Biphasic Cholinergic Modulation of Reverberatory Activity in Neuronal Networks / 神经科学通报·英文版

Acetylcholine (ACh) is an important neuromodulator in various cognitive functions. However, it is unclear how ACh influences neural circuit dynamics by altering cellular properties. Here, we investigated how ACh influences reverberatory activity in cultured neuronal networks. We found that ACh suppressed the occurrence of evoked reverberation at low to moderate doses, but to a much lesser extent at high doses. Moreover, high doses of ACh caused a longer duration of evoked reverberation, and a higher occurrence of spontaneous activity. With whole-cell recording from single neurons, we found that ACh inhibited excitatory postsynaptic currents (EPSCs) while elevating neuronal firing in a dose-dependent manner. Furthermore, all ACh-induced cellular and network changes were blocked by muscarinic, but not nicotinic receptor antagonists. With computational modeling, we found that simulated changes in EPSCs and the excitability of single cells mimicking the effects of ACh indeed modulated the evoked network reverberation similar to experimental observations. Thus, ACh modulates network dynamics in a biphasic fashion, probably by inhibiting excitatory synaptic transmission and facilitating neuronal excitability through muscarinic signaling pathways.

Basal Forebrain Cholinergic Innervation Induces Depression-Like Behaviors Through Ventral Subiculum Hyperactivation / 神经科学通报·英文版

Malfunction of the ventral subiculum (vSub), the main subregion controlling the output connections from the hippocampus, is associated with major depressive disorder (MDD). Although the vSub receives cholinergic innervation from the medial septum and diagonal band of Broca (MSDB), whether and how the MSDB-to-vSub cholinergic circuit is involved in MDD is elusive. Here, we found that chronic unpredictable mild stress (CUMS) induced depression-like behaviors with hyperactivation of vSub neurons, measured by c-fos staining and whole-cell patch-clamp recording. By retrograde and anterograde tracing, we confirmed the dense MSDB cholinergic innervation of the vSub. In addition, transient restraint stress in CUMS increased the level of ACh in the vSub. Furthermore, chemogenetic stimulation of this MSDB-vSub innervation in ChAT-Cre mice induced hyperactivation of vSub pyramidal neurons along with depression-like behaviors; and local infusion of atropine, a muscarinic receptor antagonist, into the vSub attenuated the depression-like behaviors induced by chemogenetic stimulation of this pathway and CUMS. Together, these findings suggest that activating the MSDB-vSub cholinergic pathway induces hyperactivation of vSub pyramidal neurons and depression-like behaviors, revealing a novel circuit underlying vSub pyramidal neuronal hyperactivation and its associated depression.

Atopia e/ou angioedema no paciente com urticária colinérgica com revisão da literatura / Atopy and/or angioedema in patients with cholinergic urticaria with a literature review

Introdução: A urticária colinérgica (UCol) é um subtipo de urticária crônica induzida, desencadeada pela sudorese e o aumento da temperatura corporal. A associação de UCol com atopia é referida como um possível subtipo mais grave. A manifestação de angioedema estaria associada a um quadro mais prolongado de urticária e a sintomas extracutâneos, por exemplo, anafilaxia. Objetivo: Avaliar a frequência de atopia e/ou angioedema nos pacientes com UCol, em um centro terciário. Métodos: Estudo retrospectivo de prontuários de pacientes com UCol acompanhados em um centro terciário. Todos apresentavam teste de provocação para UCol positivo. A frequência de atopia e/ou angioedema foi avaliada nestes pacientes, como também as características gerais nestes subgrupos. Resultados: Foram incluídos 30 pacientes, sendo 60% do gênero feminino e idade (média) de 32,9 anos e tempo de doença (média) de 7,5 anos. O angioedema foi referido por 8 pacientes (26,7%), não foram observadas diferenças significantes entre os dois grupos (com e sem angioedema). Em relação à atopia, 9 pacientes (30%) realizaram a investigação através de IgE específica para aeroalérgenos, sendo positivo em 6 destes (66,7%). Embora sem diferença estatística, o grupo de pacientes com UCol e atopia apresentava valores de IgE sérica total mais elevados e maior frequência de associação com outras urticárias induzidas. Conclusões: Neste estudo, a frequência de atopia foi elevada e associada a níveis elevados de IgE sérica total. O angioedema foi relatado em mais de um quarto dos pacientes, independente da associação com UCE, favorecendo a uma maior gravidade à UCol. Doze pacientes (40%) não responderam aos anti-histamínicos, apesar da dose quadruplicada, sendo necessários outros esquemas terapêuticos.

Introduction: Cholinergic urticaria (CholU) is a subtype of chronic induced urticaria that is triggered by sweating and increased body temperature. The association of CholU with atopy is referred to as a possible subtype but more severe. The manifestation of angioedema is believed to be associated with more prolonged urticaria and extracutaneous symptoms such as anaphylaxis. Objective: To assess the frequency of atopy and/or angioedema in patients with CholU in a tertiary care center. Methods: A retrospective study of medical records of patients with CholU followed-up at a tertiary care center was conducted. All patients had a positive test for CholU. The frequency of atopy and/or angioedema was assessed in these patients, as well as the general characteristics in the subgroups. Results: Thirty patients were included in the study; 60% were female, mean age was 32.9 years, and mean disease duration was 7.5 years. Angioedema was reported by eight patients (26.7%). There were no significant differences between the two groups (with and without angioedema). Concerning atopy, nine patients (30%) underwent investigation using specific IgE for aeroallergens, with six positive results (66.7%). Although there was no statistical difference, the group of patients with CholU and atopy had higher total serum IgE values and a higher frequency of association with other induced urticaria. Conclusions: In this study, the frequency of atopy was high and associated with high levels of total serum IgE. Angioedema was reported in more than a quarter of patients, regardless of the association with ECU , favoring greater severity of ChoIU. Twelve patients (40%) did not respond to antihistamines, despite the quadrupled dose, requiring other therapeutic regimens.

Efectos clinicos e histopatologicos agudos y subagudos del veneno de Tityus breweri en miocardio de hamsters / Clinical and histopathological effects of acute and subagude of the poison of Tityus breweri in hamsters myocardia

Resumen Los escorpiones del género Tityus presentan la mayor distribución mundial, de mayor importancia clínica, epidemiológica y más peligrosa del continente americano. Las toxinas de su veneno producen perturbación severa de los procesos de excitación y conducción del impulso nervioso. Desde el punto de vista histopatológicos se han observado cambios estructurales en diferentes tejidos de ratones, con el veneno de varias especies de Tityus venezolanos. Objetivo: Describir los efectos clínicos e histopatológicos agudos y subagudos del veneno de escorpión (Buthidae: T. breweri) en el miocardio de hámster. Método: Estudio experimental, exploratoria, descriptivo, analítica y correlacional. Se utilizaron hámsteres de ambos sexos del genero Cricetus y se obtuvo el veneno de 26 escorpiones T. breweri, se escogieron 6 hámster al azar, inyectándoles vía intraperitonial (VIP) veneno de Tityus breweri, 3 sacrificados a los 30 minutos y los otros 3 a los 60 minutos, 3 inyectados con agua destilada constituyeron el grupo control. Resultados: La mayoría de los animales expuestos presentaron manifestaciones de tipo colinérgicas y adrenérgicas. Las alteraciones histopatológicas agudas observadas fueron edema interfascicular y congestión vascular, infiltrado linfohistiocítico perivascular. Al transcurrir 12, 24, 48 y 72 horas de exposición del veneno, no se evidenciaron cambios histopatológicos, lo que hace presumir que se activaron los procesos de reparación de los tejidos dañados. Conclusión: el veneno de T. breweri produjo alteración histológicas agudas y subagudas en el tejido miocárdico en los hámsteres sin evidencia de alteración en el grupo control.

Abstract Scorpions of the genus Tityus present the largest distribution of the world, of greater clinical, epidemiological and more dangerous importance of the American continent. The toxins from its venom produce severe disturbance of the excitation and conduction processes of the nerve impulse. From the histopathological point of view structural changes have been observed in different tissues of mice, with the venom of several species of Venezuelan Tityus. Objective: To describe the acute and subacute clinical and histopathological effects of scorpion venom (Buthidae: T. breweri) on the hamster myocardium. Method: Experimental, exploratory, descriptive, analytical and correlational study. Hersters of both sexes of the genus Cricetus were obtained and venom of 26 T. breweri scorpions were obtained, 6 random hamsters were chosen, injecting intravenously (VIP) venom of Tityus breweri, 3 sacrificed at 30 minutes and the other 3 a The 60 minutes, 3 injected with distilled water constituted the control group. Results: Most of the exposed animals presented cholinergic and adrenergic type manifestations. The acute histopathological alterations observed were interfascicular edema and vascular congestion, perivascular lymphohistiocytic infiltrate. At the end of 12, 24, 48 and 72 hours of exposure of the venom, no histopathological changes were evidenced, which suggests that the repair processes of the damaged tissues were activated. Conclusion: T. breweri venom caused acute and subacute histological alterations in myocardial tissue in hamsters with no evidence of alteration in the control group.

Efecto de Petiveria alliacea y drogas colinérgicas sobre la habituación / Effects of Petiveria alliacea and cholinergic drugs on the habituation cognitive behavior

Petiveria alliacea (PA) have anxiolytic, antidepressant and cognitive effects. In the present paper the effect of PA water infusion and cholinergic drugs on cognitive behavior were studied. For that, 40 male NMRI mice were divided in 4 groups: Control (n=10), Drug Control (n=10), PA (n=10) and PA plus Drug (n=10). PA 1% was administered orally (7.59±1.39 ml/day); while scopolamine (2 mg/Kg), galantamine (1 mg/Kg) and nicotine (0.1 mg/Kg) were administered intraperitoneally. Behavioral tests included: anxiety maze (AM), open field (OF) and marble burying (MB). Habituation cognitive behavior was evaluated in 4 sessions, one week each session. PA had anxiolytic and antidepressant effect effect in AM, combined with nicotine potentiated an anxiogenic effect in AM, galantamine favored habituation in OF. Scopolamine potentiated the habituation in LA and decreased the obsessive-compulsive behavior in OF. In conclusion; PA had an anxiolytic effect and favored deshabituation, combined with nicotine induced an anxiogenic effect, galantamine favored habituation and scopolamine decreased obsessive-compulsive behavior and favored motor habituation indicated a possible anxiolytic effect.

La Petiveria alliacea (PA) está relacionada con efectos ansiolíticos, antidepresivos y cognitivos. El presente trabajo estudió el efecto de la infusión de PA y drogas colinérgicas sobre la habituación. 40 ratones NMRI machos fueron divididos en 4 grupos: Control (n=10), Control Drogas (n=10), PA (n=10) y PA plus Drogas (n=10). La PA (1%) fue administrada vía oral (7.59±1.39 ml/día); escopolamina (2 mg/Kg), galantamina (1 mg/Kg) y nicotina (0.1 mg/Kg) fueron administrados vía intraperitoneal. Los ensayos conductuales incluyeron: laberinto de ansiedad (LA), campo abierto (CA) y enterramiento aversivo (EA). La habituación fue evaluada en 4 sesiones con duración de una semana cada una. PA mostró un efecto ansiolítico en el LA, combinada con nicotina potenció un efecto ansiogénico en el LA. Galantamina favoreció la habituación en CA, y escopolamina potenció el fenómeno de habituación en LA y disminuyó la conducta obsesivo-compulsiva en CA. En conclusión, la PA mostró un efecto ansiolítico y antidepresivo que potencia la deshabituación, combinada con nicotina indujo un efecto ansiogénico, galantamina favoreció la habituación y escopolamina disminuyó la conducta obsesivo­ compulsiva y favoreció la habituación motora indicando un posible efecto ansiolítico.

Influencia adrenérgica y colinérgica sobre la producción de especies reactivas de oxígeno en neutrófilos humanos* / Adrenergic and cholinergic influence on the production of reactive oxygen species in human neutrophils*

RESUMEN Objetivos. Determinar y comparar el efecto de fármacos agonistas adrenérgicos y colinérgicos sobre la producción de especies reactivas de oxígeno (ROS) en neutrófilos de individuos sanos. Materiales y métodos. Se tomaron muestras de sangre total de cinco participantes para purificar los neutrófilos mediante el método de gelatina. Se midió la producción de ROS por quimioluminiscencia (QLM) usando un contador de centelleo y forbol-12-miristato-13-acetato (PMA) como estímulo. También se realizaron pruebas sin PMA para medir la producción espontánea. Posteriormente, con el mismo método se midió la formación de ROS en presencia de nicotina (agonista colinérgico), salbutamol y clonidina (agonistas adrenérgicos), cada uno en concentraciones de 10-2 M, 10-3 M, 10-4 M y 10-5 M. Se calculó el área integrada bajo las curvas de QLM y se halló el porcentaje de inhibición o de estimulación según sea el caso. Se comparó el efecto provocado por las drogas con sus controles correspondientes y se realizó el análisis estadístico. Resultados. Se obtuvo una disminución de la producción de ROS como efecto de las sustancias estudiadas con una diferencia significativa entre los controles y el efecto producido a 10-2 M, 10-3 M y 10-4 M. Este efecto aumentó de intensidad conforme la concentración de las drogas se incrementó. Los mayores porcentajes de inhibición se mostraron a 10-2 M y 10-3 M. Salbutamol presentó los máximos valores con todas las concentraciones con diferencia significativa entre su inhibición y la generada por las demás drogas. Conclusiones. Los estímulos adrenérgico y colinérgico tienen un efecto inhibitorio de la producción de ROS en neutrófilos de individuos sanos.

ABSTRACT Objectives. To determine and compare the effect of adrenergic and cholinergic agonist drugs on the production of reactive oxygen species (ROS) in neutrophils of healthy individuals. Materials and Methods. Whole blood samples were taken from five participants to purify neutrophils using the gelatin method. The production of chemiluminescent (QLM) ROS was measured using a scintillation counter and phorbol-12-myristat-13-acetate (PMA) as a stimulus. Non-PLA tests were also conducted to measure spontaneous production. Subsequently, with the same method, ROS formation was measured in the presence of nicotine (cholinergic agonist), salbutamol, and clonidine (adrenergic agonists), each in concentrations of 10-2 M, 10-3 M, 10-4 M, and 10-5 M. The area integrated under the QLM curves was calculated and the percentage of inhibition or stimulation was found as the case may be. The effect of the drugs was compared with their corresponding controls and statistical analysis was carried out. Results. A decrease in the production of ROS was obtained as an effect of the substances studied with a significant difference between the controls and the effect produced at 10-2 M, 10-3 M, and 10-4 M . This effect increased in intensity as drug concentration increased. The highest percentages of inhibition were shown at 10-2 M and 10-3 M. Salbutamol presented the maximum values with all the concentrations with a significant difference between its inhibition and that generated by the other drugs. Conclusions. Adrenergic and cholinergic stimuli have an inhibitory effect on the production of ROS in neutrophils of healthy individuals.

Pharmacological Modulation of Vagal Nerve Activity in Cardiovascular Diseases / 神经科学通报·英文版

Cardiovascular diseases are life-threatening illnesses with high morbidity and mortality. Suppressed vagal (parasympathetic) activity and increased sympathetic activity are involved in these diseases. Currently, pharmacological interventions primarily aim to inhibit over-excitation of sympathetic nerves, while vagal modulation has been largely neglected. Many studies have demonstrated that increased vagal activity reduces cardiovascular risk factors in both animal models and human patients. Therefore, the improvement of vagal activity may be an alternate approach for the treatment of cardiovascular diseases. However, drugs used for vagus nerve activation in cardiovascular diseases are limited in the clinic. In this review, we provide an overview of the potential drug targets for modulating vagal nerve activation, including muscarinic, and β-adrenergic receptors. In addition, vagomimetic drugs (such as choline, acetylcholine, and pyridostigmine) and the mechanism underlying their cardiovascular protective effects are also discussed.

Abstinência à cocaína e suas consequências no sistema colinérgico muscarínico / Abstinencia a la cocaína y sus consecuencias en el sistema colinérgico muscarínico / Abstinence from cocaine and its consequences on the muscarinic cholinergic system

Uma das principais dificuldades enfrentadas na dependência à cocaína está relacionada aos sintomas de abstinência, como ansiedade, desejo e irritabilidade. Estes efeitos podem durar meses ou anos após a interrupção do consumo prolongado, fazendo com que o indivíduo volte a procurá-la. Os efeitos recompensadores da cocaína levam a alterações neurobiológicas do sistema mesocorticolímbico dopaminérgico, que se origina na área tegmental ventral e se projeta para o núcleo accumbens, e córtex pré-frontal, áreas intimamente ligadas ao desenvolvimento da dependência. Esses neurônios dopaminérgicos recebem estímulos dos neurônios colinérgicos que contribuem para os aspectos cognitivos da dependência. Devido à complexidade neurobilógica envolvida durante a abstinência, pouco se sabe sobre as alterações no sistema colinérgico muscarínico durante este período no encéfalo, objetivo deste estudo. Para tal, camundongos machos adultos Swiss-Webster foram submetidos à cocaína em padrão agudo em binge (3×30 mg/kg/dia) e cronicamente por escalonamento de dose em binge por 14 dias (3×15 mg/kg/dia nos dias 1-4; 3×20 mg/kg/dia nos dias 5-8; 3×25 mg/kg/dia nos dias 9-12; e 3×30 mg/kg/dia nos dias 13 e 14). A atividade locomotora de cada animal foi avaliada em campo aberto (CA), onde permaneceram no aparato por 60 minutos entre cada administração. Após o período de exposição os animais permaneceram 14 dias em abstinência, a fim de avaliar a ansiedade no labirinto em cruz elevado (LCE). Em seguida os animais foram eutaniasiados, sendo o córtex pré-frontal (CPF), o estriado e o hipocampo dissecados e armazenados a -80ºC para a análise dos receptores dopaminérgicos D1 e D2, receptores colinérgicos muscarínicos M1, M2, M3, M4 e M5 (mAChRs) e moléculas colinérgicas (acetilcolinesterase, AChE; colina acetiltransferase, ChAT e transportador vesicular de acetilcolina, VAChT) por Western Blotting (n=6). Os resultados comportamentais mostraram maior atividade locomotora nos animais tratados com cocaína no tratamento agudo ou crônico, quando comparado ao basal. Mais ainda, a sensibilização comportamental foi detectada a partir do segundo dia de administração de cocaína. No teste de LCE, realizado 14 dias após a interrupção da administração de cocaína, não foi observada diferença estatística entre os animais previamente expostos à cocaína e grupo controle. No CPF observou-se diminuição de D2R, M1 mAChRs e aumento M2 e M4 mAChRs no tratamento agudo; no tratamento crônico houve diminuição de M1 e M5 mAChRs e ChAT. No estriado observou-se aumento de D1R, M1 e M2 mAChRs, ChAT no tratamento agudo; e aumento D1R, VAChT, ChAT e diminuição D2R, M1 e M2 mAChRs no tratamento crônico. Já no hipocampo observou-se aumento de D1R, D2R, M2 mAChRs, VAChT e diminuição M1 mAChRs no tratamento agudo; e aumento de D1R, VAChT e diminuição D2R, M1 mAChRs no tratamento crônico. Nossos resultados mostram envolvimento de processo de neuroplasticidade, tanto no sistema dopaminérgico quanto no colinérgico muscarínico, em ambos os protocolos utilizados, mesmo após 14 dias de abstinência

Una de las dificultades enfrentadas en la dependencia de cocaína son los síntomas de abstinencia, como ansiedad, deseo y irritabilidad. Estos efectos pueden durar meses o años después de la interrupción del consumo prolongado, haciendo que el individuo vuelva a consumirlo. Los efectos recompensadores de la cocaína causa alteraciones neurobiológicas del sistema mesocorticolímbico dopaminérgico, que se origina en el área tegmental ventral y se proyecta hacia el núcleo accumbens y córtex pré-frontal, áreas íntimamente ligadas al desenvolvimiento de la dependencia. Esas neuronas dopaminérgicas reciben estímulos de neuronas colinérgicas la cual contribuyen para los aspectos cognitivos de la dependencia. Debido a la complejidad neurobiológica involucrada durante la abstinencia, poco se sabe sobre las alteraciones del sistema colinérgico muscarínico durante este periodo en el encéfalo, objetivo de este estudio. Por tanto, ratones adultos macho Swiss-Webster fueron sometidos a cocaína en dosis padrón agudo en binge (3×30 mg/kg/día) y crónicamente por escalonamiento de dosis en binge por 14 días (3×15 mg/kg/día en los días 1-4; 3×20 mg/kg/día en los días 5-8; 3×25 mg/kg/día en los días 9-12; y 3×30 mg/kg/día en los días 13 e 14). La actividad locomotora de cada animal fue evaluada en el test de campo abierto (CA), donde permanecieron por 60 minutos entre cada administración. Después del periodo de exposición los animales permanecieron 14 días de abstinencia, a fin de evaluar la ansiedad en el labirinto de cruz elevado (LCE). En seguida los animales fueron eutanasiados, donde el córtex pré-frontal (CPF), estriado y hipocampo fueron disecados y almacenados a -80ºC para analizar los receptores dopaminérgicos D1 e D2, receptores colinérgicos muscarínicos M1, M2, M3, M4 y M5 (mAChRs) y moléculas colinérgicas (acetilcolinesterasa, AChE; colina acetiltransferasa, ChAT y transportador vesicular de acetilcolina, VAChT) por Western Blotting (n=6). Los resultados comportamentales mostraron mayor actividad locomotora en los animales tratados con cocaína en tratamiento agudo y crónico, comparado al control. Por otra parte, la sensibilización comportamental fue detectado a partir de segundo día de administración de cocaína. En la prueba de LCE, realizado después de 14 días de interrupción de la administración de cocaína, no fue observado diferencia estadística entre los animales previamente expuestos a la cocaína y el grupo control. En CPF se observó disminución de D2R, M1 mAChRs y aumento de M2 y M4 mAChRs en tratamiento agudo; en el tratamiento crónico mostro disminución de M1 y M5 mAChRs y ChAT. En el estriado se observó aumento de D1R, M1 y M2 mAChRs, ChAT en el tratamiento agudo; aumento D1R, VAChT, ChAT y disminución de D2R, M1 y M2 mAChRs en el tratamiento crónico. Por último, en el hipocampo se observó aumento de D1R, D2R, M2 mAChRs, VAChT y disminución M1 mAChRs en el tratamiento agudo; aumento de D1R, VAChT y disminución D2R, M1 mAChRs en el tratamiento crónico. Nuestros resultados muestran envolvimiento de procesos de neuroplasticidad, tanto en el sistema dopaminérgico como el sistema colinérgico muscarínico, en ambos protocolos utilizados, después de 14 días de abstinencia

Development of New Therapies for Severe Asthma

Persistent asthma has long been treated with inhaled corticosteroids (CSs), as the mainstay of therapy. However, their efficacy in patients with more severe disease is limited, which led to the incorporation of poor response to ICSs (and thereby use of high doses of ICS) into recent definitions of severe asthma. Several studies have suggested that severe asthma might consist of several different phenotypes, each with ongoing symptoms and health care utilization, despite the use of high doses of ICS, usually in combination with a second or third controller. Several new therapies have been approved for severe asthma. Long-acting muscarinic agents have recently been approved as an additional controller agent and appear to improve lung function, although their effect on symptoms and exacerbations is less. Although bronchial thermoplasty (BT) has emerged as a therapy for severe asthma, little is understood regarding the appropriate selection of these patients. Considerable data have emerged to support the presence of a group of patients with severe asthma who have ongoing Type 2 inflammation. These patients appear to respond to targeted biologic approaches which are at the current time mostly investigational. In contrast, few effective therapies for patients with less or no evidence for Type 2 inflammation have emerged. Many new and exciting therapies are at the forefront for severe asthma therapy and, in conjunction with precision medicine approaches to identify the group of patients likely to respond to these approaches, will change the way we think about treating severe asthma.

Basal Forebrain Cholinergic Deficits Reduce Glucose Metabolism and Function of Cholinergic and GABAergic Systems in the Cingulate Cortex

PURPOSE: Reduced brain glucose metabolism and basal forebrain cholinergic neuron degeneration are common features of Alzheimer's disease and have been correlated with memory function. Although regions representing glucose hypometabolism in patients with Alzheimer's disease are targets of cholinergic basal forebrain neurons, the interaction between cholinergic denervation and glucose hypometabolism is still unclear. The aim of the present study was to evaluate glucose metabolism changes caused by cholinergic deficits. MATERIALS AND METHODS: We lesioned basal forebrain cholinergic neurons in rats using 192 immunoglobulin G-saporin. After 3 weeks, lesioned animals underwent water maze testing or were analyzed by 18F-2-fluoro-2-deoxyglucose positron emission tomography. RESULTS: During water maze probe testing, performance of the lesioned group decreased with respect to time spent in the target quadrant and platform zone. Cingulate cortex glucose metabolism in the lesioned group decreased, compared with the normal group. Additionally, acetylcholinesterase activity and glutamate decarboxylase 65/67 expression declined in the cingulate cortex. CONCLUSION: Our results reveal that spatial memory impairment in animals with selective basal forebrain cholinergic neuron damage is associated with a functional decline in the GABAergic and cholinergic system associated with cingulate cortex glucose hypometabolism.

Effects and mechanisms of the inflammatory reaction related to NASH and induced by activation of the cholinergic anti-inflammatory pathway / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate the effects and mechanisms of the inflammatory reaction related to nonalcoholic steatohepatitis (NASH) and induced by activation of the cholinergic anti-inflammatory pathway.</p><p><b>METHODS</b>A mouse model of NASH was established by feeding a high-fat and high-sugar diet.Activation of the cholinergic anti-inflammatory pathway was achieved by nicotine administration to the NASH modeled mice and normal controls. Liver biopsies were taken and the concentrations of cytokines were measured. Isolated liver primary Kupffer cells and RAw264.7 cells were cultured, pre-treated or not with lipopolysaccharide (LPS) and exposed to nicotine, after which the supernatant concentrations of IL-6 and TNFa were determined by ELISA. The protein expression levels of phosphorylated (p)-NF-kB and I k B were detected in primary cultured Kupffer cells by western blotting.</p><p><b>RESULTS</b>The mouse model of NASH was successfully established, as evidenced by findings from liver biopsy and serum liver function tests. The degree of liver inflammation in the NASH mice decreased after nicotine administration, and the level of serum TNFa also significantly decreased. The levels of serum TNFa were 21.95+/-0.8 pg/mL in nicotine-treated mice and 38.07+/-1.7 pg/mL in the non-nicotine-treated NASH mice (P less than 0.05). The nicotine treatment also significantly reduced the concentration of TNFa in the culture supernatants of Kupffer cells after LPS stimulation; moreover, the supernatant level of TNFa decreased significantly after the nicotine treatment (Pless than 0.05). LPS stimulation of the RAw264.7 cells led to an increased level ofp-NF-kB and a reduced level ofI-kB, suggesting that the NF-kB pathway had been activated; different doses of nicotine pre-treatment led to down-regulation of the p-NF-kB level and up-regulation of the I-kB level, both in dose-dependent manners.</p><p><b>CONCLUSION</b>Activating the cholinergic anti-inflammatory pathway inhibits the NASH-related inflammatory reaction, and the mechanism for this inhibition involves the NF-kB signaling pathway.</p>

Relaxant effects of a hydroalcoholic extract of Ruta graveolens on isolated rat tracheal rings

BACKGROUND: Ruta graveolens L. (R. graveolens) is a medicinal plant employed in non-traditional medicines that has various therapeutic properties, including anthelmintic, and vasodilatory actions, among others. We evaluated the trachea-relaxant effects of hydroalcoholic extract of R. graveolens against potassium chloride (KCl)- and carbachol-induced contraction of rat tracheal rings in an isolated organ bath. RESULTS: The results showed that the airway smooth muscle contraction induced by the depolarizing agent (KCl) and cholinergic agonist (carbachol) was markedly reduced by R. graveolens in a concentration-dependent manner, with maximum values of 109 ± 7.9 % and 118 ± 2.6 %, respectively (changes in tension expressed as positive percentages of change in proportion to maximum contraction), at the concentration of 45 µg/mL (half-maximal inhibitory concentration IC50: 35.5 µg/mL and 27.8 µg/mL for KCl- and carbachol-induced contraction, respectively). Additionally, the presence of R. graveolens produced rightward parallel displacement of carbachol dose-response curves and reduced over 35 % of the maximum smooth muscle contraction. CONCLUSIONS: The hydroalcoholic extract of R. graveolens exhibited relaxant activity on rat tracheal rings. The results suggest that the trachea-relaxant effect is mediated by a non-competitive antagonistic mechanism. More detailed studies are needed to identify the target of the inhibition, and to determine more precisely the pharmacological mechanisms involved in the observed biological effects.

Outcomes of Drug-Resistant Urinary Retention in Patients in the Early Stage of Stroke

OBJECTIVE: To investigate the prognosis of patients with stroke and urinary retention resistant to alpha blockers and cholinergic agents. METHODS: Post-void residual urine volume (PVR) was measured in 33 patients with stroke (14 men and 19 women) who were admitted to the department of rehabilitation medicine of our hospital within 30 days after stroke onset. An alpha-blocker and cholinergic agent were administered to patients with PVR >100 mL. If urinary retention had not improved despite the maximum drug doses, the patient was diagnosed with drug-resistant urinary retention. We retrospectively reviewed patient's charts, including PVR at discharge and prognostic factors for PVR. RESULTS: Ten patients (30.3%) could not void or their PVR was >400 mL at discharge (45.7+/-15.4 days after onset) after rehabilitation. Twelve patients (36.4%) could void, and their PVR was 100-400 mL. PVR was consistently <100 mL in 11 patients (33.3%). These measurements correlated with the Korean version of the Modified Barthel Index score, Functional Ambulation Category, and the presence of a communication disorder. CONCLUSION: The results show that 22 patients (66.7%) had incomplete bladder emptying or required catheterization at discharge. Outcomes correlated with functional status, walking ability, and the presence of a communication disorder. Patients with urinary retention and poor general condition require close observation to prevent complications of urinary retention.

Development of an Ex Vivo Model for the Study of Cerebrovascular Function Utilizing Isolated Mouse Olfactory Artery

OBJECTIVE: Cerebral vessels, such as intracerebral perforating arterioles isolated from rat brain, have been widely used as an ex vivo model to study the cerebrovascular function associated with cerebrovascular disorders and the therapeutic effects of various pharmacological agents. These perforating arterioles, however, have demonstrated differences in the vascular architecture and reactivity compared with a larger leptomeningeal artery which has been commonly implicated in cerebrovascular disease. In this study, therefore, we developed the method for studying cerebrovascular function utilizing the olfactory artery isolated from the mouse brain. METHODS: The olfactory artery (OA) was isolated from the C57/BL6 wild-type mouse brain. After removing connective tissues, one side of the isolated vessel segment (approximately -500 microm in length) was cannulated and the opposite end of the vessel was completely sealed while being viewed with an inverted microscope. After verifying the absence of pressure leakage, we examined the vascular reactivity to various vasoactive agents under the fixed intravascular pressure (60 mm Hg). RESULTS: We found that the isolated mouse OAs were able to constrict in response to vasoconstrictors, including KCl, phenylephrine, endothelin-1, and prostaglandin PGH2. Moreover, this isolated vessel demonstrated vasodilation in a dose-dependent manner when vasodilatory agents, acetylcholine and bradykinin, were applied. CONCLUSION: Our findings suggest that the isolated olfactory artery would provide as a useful ex vivo model to study the molecular and cellular mechanisms of vascular function underlying cerebrovascular disorders and the direct effects of such disease-modifying pathways on cerebrovascular function utilizing pharmacological agents and genetically modified mouse models.

Psychotropic Prescription Patterns for Inpatients with Schizophrenia: 10-Year Comparison in a University-Affiliated Hospital in South Korea

OBJECTIVES: Previous literature on the prescription change among patients with schizophrenia mainly focused on antipsychotics. This study investigated chronological change in the patterns of discharge medication among inpatients with schizophrenia at a psychiatric inpatient unit of a university-affiliated hospital. METHODS: All admission records at a psychiatric unit of Hanyang University Guri Hospital with discharge diagnosis of schizophrenia during two different five-year time frames (1996-2000 and 2006-2010) were reviewed including the demographic and clinical data and discharge medications. The data were gathered from a total of 207 patients (95 in 1990s and 112 in 2000s). RESULTS: The frequency in use of atypical antipsychotics (p < 0.01), antidepressants (p < 0.05), beta-blockers (p < 0.01), and benzodiazepine (p < 0.01) was significantly higher in 2000s. Anticholinergic drugs were less likely used in 2000s (p < 0.01). We did not find significant differences in the equivalent dose of antipsychotic drugs, the use of mood stabilizers and cholinergic drugs between two time frames. CONCLUSIONS: Increased proportion of atypical antipsychotics and decreased use of anti-parkinsonian drugs are in line with literature. Our results show that more diverse classes of psychotic medications are used for schizophrenia in recent years. It is likely that psychiatrists are becoming more conscious of negative symptoms, anxiety, and depression in the pharmacotherapy of schizophrenia as well as positive symptoms of the illness.

Expression of non-neuronal cholinergic system in maxilla of rat in vivo

BACKGROUND: Acetylcholine (ACh) is known to be a key neurotransmitter in the central and peripheral nervous systems, which is also produced in a variety of non-neuronal tissues and cell. The existence of ACh in maxilla in vivo and potential regulation role for osteogenesis need further study. RESULTS: Components of the cholinergic system (ACh, esterase, choline acetyltransferase, high-affinity choline uptake, n- and mAChRs) were determined in maxilla of rat in vivo, by means of Real-Time PCR and immunohistochemistry. Results showed RNA for CarAT, carnitine/acylcarnitine translocase member 20 (Slc25a20), VAChT, OCTN2, OCT1, OCT3, organic cation transporter member 4 (Slc22a4), AChE, BChE, nAChR subunits α1, α2, α3, α5, α7, α10, ß1, ß2, ß4, γ and mAChR subunits M1, M2, M3, M4, M5 were detected in rat's maxilla. RNA of VAChT, AChE, nAChR subunits α2, ß1, ß4 and mAChR subunits M4 had abundant expression (2(-ΔCt) > 0.03). Immunohistochemical staining was conducted for ACh, VAChT, nAChRα7 and AChE. ACh was expressed in mesenchymal cells, chondroblast, bone and cartilage matrix and bone marrow cells, The VAChT expression was very extensively while ACh receptor α7 was strongly expressed in newly formed bone matrix of endochondral and bone marrow ossification, AchE was found only in mesenchymal stem cells, cartilage and bone marrow cells. CONCLUSIONS: ACh might exert its effect on the endochondral and bone marrow ossification, and bone matrix mineralization in maxilla.

Cardiac arrest following reversal of muscle relaxation by pyridostigmine: A case report

The anticholinesterase pyridostigmine is usually used as a reversal agent of non-depolarizing muscle relaxants in general anesthesia. Most adverse muscarinic effects of anticholinesterases are controlled by anticholinergics; however, there is still a potential for fatal cardiac complications. We report a case of cardiac arrest associated with coronary vasospasm that developed during emergence from general anesthesia in a 61-year-old male patient undergoing uvulopalatopharyngoplasty with preoperatively undiagnosed coronary vasospastic angina. Anticholinesterases should be administered with caution for neuromuscular blockade reversal, especially in patients with coronary vasospastic angina.

Meynert and the basal nucleus / Meynert e o núcleo basal

Meynert described the "loop of the peduncular foot" (Schlinge des Hirnschenkelfusses), and its ganglion (Ganglion der Hirnschenkelschlinge) and related them to Reil's Substantia innominata and Gratiolet's Ansa peduncularis, from which he apparently built up his findings. Koelliker renamed the ganglion with the eponymous designation Meynert'sches Basalganglion (Meynert's basal ganglion), a name which endures to the present day, and described its topographical spread in relation to neighboring structures. Meynert and Koelliker also described aspects of cell composition of the ganglion (or nucleus) with a better account of the latter. Both, together with Reil and Gratiolet, were the outstanding personalities of the 19th century who performed the pioneering studies on basal formations of the forebrain. After these works, a considerable body of research appeared in the 20th century, with a focus on Meynert's basal nucleus and related structures. The development of further knowledge about these structures revealed their great importance in the activity of the brain, as evidenced in both normal and pathological states.

Meynert descreveu a "alça do pé do pedúnculo" (Schlingedes Hirnschenkelfusses) e seu gânglio (Ganglion der Hirnschenkelschlinge), relacionando-os à Substantia innominata de Reil e à Ansa peduncularis de Gratiolet, a partir dos quais aparentemente desenvolveu seus achados. Koelliker renomeou o gânglio com a designação epônima de Meynert'sches Basalganglion (gânglio basal de Meynert), que perdura até o presente, e descreveu sua extensão topográfica em relação às estruturas vizinhas. Meynert e Koelliker descreveram também aspectos da composição celular do gânglio (ou núcleo), com um relato melhor do segundo. Ambos, juntamente com Reil e Gratiolet, foram as personalidades de destaque do século 19 que realizaram os estudos pioneiros sobre formações basais do prosencéfalo. Após esses, um número considerável de estudos apareceu no século 20, com foco no núcleo basal de Meynert e estruturas relacionadas. O desenvolvimento ulterior do saber sobre as mesmas mostraram sua grande importância na atividade cerebral, como visto em condições normais e patológicas.

Sleep pattern and learning in knockdown mice with reduced cholinergic neurotransmission

Impaired cholinergic neurotransmission can affect memory formation and influence sleep-wake cycles (SWC). In the present study, we describe the SWC in mice with a deficient vesicular acetylcholine transporter (VAChT) system, previously characterized as presenting reduced acetylcholine release and cognitive and behavioral dysfunctions. Continuous, chronic ECoG and EMG recordings were used to evaluate the SWC pattern during light and dark phases in VAChT knockdown heterozygous (VAChT-KDHET, n=7) and wild-type (WT, n=7) mice. SWC were evaluated for sleep efficiency, total amount and mean duration of slow-wave, intermediate and paradoxical sleep, as well as the number of awakenings from sleep. After recording SWC, contextual fear-conditioning tests were used as an acetylcholine-dependent learning paradigm. The results showed that sleep efficiency in VAChT-KDHET animals was similar to that of WT mice, but that the SWC was more fragmented. Fragmentation was characterized by an increase in the number of awakenings, mainly during intermediate sleep. VAChT-KDHET animals performed poorly in the contextual fear-conditioning paradigm (mean freezing time: 34.4±3.1 and 44.5±3.3 s for WT and VAChT-KDHET animals, respectively), which was followed by a 45% reduction in the number of paradoxical sleep episodes after the training session. Taken together, the results show that reduced cholinergic transmission led to sleep fragmentation and learning impairment. We discuss the results on the basis of cholinergic plasticity and its relevance to sleep homeostasis. We suggest that VAChT-KDHET mice could be a useful model to test cholinergic drugs used to treat sleep dysfunction in neurodegenerative disorders.

Trastorno Bipola: respuesta paradojar a la supresión de antidepresivos y neurotransmisión colinérgica / Bipolar disorder: paradoxical response to antidepressants withdrawal and cholinergic neurotransmission

El tratamiento farmacológico de los episodios depresivos en el trastorno bipolar resulta más complejo que el de los episodios maníacos. Además de restituir a un paciente a su estado eutímico, se pretende que su tratamiento no produzca virajes a la manía, ciclado rápido o episodios mixtos. Cuando los fármacos considerados de 1ª línea, litio, lamotrigina, fluoxetina asociada con olanzapina o quetiapina no han dado resultados adecuados, se han ensayado otras asociaciones, entre las que se encuentran aquellas controversiales con los antidepresivos. De manera muy poco frecuente, la aparición paradojal de hipomanías o manías, cuando se suspenden los antidepresivos que están asociados a antirecurrenciales, ha dado lugar a explicaciones que abordan el problema de la neurotransmisión colinérgica en el trastorno bipolar. Este trabajo pretende realizar una revisión sobre ese tema y mencionar posibilidades terapéuticas actuales que se sostienen en dicha neurotransmisión.

The pharmacological treatment of depressive episodes in bipolar disorder is more complex than the pharmacological treatment of manic episodes. In addition to returning a patient to their euthymic state, its treatment is intended not to produce returns to mania, rapid cycling, or mixed episodes. When drugs considered first line, like Lithium, Lamotrigine, Fluoxetine associated with Olanzapine, or Quetiapine, did not show adequate results, other associations have been tested, among which are those ones controversial with antidepressants. Infrequently, the paradoxical appearance of hypomania or mania, whenever the antidepressants which are associated to mood stabilizers are suspended, has led to explanations that address the problem of cholinergic neurotransmission in bipolar disorder. This paper aims to provide a review on the subject and to mention current therapeutic options that are held in such neurotransmission.