Participation of nuclear receptors PPARγ and RXR in the remyelination process.

ANA M. ADAMO. ; DÉBORA RODRÍGUEZ; LAURA GÓMEZ PINTO; PATRICIA MATHIEU

CABA

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Participation of nuclear receptors PPARγ and RXR in the remyelination process Débora Rodríguez, Laura Gómez Pinto, Patricia Mathieu and Ana M. Adamo. Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, IQUIFIB-CONICET, Argentina.Demyelination is a pathological process by which myelin is lost from around axons and, in the CNS, it is usually the consequence of a direct insult on oligodendrocytes (OL). In turn, remyelination is the process by which myelin sheaths are restored to demyelinated axons, a function attributed to adult CNS oligodendroglial precursor cells (OPC). Some of these OPC reside in the adult brain, while others are derived from neural precusor cells (NPC) present in the subventricular zone (SVZ) and help remyelinate neighboring areas. Recent work using demyelination models has proven a significant increase in the transcript of retinoid X receptor γ (RXRγ) during remyelination in the CNS. RXRs are nuclear receptors regulating cell proliferation and differentiation, and form homodimers or heterodimers with other nuclear receptors including peroxisome proliferator activator proteins (PPAR), which also participate in the regulation of OL differentiation and maturation. The aim of the present work is to study joint activation of RXRγ and PPARγ by specific agonists 9 cis retinoic acid (RA) and Pioglitazone (PIO), respectively, in remyelination through in vivo experiments using cuprizone (CPZ)-induced demyelination in mice. Eighy-week-old mice were fed 0.2% CPZ for 5 weeks, when they were stereotaxically injected vehicle or 1 µl containing 0.1µg RA, PIO or PIO+RA, unilaterally into the corpus callosum (CC). Animals were then sacrificed either 2 or 4 days after injection. Immunohistochemical studies in the CC rendered a higher percentage of APC+ differentiated OL in animals sacrificed 2 days after either PIO or PIO+RA injection, without changes in the proportion of PDGFRα+ OPC. In addition, actívated microglia and their phenotypic characterization (M1 or M2) are currently being assessed through both immunohistochemical and Western blot analyses of both the CC and SVZ. Preliminary results indicate a pro-myelinating effect of joint RXRγ and PPARγ activation by specific agonists.