KMUP-1 attenuates serum deprivation-induced neurotoxicity in SH-SY5Y cells: roles of PKG, PI3K/Akt and Bcl-2/Bax pathways.

Abstract

Aging populations with neurodegenerative disorders will gradually become a greater problem for society. Serum deprivation-induced cell death is recognized as one of the standard models for the study of neurotoxicity. Increasing evidence indicates that cGMP/PKG pathway may play a rescue role in serum deprivation-induced toxicity. The aim of this study was to investigate protective effects of KMUP-1, an enhancer of cGMP/PKG signaling on serum deprivation-induced neurotoxicity in SH-SY5Y neuroblastoma cells. Under normal serum condition, KMUP-1 enhanced protein expression of nNOS, PKG and sGCalpha1, increased intracellular cyclic GMP level, and attenuated PDE5 expression. KMUP-1 also increased expression of BDNF and Bcl-2, but it did not affect Bax expression. The phosphorylation of Akt and CREB induced by KMUP-1 was inhibited by tyrosine kinase (TrK) inhibitor K252a and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, respectively. Under serum deprivation condition, flow cytometric analysis using Annexin V showed KMUP-1 increased cell viability, but lacked protective effects in the presence of nitric oxide synthase inhibitor l-NAME, PKG inhibitor Rp-8-pCPT-cGMPS or LY294002. KMUP-1 not only enhanced expression of nNOS, sGCalpha1, PKG, p-CREB, p-Akt and Bcl-2, but also attenuated Bax expression in serum deprivation-treated cultures. In conclusion, cGMP/PKG, PI3K/Akt/CREB and Bcl-2/Bax signals play critical roles in the neuroprotective effects of KMUP-1 on serum deprivation-induced toxicity.

• Authors: Ya-Yun Hsu, Chi-Ming Liu, Hsin-Hung Tsai, Yuh-Jyh Jong, Ing-Jun Chen, Yi-Ching Lo
• Journal: Toxicology (Toxicology) Vol. 268 Issue 1-2 Pg. 46-54 (Jan 31 2010) ISSN: 1879-3185 [Electronic] Ireland
• PMID: 19962417 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2009 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Brain-Derived Neurotrophic Factor
• Culture Media, Serum-Free
• Piperidines
• Xanthines
• bcl-2-Associated X Protein
• KMUP 1
• Nitric Oxide
• Cyclic AMP
• Nitric Oxide Synthase Type I
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Cyclic GMP-Dependent Protein Kinases
• Cyclic Nucleotide Phosphodiesterases, Type 5

Topics

• Blotting, Western
• Brain-Derived Neurotrophic Factor (metabolism)
• Cell Line, Tumor
• Culture Media, Serum-Free
• Cyclic AMP (pharmacology)
• Cyclic GMP-Dependent Protein Kinases (metabolism)
• Cyclic Nucleotide Phosphodiesterases, Type 5 (metabolism)
• Humans
• Nervous System (drug effects, enzymology, metabolism)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type I (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Piperidines (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Up-Regulation (drug effects)
• Xanthines (pharmacology)
• bcl-2-Associated X Protein (metabolism)