RESUMEN
The atrioventricular node (AVN) is a key component of the cardiac conduction system and takes over pacemaking of the ventricles if the sinoatrial node fails. IP3 (inositol 1,4,5 trisphosphate) can modulate excitability of myocytes from other regions of the heart, but it is not known whether IP3 receptor (IP3-R) activation modulates AVN cell pacemaking. Consequently, this study investigated effects of IP3 on spontaneous action potentials (APs) from AVN cells isolated from rabbit hearts. Immunohistochemistry and confocal imaging demonstrated the presence of IP3-R2 in isolated AVN cells, with partial overlap with RyR2 ryanodine receptors seen in co-labelling experiments. In whole-cell recordings at physiological temperature, application of 10 µM membrane-permeant Bt3-(1,4,5)IP3-AM accelerated spontaneous AP rate and increased diastolic depolarization rate, without direct effects on ICa,L, IKr, If or INCX. By contrast, application via the patch pipette of 5 µM of the IP3-R inhibitor xestospongin C led to a slowing in spontaneous AP rate and prevented 10 µM Bt3-(1,4,5)IP3-AM application from increasing the AP rate. UV excitation of AVN cells loaded with caged-IP3 led to an acceleration in AP rate, the magnitude of which increased with the extent of UV excitation. 2-APB slowed spontaneous AP rate, consistent with a role for constitutive IP3-R activity; however, it was also found to inhibit ICa,L and IKr, confounding its use for studying IP3-R. Under AP voltage clamp, UV excitation of AVN cells loaded with caged IP3 activated an inward current during diastolic depolarization. Collectively, these results demonstrate that IP3 can modulate AVN cell pacemaking rate.
Asunto(s)
Potenciales de Acción , Nodo Atrioventricular , Receptores de Inositol 1,4,5-Trifosfato , Inositol 1,4,5-Trifosfato , Miocitos Cardíacos , Animales , Conejos , Potenciales de Acción/efectos de los fármacos , Nodo Atrioventricular/efectos de los fármacos , Nodo Atrioventricular/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Inositol 1,4,5-Trifosfato/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Oxazoles/farmacología , MasculinoRESUMEN
BACKGROUND AND OBJECTIVES: Autoantibodies against the protein leucine-rich glioma inactivated 1 (LGI1) cause the most common subtype of autoimmune encephalitis with predominant involvement of the limbic system, associated with seizures and memory deficits. LGI1 and its receptor ADAM22 are part of a transsynaptic protein complex that includes several proteins involved in presynaptic neurotransmitter release and postsynaptic glutamate sensing. Autoantibodies against LGI1 increase excitatory synaptic strength, but studies that genetically disrupt the LGI1-ADAM22 complex report a reduction in postsynaptic glutamate receptor-mediated responses. Thus, the mechanisms underlying the increased synaptic strength induced by LGI1 autoantibodies remain elusive, and the contributions of presynaptic molecules to the LGI1-transsynaptic complex remain unclear. We therefore investigated the presynaptic mechanisms that mediate autoantibody-induced synaptic strengthening. METHODS: We studied the effects of patient-derived purified polyclonal LGI1 autoantibodies on synaptic structure and function by combining direct patch-clamp recordings from presynaptic boutons and somata of hippocampal neurons with super-resolution light and electron microscopy of hippocampal cultures and brain slices. We also identified the protein domain mediating the presynaptic effect using domain-specific patient-derived monoclonal antibodies. RESULTS: LGI1 autoantibodies dose-dependently increased short-term depression during high-frequency transmission, consistent with increased release probability. The increased neurotransmission was not related to presynaptic calcium channels because presynaptic Cav2.1 channel density, calcium current amplitude, and calcium channel gating were unaffected by LGI1 autoantibodies. By contrast, application of LGI1 autoantibodies homogeneously reduced Kv1.1 and Kv1.2 channel density on the surface of presynaptic boutons. Direct presynaptic patch-clamp recordings revealed that LGI1 autoantibodies cause a pronounced broadening of the presynaptic action potential. Domain-specific effects of LGI1 autoantibodies were analyzed at the neuronal soma. Somatic action potential broadening was induced by polyclonal LGI1 autoantibodies and patient-derived monoclonal autoantibodies targeting the epitempin domain, but not the leucin-rich repeat domain. DISCUSSION: Our results indicate that LGI1 autoantibodies reduce the density of both Kv1.1 and Kv1.2 on presynaptic boutons, without actions on calcium channel density or function, thereby broadening the presynaptic action potential and increasing neurotransmitter release. This study provides a molecular explanation for the neuronal hyperactivity observed in patients with LGI1 autoantibodies.
Asunto(s)
Potenciales de Acción , Autoanticuerpos , Péptidos y Proteínas de Señalización Intracelular , Terminales Presinápticos , Transmisión Sináptica , Autoanticuerpos/inmunología , Autoanticuerpos/farmacología , Humanos , Animales , Transmisión Sináptica/fisiología , Péptidos y Proteínas de Señalización Intracelular/inmunología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Terminales Presinápticos/metabolismo , Potenciales de Acción/fisiología , Potenciales de Acción/efectos de los fármacos , Hipocampo/metabolismo , Ratas , Canal de Potasio Kv.1.1/inmunología , Proteínas/inmunología , Proteínas/metabolismo , Masculino , Células CultivadasRESUMEN
Anethole is a terpenoid with antioxidant, anti-inflammatory, and neuronal blockade effects, and the present work was undertaken to study the neuroprotective activity of anethole against diabetes mellitus (DM)-induced neuropathy. Streptozotocin-induced DM rats were used to investigate the effects of anethole treatment on morphological, electrophysiological, and biochemical alterations of the sciatic nerve (SN). Anethole partially prevented the mechanical hyposensitivity caused by DM and fully prevented the DM-induced decrease in the cross-sectional area of the SN. In relation to electrophysiological properties of SN fibers, DM reduced the frequency of occurrence of the 3rd component of the compound action potential (CAP) by 15%. It also significantly reduced the conduction velocity of the 1st and 2nd CAP components from 104.6 ± 3.47 and 39.8 ± 1.02 to 89.9 ± 3.03 and 35.4 ± 1.56 m/s, respectively, and increased the duration of the 2nd CAP component from 0.66 ± 0.04 to 0.82 ± 0.09 ms. DM also increases oxidative stress in the SN, altering values related to thiol, TBARS, SOD, and CAT activities. Anethole was capable of fully preventing all these DM electrophysiological and biochemical alterations in the nerve. Thus, the magnitude of the DM-induced neural effects seen in this work, and the prevention afforded by anethole treatment, place this compound in a very favorable position as a potential therapeutic agent for treating diabetic peripheral neuropathy.
Asunto(s)
Derivados de Alilbenceno , Anisoles , Diabetes Mellitus Experimental , Estrés Oxidativo , Nervio Ciático , Animales , Derivados de Alilbenceno/farmacología , Nervio Ciático/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Ratas , Anisoles/farmacología , Anisoles/uso terapéutico , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Neuropatías Diabéticas/tratamiento farmacológico , Neuropatías Diabéticas/prevención & control , Neuropatías Diabéticas/metabolismo , Potenciales de Acción/efectos de los fármacos , Antioxidantes/farmacología , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéuticoRESUMEN
ABSTRACT: Previous studies have found that anxiety disorders may increase the incidence of atrial fibrillation (AF). More and more studies have shown that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are involved in the occurrence and development of cardiovascular diseases. However, the role of AMPARs in AF associated with anxiety disorder remains unclear. The aim of this study was to investigate the effect of AMPARs on AF susceptibility in rats with anxiety disorder and its possible mechanism. The anxiety disorder rat model was established by unpredictable empty bottle stimulation and was treated with AMPARs agonist and antagonist. Our results showed that AMPARs antagonist treatment significantly reduced sympathetic activity, improved heart rate variability, shortened action potential duration, prolonged effective refractory period, reduced AF induction rate, and improved cardiac electrical remodeling and the expression of inflammatory factors. In addition, inhibition of AMPARs reduced the phosphorylation of IκBα and p65. Our experimental results suggest that inhibition of AMPARs can reduce autonomic remodeling, improve atrial electrical remodeling, and suppress myocardial inflammation, which provides a potential therapeutic strategy for the treatment of AF associated with anxiety disorder.
Asunto(s)
Trastornos de Ansiedad , Fibrilación Atrial , Modelos Animales de Enfermedad , Atrios Cardíacos , Ratas Sprague-Dawley , Receptores AMPA , Animales , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/metabolismo , Masculino , Trastornos de Ansiedad/tratamiento farmacológico , Trastornos de Ansiedad/metabolismo , Trastornos de Ansiedad/fisiopatología , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Receptores AMPA/metabolismo , Remodelación Atrial/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Potenciales de Acción/efectos de los fármacos , Fosforilación , Transducción de Señal , Sistema Nervioso Simpático/fisiopatología , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/metabolismo , Factor de Transcripción ReIA/metabolismo , Ratas , Antiinflamatorios/farmacología , Periodo Refractario Electrofisiológico/efectos de los fármacos , Inhibidor NF-kappaB alfa/metabolismoRESUMEN
Dimethyl sulfoxide (DMSO) is commonly used to dissolve water-insoluble drugs due to its dipolar and aprotic properties. It also serves as a vehicle in many pharmacological studies. However, it has been reported that DMSO can induce seizures in human patients, lower seizure threshold in vivo, and modulate ion receptors activities in vitro. Therefore, we investigated here the effect of 0.03â¯% and 0.06â¯% DMSO, which are 10-50â¯times lower than what usually employed in previous studies, in the 4-aminopyridine (4AP) model of epileptiform synchronization in male mouse brain slices. We found that 0.03â¯% and 0.06â¯% DMSO increase 4AP-induced ictal discharge rate, while 0.06â¯% DMSO decreases ictal discharge duration. Our results suggest that the effects of DMSO on neuronal excitability deserve further analysis and that investigators need to be aware of its confounding effect as a solvent, even at very low concentrations.
Asunto(s)
4-Aminopiridina , Dimetilsulfóxido , Animales , 4-Aminopiridina/farmacología , Dimetilsulfóxido/farmacología , Masculino , Ratones , Epilepsia/fisiopatología , Epilepsia/inducido químicamente , Epilepsia/tratamiento farmacológico , Bloqueadores de los Canales de Potasio/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiologíaRESUMEN
Insulin has been shown to modulate neuronal processes through insulin receptors. The ion channels located on neurons may be important targets for insulin/insulin receptor signaling. Both insulin receptors and acid-sensing ion channels (ASICs) are expressed in dorsal root ganglia (DRG) neurons. However, it is still unclear whether there is an interaction between them. Therefore, the purpose of this investigation was to determine the effects of insulin on the functional activity of ASICs. A 5 min application of insulin rapidly enhanced acid-evoked ASIC currents in rat DRG neurons in a concentration-dependent manner. Insulin shifted the concentration-response plot for ASIC currents upward, with an increase of 46.2 ± 7.6% in the maximal current response. The insulin-induced increase in ASIC currents was eliminated by the insulin receptor antagonist GSK1838705, the tyrosine kinase inhibitor lavendustin A, and the phosphatidylinositol-3 kinase antagonist wortmannin. Moreover, insulin increased the number of acid-triggered action potentials by activating insulin receptors. Finally, local administration of insulin exacerbated the spontaneous nociceptive behaviors induced by intraplantar acid injection and the mechanical hyperalgesia induced by intramuscular acid injections through peripheral insulin receptors. These results suggested that insulin/insulin receptor signaling enhanced the functional activity of ASICs via tyrosine kinase and phosphatidylinositol-3 kinase pathways. Our findings revealed that ASICs were targets in primary sensory neurons for insulin receptor signaling, which may underlie insulin modulation of pain.
Asunto(s)
Canales Iónicos Sensibles al Ácido , Ganglios Espinales , Insulina , Receptor de Insulina , Células Receptoras Sensoriales , Animales , Canales Iónicos Sensibles al Ácido/metabolismo , Insulina/metabolismo , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/efectos de los fármacos , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/citología , Ratas , Receptor de Insulina/metabolismo , Masculino , Transducción de Señal/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Ratas Sprague-Dawley , Hiperalgesia/metabolismo , Células CultivadasRESUMEN
Homeostatic plasticity represents a set of mechanisms thought to stabilize some function of neural activity. Here, we identified the specific features of cellular or network activity that were maintained after the perturbation of GABAergic blockade in two different systems: mouse cortical neuronal cultures where GABA is inhibitory and motoneurons in the isolated embryonic chick spinal cord where GABA is excitatory (males and females combined in both systems). We conducted a comprehensive analysis of various spiking activity characteristics following GABAergic blockade. We observed significant variability in many features after blocking GABAA receptors (e.g., burst frequency, burst duration, overall spike frequency in culture). These results are consistent with the idea that neuronal networks achieve activity goals using different strategies (degeneracy). On the other hand, some features were consistently altered after receptor blockade in the spinal cord preparation (e.g., overall spike frequency). Regardless, these features did not express strong homeostatic recoveries when tracking individual preparations over time. One feature showed a consistent change and homeostatic recovery following GABAA receptor block. We found that spike rate within a burst (SRWB) increased after receptor block in both the spinal cord preparation and cortical cultures and then returned to baseline within hours. These changes in SRWB occurred at both single cell and population levels. Our findings indicate that the network prioritizes the burst spike rate, which appears to be a variable under tight homeostatic regulation. The result is consistent with the idea that networks can maintain an appropriate behavioral response in the face of challenges.
Asunto(s)
Potenciales de Acción , Homeostasis , Neuronas Motoras , Médula Espinal , Animales , Homeostasis/fisiología , Homeostasis/efectos de los fármacos , Médula Espinal/fisiología , Médula Espinal/efectos de los fármacos , Potenciales de Acción/fisiología , Potenciales de Acción/efectos de los fármacos , Femenino , Neuronas Motoras/fisiología , Neuronas Motoras/efectos de los fármacos , Ratones , Masculino , Células Cultivadas , Embrión de Pollo , Corteza Cerebral/fisiología , Corteza Cerebral/efectos de los fármacos , Antagonistas de Receptores de GABA-A/farmacología , Neuronas/fisiología , Neuronas/efectos de los fármacos , Receptores de GABA-A/metabolismo , Plasticidad Neuronal/fisiología , Plasticidad Neuronal/efectos de los fármacos , Ratones Endogámicos C57BLRESUMEN
Preclinical data have confirmed that human pluripotent stem cell-derived cardiomyocytes (PSC-CMs) can remuscularize the injured or diseased heart, with several clinical trials now in planning or recruitment stages. However, because ventricular arrhythmias represent a complication following engraftment of intramyocardially injected PSC-CMs, it is necessary to provide treatment strategies to control or prevent engraftment arrhythmias (EAs). Here, we show in a porcine model of myocardial infarction and PSC-CM transplantation that EAs are mechanistically linked to cellular heterogeneity in the input PSC-CM and resultant graft. Specifically, we identify atrial and pacemaker-like cardiomyocytes as culprit arrhythmogenic subpopulations. Two unique surface marker signatures, signal regulatory protein α (SIRPA)+CD90-CD200+ and SIRPA+CD90-CD200-, identify arrhythmogenic and non-arrhythmogenic cardiomyocytes, respectively. Our data suggest that modifications to current PSC-CM-production and/or PSC-CM-selection protocols could potentially prevent EAs. We further show that pharmacologic and interventional anti-arrhythmic strategies can control and potentially abolish these arrhythmias.
Asunto(s)
Arritmias Cardíacas , Miocitos Cardíacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/trasplante , Animales , Arritmias Cardíacas/terapia , Humanos , Modelos Animales de Enfermedad , Infarto del Miocardio/terapia , Porcinos , Células Cultivadas , Diferenciación Celular , Células Madre Pluripotentes Inducidas/trasplante , Potenciales de Acción/fisiología , Potenciales de Acción/efectos de los fármacos , Fenotipo , Biomarcadores/metabolismo , Células Madre Pluripotentes/trasplante , Trasplante de Células Madre/métodos , Antiarrítmicos/uso terapéutico , Antiarrítmicos/farmacología , Frecuencia Cardíaca/fisiologíaRESUMEN
BACKGROUND: Cardiovascular disease remains one of the leading causes of death globally. Myocardial ischemia and infarction, in particular, frequently cause disturbances in cardiac electrical activity that can trigger ventricular arrhythmias. We aimed to investigate whether catestatin, an endogenous catecholamine-inhibiting peptide, ameliorates myocardial ischemia-induced ventricular arrhythmias in rats and the underlying ionic mechanisms. METHODS AND RESULTS: Adult male Sprague-Dawley rats were randomly divided into control and catestatin groups. Ventricular arrhythmias were induced by ligation of the left anterior descending coronary artery and electrical stimulation. Action potential, transient outward potassium current, delayed rectifier potassium current, inward rectifying potassium current, and L-type calcium current (ICa-L) of rat ventricular myocytes were recorded using a patch-clamp technique. Catestatin notably reduced ventricular arrhythmia caused by myocardial ischemia/reperfusion and electrical stimulation of rats. In ventricular myocytes, catestatin markedly shortened the action potential duration of ventricular myocytes, which was counteracted by potassium channel antagonists TEACl and 4-AP, and ICa-L current channel agonist Bay K8644. In addition, catestatin significantly increased transient outward potassium current, delayed rectifier potassium current, and inward rectifying potassium current density in a concentration-dependent manner. Catestatin accelerated the activation and decelerated the inactivation of the transient outward potassium current channel. Furthermore, catestatin decreased ICa-L current density in a concentration-dependent manner. Catestatin also accelerated the inactivation of the ICa-L channel and slowed down the recovery of ICa-L from inactivation. CONCLUSIONS: Catestatin enhances the activity of transient outward potassium current, delayed rectifier potassium current, and inward rectifying potassium current, while suppressing the ICa-L in ventricular myocytes, leading to shortened action potential duration and ultimately reducing the ventricular arrhythmia in rats.
Asunto(s)
Potenciales de Acción , Cromogranina A , Miocitos Cardíacos , Fragmentos de Péptidos , Ratas Sprague-Dawley , Animales , Masculino , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Cromogranina A/farmacología , Cromogranina A/metabolismo , Potenciales de Acción/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Canales de Calcio Tipo L/metabolismo , Canales de Calcio Tipo L/efectos de los fármacos , Arritmias Cardíacas/fisiopatología , Arritmias Cardíacas/prevención & control , Arritmias Cardíacas/metabolismo , Antiarrítmicos/farmacología , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/fisiopatología , Canales de Potasio de Rectificación Interna/metabolismo , Canales de Potasio de Rectificación Interna/efectos de los fármacos , Modelos Animales de Enfermedad , Bloqueadores de los Canales de Potasio/farmacología , Ratas , Técnicas de Placa-Clamp , Canales de Potasio de Tipo Rectificador Tardío/metabolismo , Canales de Potasio de Tipo Rectificador Tardío/efectos de los fármacos , Canales de Potasio/metabolismo , Canales de Potasio/efectos de los fármacosRESUMEN
The effects of enhanced late INa, a persistent component of the Na+ channel current, on the intracellular ion dynamics and the automaticity of the pulmonary vein cardiomyocytes were studied with fluorescent microscopy. Anemonia viridis toxin II (ATX- II), an enhancer of late INa, caused increases in the basal Na+ and Ca2+ concentrations, increases in the number of Ca2+ sparks and Ca2+ waves, and the generation of repetitive Ca2+ transients. These phenomena were inhibited by eleclazine, a blocker of the late INa; SEA0400, an inhibitor of the Na+/Ca2+ exchanger (NCX); H89, a protein kinase A (PKA) inhibitor; and KN-93, a Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor. These results suggest that enhancement of late INa in the pulmonary vein cardiomyocytes causes disturbance of the intracellular ion environment through activation of the NCX and Ca2+-dependent enzymes. Such mechanisms are probably involved in the ectopic electrical activity of the pulmonary vein myocardium.
Asunto(s)
Calcio , Venenos de Cnidarios , Miocitos Cardíacos , Venas Pulmonares , Intercambiador de Sodio-Calcio , Animales , Venas Pulmonares/metabolismo , Venas Pulmonares/citología , Venas Pulmonares/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Cobayas , Calcio/metabolismo , Venenos de Cnidarios/farmacología , Intercambiador de Sodio-Calcio/metabolismo , Sodio/metabolismo , Masculino , Potenciales de Acción/efectos de los fármacos , Canales de Sodio/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Compuestos de Anilina/farmacología , Sulfonamidas/farmacología , Señalización del Calcio/efectos de los fármacos , Isoquinolinas , Éteres FenílicosRESUMEN
Promising new pharmacological strategies for the enhancement of cognition target either nicotinic acetylcholine receptors (nAChR) or N-methyl-D-aspartate receptors (NMDAR). There is also an increasing interest in low-dose combination therapies co-targeting the above neurotransmitter systems to reach greater efficacy over the monotreatments and to reduce possible side effects of high-dose monotreatments. In the present study, we assessed modulatory effects of the α7 nAChR-selective agonist PHA-543613 (PHA), a novel α7 nAChR positive allosteric modulator compound (CompoundX) and the NMDAR antagonist memantine on the in vivo firing activity of CA1 pyramidal neurons in the rat hippocampus. Three different test conditions were applied: spontaneous firing activity, NMDA-evoked firing activity and ACh-evoked firing activity. Results showed that high but not low doses of memantine decreased NMDA-evoked firing activity, and low doses increased the spontaneous and ACh-evoked firing activity. Systemically applied PHA robustly potentiated ACh-evoked firing activity with having no effect on NMDA-evoked activity. In addition, CompoundX increased both NMDA- and ACh-evoked firing activity, having no effects on spontaneous firing of the neurons. A combination of low doses of memantine and PHA increased firing activity in all test conditions and similar effects were observed with memantine and CompoundX but without spontaneous firing activity increasing effects. Our present results demonstrate that α7 nAChR agents beneficially interact with Alzheimer's disease medication memantine. Moreover, positive allosteric modulators potentiate memantine effects on the right time and the right place without affecting spontaneous firing activity. All these data confirm previous behavioral evidence for the viability of combination therapies for cognitive enhancement.
Asunto(s)
Hipocampo , Memantina , Receptor Nicotínico de Acetilcolina alfa 7 , Animales , Memantina/farmacología , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Receptor Nicotínico de Acetilcolina alfa 7/antagonistas & inhibidores , Hipocampo/efectos de los fármacos , Masculino , Ratas , Neuronas/efectos de los fármacos , Neuronas/fisiología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Relación Dosis-Respuesta a Droga , Cognición/efectos de los fármacos , Cognición/fisiología , Antagonistas de Aminoácidos Excitadores/farmacología , Nootrópicos/farmacología , Ratas Wistar , Ligandos , Agonistas Nicotínicos/farmacologíaRESUMEN
The striatum integrates dopaminergic and glutamatergic inputs to select preferred versus alternative actions. However, the precise mechanisms underlying this process remain unclear. One way to study action selection is to understand how it breaks down in pathological states. Here, we explored the cellular and synaptic mechanisms of levodopa-induced dyskinesia (LID), a complication of Parkinson's disease therapy characterized by involuntary movements. We used an activity-dependent tool (FosTRAP) in conjunction with a mouse model of LID to investigate functionally distinct subsets of striatal direct pathway medium spiny neurons (dMSNs). In vivo, levodopa differentially activates dyskinesia-associated (TRAPed) dMSNs compared to other dMSNs. We found this differential activation of TRAPed dMSNs is likely to be driven by higher dopamine receptor expression, dopamine-dependent excitability, and excitatory input from the motor cortex and thalamus. Together, these findings suggest how the intrinsic and synaptic properties of heterogeneous dMSN subpopulations integrate to support action selection.
Asunto(s)
Cuerpo Estriado , Dopamina , Levodopa , Neuronas , Animales , Dopamina/metabolismo , Levodopa/farmacología , Ratones , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Neuronas/metabolismo , Discinesia Inducida por Medicamentos/metabolismo , Discinesia Inducida por Medicamentos/patología , Sinapsis/metabolismo , Masculino , Ratones Endogámicos C57BL , Potenciales de Acción/efectos de los fármacosRESUMEN
ABSTRACT: Heart rate (HR) stands as a prognostic indicator of cardiovascular disease and a modifiable risk factor in heart failure (HF). Medication intolerance can curtail the application of conventional HR-lowering ß-blockers to the optimum target dose. Ivabradine (IVA), a specific negative-chronotropic agent, selectively inhibits I f current in pacemaker cells of the sinoatrial node without depressing myocardial contractility or comprising hemodynamics. This review summarized ivabradine's clinical labeled and off-label uses and mechanism of action focusing on the clinical outcomes. PubMed was searched up to January 2024 using the main keywords of IVA, coronary artery disease (CAD), HF, postural tachycardia syndrome (POTS), and tachyarrhythmia. To comprehensively review IVA's clinical indications, mechanisms, and therapeutic effects, all studies investigating treatment with IVA in humans were included, comprising different types of studies such as randomized controlled trials and longitudinal prospective observational studies. After screening, 141 studies were included in our review. A large number of reviewed articles were allocated to heart failure with reduced ejection fraction and CAD, suggesting IVA as an alternative to ß-blockers in case of contraindications or intolerance. The beneficial effects of IVA as premedication for coronary computed tomography angiography, HR lowering in POTS, and inappropriate sinus tachycardia constituted most studies among off-label uses. The promising results have been reported on the efficacy of IVA in controlling HR, especially in patients with inappropriate sinus tachycardia or POTS. Owing to the unique mechanism of action, IVA has the potential to be used more frequently in future clinical practice.
Asunto(s)
Fármacos Cardiovasculares , Frecuencia Cardíaca , Ivabradina , Ivabradina/uso terapéutico , Ivabradina/efectos adversos , Humanos , Frecuencia Cardíaca/efectos de los fármacos , Fármacos Cardiovasculares/uso terapéutico , Fármacos Cardiovasculares/efectos adversos , Resultado del Tratamiento , Uso Fuera de lo Indicado , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Animales , Potenciales de Acción/efectos de los fármacosRESUMEN
Ozone (O3) forms in the Earth's atmosphere, both naturally and by reactions of man-made air pollutants. Deleterious effects of O3 have been found in the respiratory system. Here, we examine whether O3 alters olfactory behavior and cellular properties in the olfactory system. For this purpose, mice were exposed to O3 at a concentration found in highly polluted city air [0.8â¯ppm], and the behavior elicited by social and non-social odors in habituation/dishabituation tests was assessed. In addition, the electrical responses of dopaminergic olfactory bulb (OB) neurons were also evaluated. O3 differentially compromises olfactory perception to odors: it reduces responses to social and non-social odors in Swiss Webster mice, while this effect was observed in C57BL/6â¯J mice only for some non-social odors. Additionally, O3 reduced the rate of spontaneous spike firing in periglomerular dopaminergic cells (PG-DA) of the OB. Because this effect could reflect changes in excitability and/or synaptic inputs, the ability of O3 to alter PG-DA spontaneous activity was also tested together with cell membrane resistance, membrane potential, rheobase and chronaxie. Taken together, our data suggest the ability of O3 to affect olfactory perception.
Asunto(s)
Neuronas Dopaminérgicas , Interneuronas , Ratones Endogámicos C57BL , Odorantes , Bulbo Olfatorio , Percepción Olfatoria , Ozono , Animales , Ozono/toxicidad , Bulbo Olfatorio/efectos de los fármacos , Bulbo Olfatorio/fisiología , Percepción Olfatoria/efectos de los fármacos , Percepción Olfatoria/fisiología , Ratones , Masculino , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/fisiología , Interneuronas/efectos de los fármacos , Interneuronas/fisiología , Potenciales de Acción/efectos de los fármacos , Habituación Psicofisiológica/efectos de los fármacos , Contaminantes Atmosféricos/toxicidadRESUMEN
Prostaglandin E2 (PGE2) is a major contributor to inflammatory pain hyperalgesia, however, the extent to which it modulates the activity of nociceptive axons is incompletely understood. We developed and characterized a microfluidic cell culture model to investigate sensitisation of the axons of dorsal root ganglia neurons. We show that application of PGE2 to fluidically isolated axons leads to sensitisation of their responses to depolarising stimuli. Interestingly the application of PGE2 to the DRG axons elicited a direct and persistent spiking activity propagated to the soma. Both the persistent activity and the membrane depolarisation in the axons are abolished by the EP4 receptor inhibitor and a blocker of cAMP synthesis. Further investigated into the mechanisms of the spiking activity showed that the PGE2 evoked depolarisation was inhibited by Nav1.8 sodium channel blockers but was refractory to the application of TTX or zatebradine. Interestingly, the depolarisation of axons was blocked by blocking ANO1 channels with T16Ainh-A01. We further show that PGE2-elicited axonal responses are altered by the changes in chloride gradient within the axons following treatment with bumetanide a Na-K-2Cl cotransporter NKCC1 inhibitor, but not by VU01240551 an inhibitor of potassium-chloride transporter KCC2. Our data demonstrate a novel role for PGE2/EP4/cAMP pathway which culminates in a sustained depolarisation of sensory axons mediated by a chloride current through ANO1 channels. Therefore, using a microfluidic culture model, we provide evidence for a potential dual function of PGE2 in inflammatory pain: it sensitises depolarisation-evoked responses in nociceptive axons and directly triggers action potentials by activating ANO1 and Nav1.8 channels.
Asunto(s)
Anoctamina-1 , Axones , Dinoprostona , Ganglios Espinales , Canal de Sodio Activado por Voltaje NAV1.8 , Canal de Sodio Activado por Voltaje NAV1.8/metabolismo , Animales , Dinoprostona/farmacología , Dinoprostona/metabolismo , Axones/metabolismo , Axones/efectos de los fármacos , Axones/fisiología , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Ratas , Anoctamina-1/metabolismo , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Ratas Sprague-Dawley , Células Cultivadas , Miembro 2 de la Familia de Transportadores de Soluto 12/metabolismo , AMP Cíclico/metabolismoRESUMEN
Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in patients suffering from this largely untreated disease. While many intracellular signalling mechanisms have been examined in preclinical models that drive spontaneous activity, none have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we showed that inhibition of mitogen-activated protein kinase interacting kinase (MNK) with tomivosertib (eFT508, 25 nM) reversibly suppresses spontaneous activity in human sensory neurons that are likely nociceptors based on size and action potential characteristics associated with painful dermatomes within minutes of treatment. Tomivosertib treatment also decreased action potential amplitude and produced alterations in the magnitude of after hyperpolarizing currents, suggesting modification of Na+ and K+ channel activity as a consequence of drug treatment. Parallel to the effects on electrophysiology, eFT508 treatment led to a profound loss of eIF4E serine 209 phosphorylation in primary sensory neurons, a specific substrate of MNK, within 2 min of drug treatment. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain.
Asunto(s)
Potenciales de Acción , Ganglios Espinales , Radiculopatía , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Humanos , Masculino , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Radiculopatía/tratamiento farmacológico , Células Cultivadas , Persona de Mediana Edad , Femenino , Anciano , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Nociceptores/efectos de los fármacos , Nociceptores/metabolismo , Sulfonas/farmacología , Sulfonas/uso terapéutico , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/metabolismoRESUMEN
We derive a next generation neural mass model of a population of quadratic-integrate-and-fire neurons, with slow adaptation, and conductance-based AMPAR, GABAR and nonlinear NMDAR synapses. We show that the Lorentzian ansatz assumption can be satisfied by introducing a piece-wise polynomial approximation of the nonlinear voltage-dependent magnesium block of NMDAR current. We study the dynamics of the resulting system for two example cases of excitatory cortical neurons and inhibitory striatal neurons. Bifurcation diagrams are presented comparing the different dynamical regimes as compared to the case of linear NMDAR currents, along with sample comparison simulation time series demonstrating different possible oscillatory solutions. The omission of the nonlinearity of NMDAR currents results in a shift in the range (and possible disappearance) of the constant high firing rate regime, along with a modulation in the amplitude and frequency power spectrum of oscillations. Moreover, nonlinear NMDAR action is seen to be state-dependent and can have opposite effects depending on the type of neurons involved and the level of input firing rate received. The presented model can serve as a computationally efficient building block in whole brain network models for investigating the differential modulation of different types of synapses under neuromodulatory influence or receptor specific malfunction.
Asunto(s)
Potenciales de Acción , Magnesio , Modelos Neurológicos , Neuronas , Dinámicas no Lineales , Receptores de N-Metil-D-Aspartato , Receptores de N-Metil-D-Aspartato/metabolismo , Magnesio/farmacología , Neuronas/fisiología , Neuronas/efectos de los fármacos , Potenciales de Acción/fisiología , Potenciales de Acción/efectos de los fármacos , Animales , Simulación por Computador , Humanos , Sinapsis/fisiología , Sinapsis/efectos de los fármacosRESUMEN
The present study investigated the impact of central α2-adrenergic mechanisms on sympathetic action potential (AP) discharge, recruitment and latency strategies. We used the microneurographic technique to record muscle sympathetic nerve activity and a continuous wavelet transform to investigate postganglionic sympathetic AP firing during a baseline condition and an infusion of a α2-adrenergic receptor agonist, dexmedetomidine (10 min loading infusion of 0.225 µg kg-1; maintenance infusion of 0.1-0.5 µg kg h-1) in eight healthy individuals (28 ± 7 years, five females). Dexmedetomidine reduced mean pressure (92 ± 7 to 80 ± 8 mmHg, P < 0.001) but did not alter heart rate (61 ± 13 to 60 ± 14 bpm; P = 0.748). Dexmedetomidine reduced sympathetic AP discharge (126 ± 73 to 27 ± 24 AP 100 beats-1, P = 0.003) most strongly for medium-sized APs (normalized cluster 2: 21 ± 10 to 5 ± 5 AP 100 beats-1; P < 0.001). Dexmedetomidine progressively de-recruited sympathetic APs beginning with the largest AP clusters (12 ± 3 to 7 ± 2 clusters, P = 0.002). Despite de-recruiting large AP clusters with shorter latencies, dexmedetomidine reduced AP latency across remaining clusters (1.18 ± 0.12 to 1.13 ± 0.13 s, P = 0.002). A subset of six participants performed a Valsalva manoeuvre (20 s, 40 mmHg) during baseline and the dexmedetomidine infusion. Compared to baseline, AP discharge (Δ 361 ± 292 to Δ 113 ± 155 AP 100 beats-1, P = 0.011) and AP cluster recruitment elicited by the Valsalva manoeuvre were lower during dexmedetomidine (Δ 2 ± 1 to Δ 0 ± 2 AP clusters, P = 0.041). The reduction in sympathetic AP latency elicited by the Valsalva manoeuvre was not affected by dexmedetomidine (Δ -0.09 ± 0.07 to Δ -0.07 ± 0.14 s, P = 0.606). Dexmedetomidine reduced baroreflex gain, most strongly for medium-sized APs (normalized cluster 2: -6.0 ± 5 to -1.6 ± 2 % mmHg-1; P = 0.008). These data suggest that α2-adrenergic mechanisms within the central nervous system modulate sympathetic postganglionic neuronal discharge, recruitment and latency strategies in humans. KEY POINTS: Sympathetic postganglionic neuronal subpopulations innervating the human circulation exhibit complex patterns of discharge, recruitment and latency. However, the central neural mechanisms governing sympathetic postganglionic discharge remain unclear. This microneurographic study investigated the impact of a dexmedetomidine infusion (α2-adrenergic receptor agonist) on muscle sympathetic postganglionic action potential (AP) discharge, recruitment and latency patterns. Dexmedetomidine infusion inhibited the recruitment of large and fast conducting sympathetic APs and attenuated the discharge of medium sized sympathetic APs that fired during resting conditions and the Valsalva manoeuvre. Dexmedetomidine infusion elicited shorter sympathetic AP latencies during resting conditions but did not affect the reductions in latency that occurred during the Valsalva manoeuvre. These data suggest that α2-adrenergic mechanisms within the central nervous system modulate sympathetic postganglionic neuronal discharge, recruitment and latency strategies in humans.
Asunto(s)
Potenciales de Acción , Agonistas de Receptores Adrenérgicos alfa 2 , Dexmedetomidina , Sistema Nervioso Simpático , Humanos , Dexmedetomidina/farmacología , Femenino , Adulto , Masculino , Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Sistema Nervioso Simpático/fisiología , Sistema Nervioso Simpático/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Adulto Joven , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Presión Sanguínea/fisiología , Presión Sanguínea/efectos de los fármacos , Músculo Esquelético/fisiología , Músculo Esquelético/inervación , Músculo Esquelético/efectos de los fármacos , Receptores Adrenérgicos alfa 2/fisiología , Receptores Adrenérgicos alfa 2/metabolismoRESUMEN
Gap junctions are channels that allow for direct transmission of electrical signals between cells. However, the ability of one cell to be impacted or controlled by other cells through gap junctions remains unclear. In this study, heterocellular coupling between ON α retinal ganglion cells (α-RGCs) and displaced amacrine cells (ACs) in the mouse retina was used as a model. The impact of the extent of coupling of interconnected ACs on the synchronized firing between coupled ON α-RGC-AC pair was investigated using the dopamine 1 receptor (D1R) antagonist-SCH23390 and agonist-SKF38393. It was observed that the synchronized firing between the ON α-RGC-ACs pairs was increased by the D1R antagonist SCH23390, whereas it was eradicated by the agonist SKF38393. Subsequently, the signaling drive was investigated by infecting coupled ON α-RGC-AC pairs with the channelrhodopsin-2(ChR2) mutation L132C engineered to enhance light sensitivities. The results demonstrated that the spikes of ON α-RGCs (without ChR2) could be triggered by ACs (with ChR2) through the gap junction, and vice versa. Furthermore, it was observed that ON α-RGCs stimulated with 3-10 Hz currents by whole cell patch could elicit synchronous spikes in the coupled ACs, and vice versa. This provided direct evidence that the firing of one cell could be influenced by another cell through gap junctions. However, this phenomenon was not observed between OFF α-RGC pairs. The study implied that the synchronized firing between ON α-RGC-AC pairs could potentially be affected by the coupling of interconnected ACs. Additionally, one cell type could selectively control the firing of another cell type, thereby forcefully transmitting information. The key role of gap junctions in synchronizing firing and driving cells between α-RGCs and coupled ACs in the mouse retina was highlighted.NEW & NOTEWORTHY This study investigates the role of gap junctions in transmitting electrical signals between cells and their potential for cell control. Using ON α retinal ganglion cells (α-RGCs) and amacrine cells (ACs) in the mouse retina, the researchers find that the extent of coupling between ACs affects synchronized firing. Bidirectional signaling occurs between ACs and ON α-RGCs through gap junctions.
Asunto(s)
Potenciales de Acción , Células Amacrinas , Uniones Comunicantes , Células Ganglionares de la Retina , Animales , Células Amacrinas/metabolismo , Células Amacrinas/fisiología , Células Amacrinas/efectos de los fármacos , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/fisiología , Ratones , Uniones Comunicantes/metabolismo , Uniones Comunicantes/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Ratones Endogámicos C57BL , Retina/metabolismo , Retina/fisiología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/agonistas , Comunicación Celular/fisiología , Masculino , Channelrhodopsins/metabolismo , Channelrhodopsins/genéticaRESUMEN
The reticular thalamic nucleus (RTN) is a thin shell that covers the dorsal thalamus and controls the overall information flow from the thalamus to the cerebral cortex through GABAergic projections that contact thalamo-cortical neurons (TC). RTN neurons receive glutamatergic afferents fibers from neurons of the sixth layer of the cerebral cortex and from TC collaterals. The firing mode of RTN neurons facilitates the generation of sleep-wake cycles; a tonic mode or desynchronized mode occurs during wake and REM sleep and a burst-firing mode or synchronized mode is associated with deep sleep. Despite the presence of cannabinoid receptors CB1 (CB1Rs) and mRNA that encodes these receptors in RTN neurons, there are few works that have analyzed the participation of endocannabinoid-mediated transmission on the electrical activity of RTN. Here, we locally blocked or activated CB1Rs in ketamine anesthetized rats to analyze the spontaneous extracellular spiking activity of RTN neurons. Our results show the presence of a tonic endocannabinoid input, since local infusion of AM 251, an antagonist/inverse agonist, modifies RTN neurons electrical activity; furthermore, local activation of CB1Rs by anandamide or WIN 55212-2 produces heterogeneous effects in the basal spontaneous spiking activity, where the main effect is an increase in the spiking rate accompanied by a decrease in bursting activity in a dose-dependent manner; this effect is inhibited by AM 251. In addition, previous activation of GABA-A receptors suppresses the effects of CB1Rs on reticular neurons. Our results show that local activation of CB1Rs primarily diminishes the burst firing mode of RTn neurons.