24-07-08(12:28:56)
Authors:
Gonzalez-Aparicio R, Fernandez-Espejo E
Institutions:
Departamento de Fisiologia Medica y Biofisica, Universidad de Sevilla, 41009 Sevilla, Spain.
Title of abstract : Improved trophic efficacy of GDNF after combination with TGF-beta1 both in vitro and in vivo models of parkinsonism
Abstract text:
The objectives were: i) to analyze the trophic effects of GDNF, TGFbeta1 and combination of both in a rat model of Parkinson’s disease, and ii) to study the protective effects of these treatments on cultured substantia nigra neurons after 6-OHDA treatment. Hemiparkinsonian rats were implanted with osmotic minipumps two months after striatal degeneration induced by 6-OHDA, pumps liberating GDNF (10 ng/day), TGFbeta1 alone (2 ng/day), or a 5:1 combination, during eigth days. Results revealed that GDNF exerted an intense recovery of TH-ir in the damaged striatum reducing functional deficits (p<0.01), TGFbeta1 alone exerted limited effects, but 5:1 combination led to a further recovery of parkinsonian rats (p<0.01) relative to GDNF alone. Cultured dopamine neurons were treated two hours before and after 6-OHDA (0, 40, 60 microM, 15-min exposure). GDNF (2.5, 5, 10 pg/microL) exerted an intense and dose-dependent protective effects as measured through the LDH and MTT tests (p<0.01). TGFbeta1 was observed to exert U-shaped effects, the 1 pg/microL dose being protective (p<0.05). The 5:1 combination of both factors nearly blocked the deleterious effect of 6-OHDA, and cell protection was observed to be higher than that induced by GDNF alone. The molecular mechanisms of these effects are under study, but it seems that TGFbeta1 exerts its co-effect through the presence of GFRalpha1 (GDNF receptor) and the mediation of the phosphatidylinositol-3-kinase pathway.
Supported by grants to EFE from Junta de Andalucia (CVI127, and Proyectos de Excelencia, EXC/2006/CVI127-1716), and Red de Terapia Celular (Instituto Carlos III, RD06).
