Activation of the PI3-K/Akt pathway mediates cGMP enhanced-neurogenesis in the adult progenitor cells derived from the subventricular zone.
The intracellular mechanisms that regulate neurogenesis remain unclear. Using neurospheres isolated from the subventricular zone (SVZ) of the adult rat, we investigated the effect of cyclic guanosine monophosphate (cGMP) and its signaling pathway on the induction of neurogenesis. Neurospheres expressed phosphodiesterase 5 (PDE5) and treatment of neurospheres with Sildenafil, a specific inhibitor of PDE5, significantly increased cGMP levels and neurogenesis. In addition, incubation of neurospheres with Sildenafil significantly phosphorylated Akt, which was associated with an increase of phosphorylation of glycogen synthase kinase 3 (GSK-3), a downstream target of Akt. Coincubation of neurospheres with Sildenafil and LY 294002, a pharmacological inhibitor of PI3-K/Akt, abolished Sildenafil-induced phosphorylated Akt and GSK-3. Furthermore, LY 294002 blocked Sildenafil-increased SVZ cell proliferation. These data suggest that Sildenafil-enhanced neurogenesis likely occurs through activation of the PI3-K/Akt/GSK-3 pathway.
Wang
Lei
L
Department of Neurology, Henry Ford Health Sciences Center, Detroit, Michigan 48202, USA.
Gang Zhang
Zheng
Z
Lan Zhang
Rui
R
Chopp
Michael
M
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D015153:Blotting, Western; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation; D002552:Cerebral Ventricles / Q000166:cytology* / Q000502:physiology; D000242:Cyclic AMP / Q000502:physiology*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D008297:Male; D009474:Neurons / Q000502:physiology*; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011687:Purines; D051381:Rats; D017208:Rats, Wistar; D015682:Retroviridae Proteins, Oncogenic / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D000068677:Sildenafil Citrate; D013234:Stem Cells / Q000502:physiology; D013450:Sulfones
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D015682:Retroviridae Proteins, Oncogenic; D013450:Sulfones; D000068677:Sildenafil Citrate; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat