adversos , Nootrópicos/farmacocinética , Nootrópicos/uso terapêutico , Oxidiazóis/efeitos adversos , Oxidiazóis/farmacocinética , Oxidiazóis/uso terapêutico , Inibidores da Fosfodiesterase 4/farmacocinética , Pica/tratamento farmacológico , Ratos , Rolipram/farmacologia , Tiazóis/efeitos adversos , Tiazóis/farmacocinética , Tiazóis/uso terapêuticoRESUMO
A three-year surveillance of non-tuberculous mycobacteria (NTM) in a hospital water distribution system was conducted at a facility located in southern Alberta. NTM was not present in any intake water samples, but was found in 106/183 (58%) of endpoint samples across 15 sites over the study period. Two different species of NTM were identified, Mycobacterium gordonae (88/183) and Mycobacterium avium (34/183); with only one strain of each M. gordonae and M. avium found. Given the sensitive nature of a healthcare facility, attention should be paid to minimize potential impact of NTM from potable water sources on patient health.
Assuntos
Água Potável/microbiologia , Mycobacterium avium/classificação , Mycobacterium avium/isolamento & purificação , Micobactérias não Tuberculosas/classificação , Micobactérias não Tuberculosas/isolamento & purificação , Alberta , Monitoramento Epidemiológico , Hospitais , Humanos , Mycobacterium avium/genética , Micobactérias não Tuberculosas/genéticaRESUMO
Delta oscillations (1-4 Hz) associate with deep sleep and are implicated in memory consolidation and replay of cortical responses elicited during wake states. A potent local generator has been characterized in thalamus, and local generators in neocortex have been suggested. Here we demonstrate that isolated rat neocortex generates delta rhythms in conditions mimicking the neuromodulatory state during deep sleep (low cholinergic and dopaminergic tone). The rhythm originated in an NMDA receptor-driven network of intrinsic bursting (IB) neurons in layer 5, activating a source of GABAB receptor-mediated inhibition. In contrast, regular spiking (RS) neurons in layer 5 generated theta-frequency outputs. In layer 2/3 principal cells, outputs from IB cells associated with IPSPs, whereas those from layer 5 RS neurons related to nested bursts of theta-frequency EPSPs. Both interlaminar spike and field correlations revealed a sequence of events whereby sparse spiking in layer 2/3 was partially reflected back from layer 5 on each delta period. We suggest that these reciprocal, interlaminar interactions may represent a "Helmholtz machine"-like process to control synaptic rescaling during deep sleep.
Assuntos
Ritmo Delta/fisiologia , Neocórtex/fisiologia , Ritmo Teta/fisiologia , Algoritmos , Animais , Simulação por Computador , Eletroencefalografia , Potenciais Evocados/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Espaço Extracelular/fisiologia , Junções Comunicantes/fisiologia , Masculino , Memória/fisiologia , Modelos Neurológicos , Ratos , Ratos Wistar , Fases do Sono/fisiologia , Sinapses/fisiologia , Vigília/fisiologiaRESUMO
Episodic memory deficits are a core feature of neurodegenerative disorders. Muscarinic M(1) receptors play a critical role in modulating learning and memory and are highly expressed in the hippocampus. We examined the effect of GSK1034702, a potent M(1) receptor allosteric agonist, on cognitive function, and in particular episodic memory, in healthy smokers using the nicotine abstinence model of cognitive dysfunction. The study utilized a randomized, double-blind, placebo-controlled, cross-over design in which 20 male nicotine abstained smokers were tested following single doses of placebo, 4 and 8 mg GSK1034702. Compared to the baseline (nicotine on-state), nicotine abstinence showed statistical significance in reducing immediate (p=0.019) and delayed (p=0.02) recall. GSK1034702 (8 mg) significantly attenuated (i.e. improved) immediate recall (p=0.014) but not delayed recall. None of the other cognitive domains was modulated by either nicotine abstinence or GSK1034702. These findings suggest that stimulating M(1) receptor mediated neurotransmission in humans with GSK1034702 improves memory encoding potentially by modulating hippocampal function. Hence, selective M(1) receptor allosteric agonists may have therapeutic benefits in disorders of impaired learning including Alzheimer's disease.
Assuntos
Comportamento Aditivo/psicologia , Benzimidazóis/uso terapêutico , Transtornos Cognitivos/psicologia , Memória Episódica , Receptor Muscarínico M1/agonistas , Abandono do Hábito de Fumar/psicologia , Adulto , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Comportamento Aditivo/tratamento farmacológico , Benzimidazóis/farmacologia , Transtornos Cognitivos/tratamento farmacológico , Estudos Cross-Over , Método Duplo-Cego , Humanos , Masculino , Pessoa de Meia-Idade , Nicotina , Receptor Muscarínico M1/fisiologia , Fumar/psicologia , Adulto JovemRESUMO
BACKGROUND: Cholinergic transmission has been implicated in learning, memory and cognition. However, the cellular effects induced by muscarinic acetylcholine receptors (mAChRs) activation are poorly understood in the neocortex. We investigated the effects of the cholinergic agonist carbachol (CCh) and various agonists and antagonists on neuronal activity in rat neocortical slices using intracellular (sharp microelectrode) and field potential recordings. RESULTS: CCh increased neuronal firing but reduced synaptic transmission. The increase of neuronal firing was antagonized by pirenzepine (M1/M4 mAChRs antagonist) but not by AF-DX 116 (M2/M4 mAChRs antagonist). Pirenzepine reversed the depressant effect of CCh on excitatory postsynaptic potential (EPSP) but had marginal effects when applied before CCh. AF-DX 116 antagonized the depression of EPSP when applied before or during CCh. CCh also decreased the paired-pulse inhibition of field potentials and the inhibitory conductances mediated by GABA(A) and GABA(B) receptors. The depression of paired-pulse inhibition was antagonized or prevented by AF-DX 116 or atropine but only marginally by pirenzepine. The inhibitory conductances were unaltered by xanomeline (M1/M4 mAChRs agonist), yet the CCh-induced depression was antagonized by AF-DX 116. Linopirdine, a selective M-current blocker, mimicked the effect of CCh on neuronal firing. However, linopirdine had no effect on the amplitude of EPSP or on the paired-pulse inhibition, indicating that M-current is involved in the increase of neuronal excitability but neither in the depression of EPSP nor paired-pulse inhibition. CONCLUSIONS: These data indicate that the three effects are mediated by different mAChRs, the increase in firing being mediated by M1 mAChR, decrease of inhibition by M2 mAChR and depression of excitatory transmission by M4 mAChR. The depression of EPSP and increase of neuronal firing might enhance the signal-to-noise ratio, whereas the concomitant depression of inhibition would facilitate long-term potentiation. Thus, this triade of effects may represent a "neuronal correlate" of attention and learning.
Assuntos
Neocórtex/citologia , Subunidades Proteicas/fisiologia , Receptores Muscarínicos/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Biofísica , Agonistas Colinérgicos/farmacologia , Interações Medicamentosas , Estimulação Elétrica , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Técnicas In Vitro , Masculino , Inibição Neural/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores Muscarínicos/classificação , Sinapses/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Ácido gama-Aminobutírico/farmacologiaRESUMO
Observations in human tumours, as well as mouse models, have indicated that telomere dysfunction may be a key event driving genomic instability and disease progression in many solid tumour types. In this scenario, telomere shortening ultimately results in telomere dysfunction, fusion and genomic instability, creating the large-scale rearrangements that are characteristic of these tumours. It is now becoming apparent that this paradigm may also apply to haematological malignancies; indeed these conditions have provided some of the most convincing evidence of telomere dysfunction in any malignancy. Telomere length has been shown in several malignancies to provide clinically useful prognostic information, implicating telomere dysfunction in disease progression. In these malignancies extreme telomere shortening, telomere dysfunction and fusion have all been documented and correlate with the emergence of increased genomic complexity. Telomeres may therefore represent both a clinically useful prognostic tool and a potential target for therapeutic intervention.