Choi, Chung‐Lit

SummaryAimsNeurodegenerative disorders are caused by progressive neuronal loss in the brain, and hence, compounds that could promote neuritogenesis may have therapeutic values. In this study, the effects of bis(heptyl)‐cognitin (B7C), a multifunctional dimer, on neurite outgrowth were investigated in both PC12 cells and primary cortical neurons.MethodsImmunocytochemical staining was used to evaluate the proneuritogenesis effects, and Western blot and short hairpin RNA assays were applied to explore the underlying mechanisms.ResultsB7C (0.1–0.5 μM) induced robust neurite outgrowth in PC12 cells, as evidenced by the neurite‐bearing morphology and upregulation of growth‐associated protein‐43 expression. In addition, B7C markedly promoted neurite outgrowth in primary cortical neurons as shown by the increase in the length of β‐III‐tubulin‐positive neurites. Furthermore, B7C rapidly increased ERK phosphorylation. Specific inhibitors of alpha7‐nicotinic acetylcholine receptor (α7‐nAChR) and MEK, but not those of p38 or JNK, blocked the neurite outgrowth as well as ERK phosphorylation induced by B7C. Most importantly, genetic depletion of α7‐nAChR significantly abolished B7C‐induced neurite outgrowth in PC12 cells.ConclusionB7C promoted neurite outgrowth through the activation of α7‐nAChR/ERK pathway, which offers novel insight into the potential application of B7C in the treatment of neurodegenerative disorders.

SummaryBackgroundNeuronal loss via apoptosis in CNS is the fundamental mechanism underlying various neurodegenerative diseases. Compounds with antiapoptotic property might have therapeutic effects for these diseases. In this study, bis(propyl)‐cognitin (B3C), a novel dimer that possesses anti‐AChE and anti‐N‐methyl‐d‐aspartate receptor activities, was investigated for its neuroprotective effect on K+ deprivation‐induced apoptosis in cerebellar granule neurons (CGNs).MethodsCerebellar granule neurons were switched to K+ deprived medium with or without B3C. 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium assay, fluorescein diacetate (FDA)/propidium iodide (PI) staining, Hoechst staining, and DNA laddering assays were applied to detect cytotoxicity and apoptosis. Additionally, the expression of p‐VEGFR‐2, p‐Akt, p‐glycogen synthase kinase 3β (GSK3β), and p‐extracellular signal‐regulated kinase (ERK) was examined in CGNs.ResultsSwitching CGNs to K+ deprived medium resulted in remarkable apoptosis, which could be substantially blocked by B3C treatment (IC50, 0.37 μM). Moreover, a rapid decrease in p‐Tyr1054‐VEGFR‐2 was observed after the switch. B3C significantly reversed the inhibition of p‐Tyr1054‐VEGFR‐2 as well as Akt and ERK pathways. VEGFR‐2 inhibitor PTK787/ZK222584, as well as PI3‐K inhibitor LY294002 and MEK inhibitor PD98059, each abolished the neuroprotective effect of B3C.ConclusionsOur results demonstrate that B3C blocks K+ deprivation‐induced apoptosis in CGNs through regulating VEGFR‐2/Akt/GSK3β and VEGFR‐2/ERK signaling pathways, providing a molecular insight into the therapeutic potential of B3C for the treatment of neurodegenerative diseases.