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 language | English (US) |
|---|---|
| Pages (from-to) | 764-772 |
| Number of pages | 9 |
| Journal | CNS Neuroscience and Therapeutics |
| Volume | 19 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 2013 |
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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 journal › Article
}
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 -