ABSTRACT
The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows that inhibiting c-Abl tyrosine kinase prevents apoptosis, reduces dendritic spine loss, and maintains N-methyl-d-aspartate (NMDA) receptor subunit 2B (NR2B) phosphorylated in in vitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promotes c-Abl phosphorylation, and disrupting c-Abl activity leads to fewer seizures, increases latency toward SE, and improved animal survival. Currently, clinically used c-Abl inhibitors are non-selective and have poor brain penetration. The allosteric c-Abl inhibitor, neurotinib, used here has favorable potency, selectivity, pharmacokinetics, and vastly improved brain penetration. Neurotinib-administered mice have fewer seizures and improved survival following pilocarpine-SE induction. Our findings reveal c-Abl kinase activation as a key factor in ictogenesis and highlight the impact of its inhibition in preventing the insurgence of epileptic-like seizures in rodents and humans.
Subject(s)
Pilocarpine , Proto-Oncogene Proteins c-abl , Seizures , Animals , Male , Mice , Apoptosis/drug effects , Mice, Inbred C57BL , Neurons/drug effects , Neurons/pathology , Neurons/metabolism , Phosphorylation/drug effects , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-abl/metabolism , Proto-Oncogene Proteins c-abl/antagonists & inhibitors , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Seizures/chemically induced , Seizures/drug therapy , Seizures/pathology , Status Epilepticus/chemically induced , Status Epilepticus/drug therapy , Status Epilepticus/pathologyABSTRACT
Among the several programs that allow access to medical specialization in Chile, the National Health Services System Entrance Contest (CONISS) is held annually for newly graduated physicians, which has a high number of applicants. The academic qualifications expressed as National Medical Qualification (CMN) are the main item of the scoring system. We reviewed the total scores and the CMN of the different medical specialization programs that exist in the country, which constitutes novel and relevant information for future medical graduates interested in applying to the program. In addition, the quotas of the different programs are reported, expressed as total, free, and used quotas.
Subject(s)
Internship and Residency , Medicine , Physicians , Chile , Humans , Specialization , State MedicineABSTRACT
Among the several programs that allow access to medical specialization in Chile, the National Health Services System Entrance Contest (CONISS) is held annually for newly graduated physicians, which has a high number of applicants. The academic qualifications expressed as National Medical Qualification (CMN) are the main item of the scoring system. We reviewed the total scores and the CMN of the different medical specialization programs that exist in the country, which constitutes novel and relevant information for future medical graduates interested in applying to the program. In addition, the quotas of the different programs are reported, expressed as total, free, and used quotas.
Subject(s)
Humans , Physicians , Internship and Residency , Medicine , Specialization , State Medicine , ChileABSTRACT
Pharmacological evidence associates type I dopamine receptors, including subtypes D1 and D5, with learning and memory. Analyses using genetic approaches have determined the relative contribution of dopamine receptor D1 (D1R) in cognitive tasks. However, the lack of drugs that can discriminate between D1R and D5R has made the pharmacological distinction between the two receptors difficult. Here, we aimed to determine the role of D5R in learning and memory. In this study we tested D5R knockout mice and wild-type littermates in a battery of behavioral tests, including memory, attention, locomotion, anxiety and motivational evaluations. Our results show that genetic deficiency of D5R significantly impairs performance in the Morris water maze paradigm, object location and object recognition memory, indicating a relevant role for D5R in spatial memory and recognition memory. Moreover, the lack of D5R resulted in decreased exploration and locomotion. In contrast, D5R deficiency had no impact on working memory, anxiety and depressive-like behavior, measured using the spontaneous alternation, open-field, tail suspension test, and forced swimming test. Electrophysiological analyses performed on hippocampal slices showed impairment in long-term-potentiation in mice lacking D5R. Further analyses at the molecular level showed that genetic deficiency of D5R results in a strong and selective reduction in the expression of the NMDA receptor subunit NR2B in the hippocampus. These findings demonstrate the relevant contribution of D5R in memory and suggest a functional interaction of D5R with hippocampal glutamatergic pathways.
Subject(s)
Hippocampus/physiology , Memory/physiology , Receptors, Dopamine D5/physiology , Receptors, N-Methyl-D-Aspartate/physiology , Animals , Anxiety/physiopathology , Attention/physiology , Long-Term Potentiation , Male , Memory, Short-Term/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity , Receptors, Dopamine D5/genetics , Recognition, Psychology/physiology , Spatial Memory/physiologyABSTRACT
Contiene: Introducción. Explorando caminos interculturales desde contextos (trans)andinos: toda belleza es relación, Koen de Munter; El desafío de la interculturalidad, Juan Ansion; Interculturalidad, policulturalidad y creolización-una reflexión y un caso, Anke Van R. Romero F.; Interculturalidad y liberación. A propósito del Carnaval de Oruro, Javier R. Romero F.; Matices cruzadas en nuestras dicotomías actuales: civilización y barbarie, Facundo y las morenadas, Jorge Vargas; El derecho humano y la migración y las ciudadanías interculturales emergentes: el caso de la minoría de origen boliviano en la Ciudad de Buenos Aires, Alcira B. Bonilla y Eduardo J. Vior (U. de Buenos Aires); Interculturalidad, a propósito del proceso político boliviano, Marcelo Lara Barrientos; Dilemas de los caminos de interculturalidad en Bolivia, Máximo Quisbert; Procesos de construcciones interculturales: un relato personal, Edgar Huarachi Mamani; Prácticas interculturales del movimiento cultural de hip-hop en la ciudad de El Alto, María Ángela Riveros Pinto; Los talleres de aprendizaje y promoción intercultural y el Centro Educativo "Santos Marka Túla", Paulo Ramiro Paricagua Titichoca; Encuentro y construcción intercultural, Fernando Rada Arteaga (Oyhana Pukara); Kimsa qamawin wakápacha: tiempo de seres sagrados con tres culturas, Teófilo laime Ajacopa
