RESUMEN
While high risk of failure is an inherent part of developing innovative therapies, it can be reduced by adherence to evidence-based rigorous research practices. Supported through the European Union's Innovative Medicines Initiative, the EQIPD consortium has developed a novel preclinical research quality system that can be applied in both public and private sectors and is free for anyone to use. The EQIPD Quality System was designed to be suited to boost innovation by ensuring the generation of robust and reliable preclinical data while being lean, effective and not becoming a burden that could negatively impact the freedom to explore scientific questions. EQIPD defines research quality as the extent to which research data are fit for their intended use. Fitness, in this context, is defined by the stakeholders, who are the scientists directly involved in the research, but also their funders, sponsors, publishers, research tool manufacturers, and collaboration partners such as peers in a multi-site research project. The essence of the EQIPD Quality System is the set of 18 core requirements that can be addressed flexibly, according to user-specific needs and following a user-defined trajectory. The EQIPD Quality System proposes guidance on expectations for quality-related measures, defines criteria for adequate processes (i.e. performance standards) and provides examples of how such measures can be developed and implemented. However, it does not prescribe any pre-determined solutions. EQIPD has also developed tools (for optional use) to support users in implementing the system and assessment services for those research units that successfully implement the quality system and seek formal accreditation. Building upon the feedback from users and continuous improvement, a sustainable EQIPD Quality System will ultimately serve the entire community of scientists conducting non-regulated preclinical research, by helping them generate reliable data that are fit for their intended use.
Asunto(s)
Investigación Biomédica/normas , Evaluación Preclínica de Medicamentos/normas , Proyectos de Investigación/normas , Conducta Cooperativa , Exactitud de los Datos , Difusión de Innovaciones , Europa (Continente) , Humanos , Comunicación Interdisciplinaria , Control de Calidad , Mejoramiento de la Calidad , Participación de los InteresadosRESUMEN
Cognitive impairments can be devastating for quality of life, and thus, preventing or counteracting them is of great value. To this end, the present study exploits the potential of the plant Rhodiola rosea and identifies the constituent ferulic acid eicosyl ester [icosyl-(2E)-3-(4-hydroxy-3-methoxyphenyl)-prop-2-enoate (FAE-20)] as a memory enhancer. We show that food supplementation with dried root material from R. rosea dose-dependently improves odor-taste reward associative memory scores in larval Drosophila and prevents the age-related decline of this appetitive memory in adult flies. Task-relevant sensorimotor faculties remain unaltered. From a parallel approach, a list of candidate compounds has been derived, including R. rosea-derived FAE-20. Here, we show that both R. rosea-derived FAE-20 and synthetic FAE-20 are effective as memory enhancers in larval Drosophila. Synthetic FAE-20 also partially compensates for age-related memory decline in adult flies, as well as genetically induced early-onset loss of memory function in young flies. Furthermore, it increases excitability in mouse hippocampal CA1 neurons, leads to more stable context-shock aversive associative memory in young adult (3-month-old) mice, and increases memory scores in old (>2-year-old) mice. Given these effects, and given the utility of R. rosea-the plant from which we discovered FAE-20-as a memory enhancer, these results may hold potential for clinical applications.
Asunto(s)
Ácidos Cumáricos/farmacología , Ésteres/farmacología , Memoria/efectos de los fármacos , Rhodiola/química , Factores de Edad , Animales , Abejas , Conducta Animal/efectos de los fármacos , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/efectos de los fármacos , Suplementos Dietéticos , Drosophila melanogaster , Miedo/efectos de los fármacos , Larva/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Extractos Vegetales/farmacología , Especificidad de la EspecieRESUMEN
Yokukansan (YKS) is a traditional Japanese herbal medicine that has been used in humans for the treatment of several neurological conditions, such as age-related anxiety and behavioral and psychological symptoms (BPSD) related to multiple forms of dementia, including Alzheimer's disease (AD). However, the cellular and molecular mechanisms targeted by YKS in the brain are not completely understood. Here, we compared the efficacy of YKS in ameliorating the age- and early-onset familial AD-related behavioral and cellular defects in two groups of animals: 18- to 22-month-old C57BL6/J wild-type mice and 6- to 9-month-old 5xFAD mice, as a transgenic mouse model of this form of AD. Animals were fed food pellets that contained YKS or vehicle. After 1-2 months of YKS treatment, we evaluated the cognitive improvements in both the aged and 5xFAD transgenic mice, and their brain tissues were further investigated to assess the molecular and cellular changes that occurred following YKS intake. Our results show that both the aged and 5xFAD mice exhibited impaired behavioral performance in novel object recognition and contextual fear conditioning (CFC) tasks, which was significantly improved by YKS. Further analyses of the brain tissue from these animals indicated that in aged mice, this improvement was associated with a reduction in astrogliosis, microglia activation and downregulation of the extracellular matrix (ECM), whereas in 5xFAD mice, none of these mechanisms were evident. These results show the differential action of YKS in healthy aged and 5xFAD mice. However, both aged and 5xFAD YKS-treated mice showed increased neuroprotective signaling through protein kinase B/Akt as the common mode of action. Our data suggest that YKS may impart its beneficial effects through Akt signaling in both 5xFAD mice and aged mice, with multiple additional mechanisms potentially contributing to its beneficial effects in aged animals.