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Desarrollo de Fármacos

Sarah E Elzinga1, Diana M Rigan2, Crystal Pacut2

  • 1Michigan State University, East Lansing, MI, USA.

Alzheimer's & dementia : the journal of the Alzheimer's Association
|December 25, 2025
PubMed
Resumen
Este resumen es generado por máquina.

El inhibidor dual SGLT1/2 sotagliflozina mejoró la salud metabólica en ratones con o sin estrés metabólico. Sin embargo, los beneficios cognitivos solo se observaron en controles sanos, lo que sugiere que el deterioro cognitivo en el estrés metabólico puede ser independiente de la glucosa.

Palabras clave:
ratonesestrés metabólicosotagliflozinainhibidores SGLT1/2función cognitivasalud metabólicaneurocienciafarmacologíaobesidadprediabetes

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Área de la Ciencia:

  • Neurociencia; Ciencia Metabólica; Farmacología

Sus antecedentes:

  • Las crecientes tasas de estrés metabólico (obesidad, prediabetes, diabetes) aumentan el riesgo de demencia, particularmente la enfermedad de Alzheimer y las demencias relacionadas (AD/ADRD).; La intervención en el estrés metabólico de mediana edad ofrece una estrategia potencial para prevenir el deterioro cognitivo en la edad avanzada.; Los inhibidores del cotransportador sodio-glucosa (SGLT) muestran promesa para las afecciones metabólicas y pueden beneficiar la salud del cerebro, pero sus efectos específicos sobre la cognición, especialmente la inhibición dual de SGLT1/2, requieren una mayor investigación.

Objetivo del estudio:

  • Investigar el impacto de un inhibidor dual de SGLT1 y SGLT2, sotagliflozina (SOTA), en la función cognitiva y la salud metabólica en un modelo de ratón de estrés metabólico.; Determinar si el tratamiento con SOTA puede mitigar los déficits cognitivos asociados con la disfunción metabólica inducida por la dieta.; Explorar la relación entre las mejoras metabólicas y los resultados cognitivos después de la administración de SOTA.

Principales métodos:

  • Se indujo estrés metabólico en ratones machos C57BL/6 utilizando una dieta alta en grasas (HFD) y L-Nitro-L-arginina metiléster.; Los ratones recibieron gavaje oral diario de sotagliflozina (SOTA; 30 mg/kg) o vehículo durante 10 semanas.; Se evaluó la función cognitiva utilizando pruebas de caja de rompecabezas y laberinto de agua de Morris; se analizaron parámetros metabólicos (peso corporal, tolerancia a la glucosa, HbA1c) y citoquinas plasmáticas.

Principales resultados:

  • El tratamiento con SOTA redujo significativamente el peso corporal, mejoró la tolerancia a la glucosa y disminuyó los niveles de HbA1c tanto en ratones con HFD como en ratones de control.; Los niveles elevados de la citoquina CCL-2 en plasma en ratones con HFD se redujeron con el tratamiento con SOTA.; Si bien la HFD afectó los resultados cognitivos, la SOTA mejoró la función ejecutiva en ratones de control, pero no afectó el rendimiento cognitivo en ratones con HFD.

Conclusiones:

  • La sotagliflozina mejoró eficazmente los parámetros metabólicos independientemente del estrés inducido por la dieta.; Se observaron mejoras cognitivas solo en ratones de control no estresados, lo que sugiere que el deterioro cognitivo inducido por el estrés metabólico puede no depender únicamente de los niveles de glucosa.; Estos hallazgos resaltan una posible disociación entre los beneficios metabólicos y cognitivos de la inhibición de SGLT en el contexto del estrés metabólico.