ABSTRACT
Neuropathic pain is a chronic disease that severely afflicts the life and emotional status of patients, but currently available treatments are often ineffective. Novel therapeutic targets for the alleviation of neuropathic pain are urgently needed. Rhodojaponin VI, a grayanotoxin from Rhododendron molle, showed remarkable antinociceptive efficacy in models of neuropathic pain, but its biotargets and mechanisms are unknown. Given the reversible action of rhodojaponin VI and the narrow range over which its structure can be modified, we perforwmed thermal proteome profiling of the rat dorsal root ganglion to determine the protein target of rhodojaponin VI. N-Ethylmaleimide-sensitive fusion (NSF) was confirmed as the key target of rhodojaponin VI through biological and biophysical experiments. Functional validation showed for the first time that NSF facilitated trafficking of the Cav2.2 channel to induce an increase in Ca2+ current intensity, whereas rhodojaponin VI reversed the effects of NSF. In conclusion, rhodojaponin VI represents a unique class of analgesic natural products targeting Cav2.2 channels via NSF.
ABSTRACT
Introdução: No contexto do Sistema Único de Saúde, o conceito da prevenção quaternária adentra timidamente os níveis de atenção à saúde, no entanto, sofre expansão significativa no âmbito da atenção primária à saúde. Objetivo: Identificar por meio da sistematização de evidências científicas, as contribuições técnicas e socioculturais da prevenção quaternária no âmbito da atenção primária à saúde no Brasil. Métodos: Trata-se de uma revisão integrativa de estudos presentes nas bases de dados científicas da Scientific Electronic Library Online, Biblioteca Virtual em Saúde, biblioteca virtual da Comissão de Aperfeiçoamento de Pessoal do Nível Superior e MEDLINE via PubMed com a utilização dos descritores "prevenção quaternária" e "atenção primária à saúde", em inglês e português. Resultados: O corpus de análise foi composto por 22 artigos, sendo que a produção científica sobre o tema se deu de forma mais intensa a partir do ano de 2015 e, em sua maioria, possuíam como abordagem metodológica ensaios teóricos. Dentre as contribuições técnicas destacaram-se a introdução do ensino da prevenção quaternária de modo continuado aos graduandos e profissionais; a construção de protocolos e documentos de amparo profissional; a utilização de modelos explicativos dinâmicos na socialização do quadro clínico; a conduta profissional com os usuários e as contribuições socioculturais envolvendo mudanças na percepção profissional e comunitária sobre o fenômeno saúde-doença, assim como o incentivo a práticas de desmedicalização sociocultural em relação à dor, incapacidade, desconforto, envelhecimento, nascimento e morte. Conclusão: Apesar do reconhecimento das potencialidades da prevenção quaternária, faz-se necessário fortalecer estratégias que possibilitem o desenvolvimento de políticas públicas para fomentar e gerenciar alianças estratégicas com tomadores de decisão, profissionais de saúde e cidadãos, para fomentar a redução de diagnósticos e tratamentos excessivos, contribuindo com a qualidade do cuidado.
Introduction: In the context of the Unified Health System, the concept of quaternary prevention shyly enters the levels of health care, however, undergoes significant expansion in the scope of primary health care. Objective: To identify, through the systematization of scientific evidence, the technical and socio-cultural contributions of quaternary prevention within the scope of primary health care in Brazil. Methods: This is an integrative review of studies present in the scientific databases of the Scientific Electronic Library Online, Regional Portal of the Virtual Health Library of the Latin American and Caribbean Center on Health Sciences Information of the Pan American Health Organization, virtual library of the Higher Education Personnel Improvement Commission, and MEDLINE through PubMed using the descriptors "quaternary prevention" and "primary health care", in English and Portuguese. Results: The corpus of analysis consisted of 22 articles, and the scientific production on the topic took place more intensively from the year 2015 and, for the most part, had theoretical essays as methodological approach. Among the technical contributions, we highlight the introduction of teaching on quaternary prevention in a continuous way to undergraduates and professionals; the construction of protocols and documents of professional support; the use of dynamic explanatory models in the socialization of the clinical picture and professional conduct with users and socio-cultural contributions involve changes in the professional and community perception about the phenomenon of illness and health conception, as well as the incentive to practices of socio-cultural demedicalization in relation to pain, disability, discomfort, aging, birth, and death. Conclusion: Despite the recognition of the potential of quaternary prevention, it is necessary to strengthen strategies that enable the development of public policies to foster and manage strategic alliances with decision makers, health professionals and citizens, to promote the reduction of excessive diagnoses and treatments, contributing to the quality of care.
Introducción: En el contexto del Sistema Único de Salud, el concepto de prevención cuaternaria entra tímidamente en los niveles de atención de salud, sin embargo, experimenta una expansión significativa en el alcance de la Atención Primaria de Salud. Objetivo: Identificar, a través de la sistematización de evidencia científica, las contribuciones técnicas y socioculturales de la prevención cuaternaria en el ámbito de la Atención Primaria de Salud en Brasil. Métodos: Esta es una revisión integradora de estudios presentes en las bases de datos científicas de la Biblioteca Electrónica Científica en línea, Portal Regional de la Biblioteca Virtual en Salud del Centro Latinoamericano y del Caribe de Información en Ciencias de la Salud de la Organización Panamericana de la Salud, biblioteca virtual de la Comisión de Mejoramiento del Personal de Educación Superior y MEDLINE a través de PubMed utilizando los descriptores de prevención cuaternaria y atención primaria de salud, en inglés y portugués. Resultados: El corpus de análisis estuvo conformado por 22 artículos, siendo la producción científica sobre el tema más intensiva desde 2015 y, en su mayor parte, tuvo ensayos teóricos como abordaje metodológico. Entre los aportes técnicos, destacamos la implantación de la docencia en prevención cuaternaria de forma continua a estudiantes de pregrado y profesionales; construcción de protocolos y documentos de apoyo profesional, uso de modelos explicativos dinámicos en la socialización del cuadro clínico y conducta profesional con los usuarios y los aportes socioculturales implican cambios en la percepción profesional y comunitaria sobre el fenómeno de la enfermedad y la concepción de la salud, así como el incentivo a prácticas de desmedicalización sociocultural en relación al dolor, discapacidad, malestar, envejecimiento, nacimiento y muerte. Conclusión: A pesar del reconocimiento del potencial de la prevención cuaternaria, es necesario fortalecer estrategias que permitan el desarrollo de políticas públicas para fomentar y gestionar alianzas estratégicas con los tomadores de decisiones, profesionales de la salud y ciudadanos, para promover la reducción de diagnósticos y tratamientos excesivos, contribuyendo a la calidad de la atención.
Subject(s)
Primary Health Care , Unified Health System , Family Practice , Medical Overuse , Quaternary PreventionABSTRACT
Aim To investigate the anti-neuropathic pain effect of DXL-A-22 and further to explore the potential mechanisms. Methods The anti-neuropathic pain effect was evaluated by chronic constriction injury (CCI) model. The potential anti-neuropathic pain mechanisms of DXL-A-22 was studied by Western blot and qPCR. The acute toxicity was evaluated by ultimate test. Results DXL-A-22 (2,1,0. 5 mg . kg-1 ,i. g.) dose-dependently elevated the mechanical withdrawal threshold (MWT) and the paw withdrawal latency (PWL) in CCI rats (P < 0. 05, P < 0. 01), the percentage of pain threshold elevation (PTE%) and the percentage of Maximal Possible Effect (MPE%) was 108%,86%,71% and 77%,56%,43% respectively on day 7 post-operation. DXL-A-22 (2 mg . kg-1 ,i. g.) significantly reduced the expression of p-CaMK II α, p-CREB, p-JAK2, p-STAT3 proteins and TNF-α mRNA, c-Fos mRNA in DRG (P < 0. 05, P < 0.01), and the percent inhibition was 37%, 48%, 35%,58%, 39% and 32% respectively. The expression of TNF-α mRNA and c-Fos mRNA in spinal pord was reduced by 47% and 72% respectively in CCI rats (P <0. 01). Acute toxicity test showed that DXL-A-22 had no obvious toxicity reaction. Conclusions Spirocyclopiperazinium salt compound DXL-A-22 exerts significant antinociceptive effect on CCI model. The anti-neuropathic pain effect of DXL-A-22 may be related to the inhibition of CaMK II α/CREB and JAK2/STAT3 signaling pathways, and the inhibition of the mRNA expression of TNF-α and c-Fos.