Guanosine stimulates neural stem cell proliferation through cAMP-CREB pathway

In previous studies, we have found that extracellular guanosine can stimulate endogenous progenitor/stem cell proliferation in the spinal cord and the subventricular zone of rats. In this study, using neural stem cells isolated from one-day old rats, we found that guanosine could stimulate neural stem cell proliferation, and confirmed that the proliferation was not due to the guanosine metabolism mechanism since guanine, which is interconverted by an ecto-purine nucleoside phosphorylase from guanosine, has no stimulating effect on the proliferation of neural stem cells. We determined that second messenger cAMP was involved in the pathway as results showed that 100 μM guanosine stimulated cAMP accumulation. Using western blot analysis, we found that 100 μM guanosine can activate the phosphorylation of CREB without changing the total amount of CREB. Real time PCR analysis showed that 100 μM guanosine increased the mRNA level of brain derived neurotrophic factor which indicated that brain derived neurotrophic factor was associated with the modulation of CREB. In conclusion, guanosine can stimulate neural stem cell proliferation, and the cAMP-CREB pathway is involved in this biological effect, with brain derived neurotrophic factor acting as a modulator. Key-Words: Guanosine, Guanine, cAMP, CREB, Brain derived neurotrophic factor, Neural stem cells, proliferation