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Bifendato inhibe la parthanatos celular activando la vía MEK/ERK
Ao-Meng Hu1, Meng Chen1, Can-Can Zhu1
1School of Preclinical Medicine, Wannan Medical College, Wuhu, 241002, China.
Biochemistry and biophysics reports
|January 26, 2026
Resumen
El bifendato (DDB), un fármaco contra la hepatitis, suprime eficazmente la parthanatos, una vía de muerte celular implicada en enfermedades neurodegenerativas. El DDB protege las células bloqueando la translocación de AIF sin comprometer la función de PARP-1, ofreciendo una estrategia terapéutica más segura.
Área de la Ciencia:
- Neurociencia
- Biología Celular
- Farmacología
Sus antecedentes:
- La parthanatos es una vía de muerte celular programada implicada en enfermedades neurodegenerativas y accidente cerebrovascular isquémico.
- Los inhibidores convencionales de PARP-1 pueden detener la parthanatos, pero pueden provocar inestabilidad genómica con el uso prolongado.
Objetivo del estudio:
- Identificar un nuevo supresor de la parthanatos a partir de una biblioteca de compuestos aprobados por la NMPA.
- Investigar el mecanismo de acción del bifendato (DDB) en la inhibición de la parthanatos.
- Evaluar el DDB como un agente terapéutico potencial para trastornos neurológicos.
Principales métodos:
- Cribado de una biblioteca de compuestos aprobados por la NMPA para identificar supresores de la parthanatos.
- Ensayos de viabilidad celular en células HeLa y SH-SY5Y tratadas con MNNG y DDB.
- Western blot para evaluar los niveles de proteína de PARP-1, AIF y MIF.
- Ensayos mitocondriales para evaluar el potencial de membrana y la translocación de AIF.
- Análisis de la vía de señalización ERK (MEK, activación de ERK, fosforilación de Bad).
Principales resultados:
- El bifendato (DDB) se identificó como un supresor eficaz de la parthanatos.
- El DDB aumentó la viabilidad celular en aproximadamente un 30% en células HeLa y un 70% en células SH-SY5Y.
- El DDB bloqueó la translocación de AIF desde las mitocondrias sin alterar los niveles de proteína de PARP-1, AIF o MIF.
- El DDB activó la vía de señalización MEK/ERK, lo que condujo a la fosforilación de Bad, manteniendo la integridad mitocondrial y previniendo la liberación de AIF.
- El DDB inhibió la parthanatos aguas abajo de la activación de PARP-1 sin afectar la actividad enzimática de PARP-1.
Conclusiones:
- El DDB es un candidato terapéutico prometedor para trastornos neurológicos debido a su capacidad para inhibir la parthanatos.
- El DDB ofrece una estrategia neuroprotectora al modular la señalización ERK y prevenir la muerte celular mediada por AIF.
- El DDB representa una alternativa más segura a los inhibidores tradicionales de PARP-1, evitando los riesgos de inestabilidad genómica.
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