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

17 Citations (Scopus)

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

Fingerprint

Vascular Endothelial Growth Factor Receptor-2
Apoptosis
Neurons
Glycogen Synthase Kinase 3
MAP Kinase Signaling System
Neuroprotective Agents
Neurodegenerative Diseases
Staining and Labeling
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Propidium
Mitogen-Activated Protein Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
Therapeutic Uses
Inhibitory Concentration 50
Neuroprotection
bis(propyl)cognitin
DNA

Keywords

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

ASJC Scopus subject areas

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

Cite this

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

In: CNS Neuroscience and Therapeutics, Vol. 19, No. 10, 10.2013, p. 764-772.

Research output: Contribution to journalArticle

@article{bb83319bcc844a40ae40ef82524089d6,
title = "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",
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.",
keywords = "Akt, Apoptosis, Bis(propyl)-cognitin, Extracellular signal-regulated kinase, K deprivation, VEGFR-2",
author = "Hu, {Sheng Quan} and Wei Cui and Xu, {Da Ping} and Mak, {Shing Hung} and Jing Tang and Choi, {Chung Lit} and Yuan-Ping Pang and Han, {Yi Fan}",
year = "2013",
month = "10",
doi = "10.1111/cns.12141",
language = "English (US)",
volume = "19",
pages = "764--772",
journal = "CNS Neuroscience and Therapeutics",
issn = "1755-5930",
publisher = "Wiley-Blackwell",
number = "10",

}

TY - JOUR

T1 - 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

AU - Hu, Sheng Quan

AU - Cui, Wei

AU - Xu, Da Ping

AU - Mak, Shing Hung

AU - Tang, Jing

AU - Choi, Chung Lit

AU - Pang, Yuan-Ping

AU - Han, Yi Fan

PY - 2013/10

Y1 - 2013/10

N2 - 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.

AB - 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.

KW - Akt

KW - Apoptosis

KW - Bis(propyl)-cognitin

KW - Extracellular signal-regulated kinase

KW - K deprivation

KW - VEGFR-2

UR - http://www.scopus.com/inward/record.url?scp=84884814549&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84884814549&partnerID=8YFLogxK

U2 - 10.1111/cns.12141

DO - 10.1111/cns.12141

M3 - Article

C2 - 23826635

AN - SCOPUS:84884814549

VL - 19

SP - 764

EP - 772

JO - CNS Neuroscience and Therapeutics

JF - CNS Neuroscience and Therapeutics

SN - 1755-5930

IS - 10

ER -