Substantial neuroprotection against K+ deprivation-induced apoptosis in primary cerebellar granule neurons by novel dimer bis(propyl)-cognitin via the activation of VEGFR-2 signaling pathway

Sheng Quan Hu, Wei Cui, Da Ping Xu, Shing Hung Mak, Jing Tang, Chung Lit Choi, Yuan Ping Pang, Yi Fan Han

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Summary: Background: Neuronal 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). Methods: Cerebellar 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. Results: Switching 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. Conclusions: Our 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.

Original languageEnglish (US)
Pages (from-to)764-772
Number of pages9
JournalCNS Neuroscience and Therapeutics
Volume19
Issue number10
DOIs
StatePublished - Oct 2013

Keywords

  • Akt
  • Apoptosis
  • Bis(propyl)-cognitin
  • Extracellular signal-regulated kinase
  • VEGFR-2

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Physiology (medical)
  • Pharmacology (medical)

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