P2X4 Purinergic Receptor- Based Therapeutic Strategies for Experimental Multiple Sclerosis
- Autores: Gilda Paloma Mata Salgado
- Directores de la Tesis: Alberto Pérez Samartin (dir. tes.), Maria Domercq Garcia (codir. tes.)
- Lectura: En la Universidad del País Vasco - Euskal Herriko Unibertsitatea ( España ) en 2025
- Idioma: inglés
- Número de páginas: 154
- Programa de doctorado: Programa de Doctorado en Neurociencias por la Universidad de A Coruña; la Universidad de Castilla-La Mancha; la Universidad del País Vasco/Euskal Herriko Unibertsitatea; la Universidad Pablo de Olavide y la Universidad Rovira i Virgili
- Menciones:
- Internacional
- Calificación: Sobresaliente Cum Laude
- Enlaces
- Tesis en acceso abierto en: addi.ehu.eus
- Resumen
P2X4 purinergic receptors, ATP-gated ion channels highly expressed in microglia, play an important role in neuroinflammatory conditions such as multiple sclerosis (MS). While microglia contribute to both damage and repair, P2X4 activation enhances beneficia! functions like myelin clearance and remyelination. This thesis explores two complementary strategies to enhance P2X4 activity and assess its therapeutic potential in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. First, a library of novel allosteric modulators (MSKs), inspired by ivermectin and synthesized via click chemistry, was screened electrophysiologically. Two compounds with distinct modulatory profiles improved motor symptoms in EAE mice, highlighting their potential as P2X4-targeting therapeutics. Second, knock-in mice overexpressing a membrane-localized P2X4 receptor (P2X4mCherrylN) showed improved EAE outcomes, but only in females. Progesterone was found to enhance P2X4 function, and ovariectomy abolished the protective effects, revealing a sex-dependent regulation of P2X4 by ovarian hormones.
