An aminopropyl carbazole compound， P7C3， has been shown to be a potent neurogenesis promoting agent; however， its fundamental signaling action has yet to be elucidated. A cerebral ischemic/reperfusional (CI/R) injury model in mice was implemented to elucidate the neuronal protective mechanism(s) of P7C3. Treating CI/R mice using P7C3 (50-100?μg/kg， i.v.) significantly improved tracking distance and walking behavior， and reduced brain damage. Specifically， P7C3 promoted the expression of neurogenesis-associated proteins， including doublecortin， beta tubulin III (β-tub3)， adam11 and adamts20， near the peri-infarct cortex， accompanied by glycogen synthase kinase 3 (GSK-3) inhibition and ?... More
An aminopropyl carbazole compound， P7C3， has been shown to be a potent neurogenesis promoting agent; however， its fundamental signaling action has yet to be elucidated. A cerebral ischemic/reperfusional (CI/R) injury model in mice was implemented to elucidate the neuronal protective mechanism(s) of P7C3. Treating CI/R mice using P7C3 (50-100?μg/kg， i.v.) significantly improved tracking distance and walking behavior， and reduced brain damage. Specifically， P7C3 promoted the expression of neurogenesis-associated proteins， including doublecortin， beta tubulin III (β-tub3)， adam11 and adamts20， near the peri-infarct cortex， accompanied by glycogen synthase kinase 3 (GSK-3) inhibition and β-catenin upregulation. The application of a specific inhibitor against glucagon-like peptide 1 receptor (GLP-1R)， exendin(9-39)， revealed that the beneficial effects of P7C3 involved triggering the activation of GLP-1R-associated PKA/Akt signaling. P7C3 elicited the GLP-1R-dependent intracellular cAMP increment and the insulin secretion in cellular models. Surface plasmon resonance assay of P7C3 showed a Kd value of 0.53?μM for GLP-1R binding， and the docking of P7C3 to the putative active site on GLP-1R was successfully predicted by molecular modeling. Our findings indicate that P7C3 promotes the expression of neurogenesis proteins by activation of the cAMP/PKA-dependent and Akt/GSK3-associated β-catenin through positive allosteric stimulation of GLP-1R. Within the P7C3 class of neuroprotective molecules， this mechanism appears to be unique to the prototypical P7C3 molecule， as other active derivatives such as P7C2-A20 and P7C3-S243 they do not engage this same pathway and have been shown to work by nicotinamide phosphoribosyltransferase (NAMPT) stimulation.
