TY - JOUR
T1 - Glial inflammation and neurodegeneration induced by candoxin, a novel neurotoxin from Bungarus candidus venom
T2 - Global gene expression analysis using microarray
AU - Pachiappan, A.
AU - Thwin, M. M.
AU - Manikandan, J.
AU - Gopalakrishnakone, P.
N1 - Funding Information:
We are grateful to Dr S. Nirthanan (Department of Neurobiology, Harvard Medical School, Boston, USA) and Dr K.N. Srinivasan (Department of Pharmacology and Molecular Sciences Johns Hopkins School of Medicine, Baltimore, USA) for their critical reading of this manuscript, comments and helpful suggestions. This research was supported by research grant R 181-000-047-305, National University of Singapore.
PY - 2005/12/15
Y1 - 2005/12/15
N2 - Candoxin (PDB #1JGK), a three-finger neurotoxin from Bungarus candidus venom, inhibits post-synaptic neuromuscular and neuronal α7nACh-receptors, and induces delayed cell-death throughout the glial population. When applied to cultured human glial cell lines, candoxin (CDX) induced cell death in a concentration (EC50∼1 μM) and time dependent manner. Results of TUNEL-histochemistry further confirm CDX-induced brain (hippocampus, frontal cortex, and temporal regions) damage when administered intracerebroventricularly (i.c.v) in adult mice. In this study, we explored differential gene expression profiles following exposure of human glial (Hs 683) cell lines to CDX at various time intervals using Affymetrix-GeneChips. By means of MAS and GeneSpring analyses, 105 genes whose expression was significantly (P<0.01) altered by at least 3-fold were selected. Results of the genome analysis reveal that the potential role of CDX at molecular level involves the regulation of genes in signal transduction, ubiquitin-inflammation, mitochondrial-dysfunction, and damage-response pathways. In addition, using QRT-PCR and rationally designed specific CDX-binding peptide (P-NT.II), we identified the genes - IL7R, IL13RA2, IL-1β, TNFRSF12A, GADD45A, CD44 and IFI44 - that might play an important role in CDX-induced glial inflammation, DNA-damage and degeneration. These findings reveal new insight into the molecular mechanisms of glial-driven neurodegeneration after exposure to neurotoxins.
AB - Candoxin (PDB #1JGK), a three-finger neurotoxin from Bungarus candidus venom, inhibits post-synaptic neuromuscular and neuronal α7nACh-receptors, and induces delayed cell-death throughout the glial population. When applied to cultured human glial cell lines, candoxin (CDX) induced cell death in a concentration (EC50∼1 μM) and time dependent manner. Results of TUNEL-histochemistry further confirm CDX-induced brain (hippocampus, frontal cortex, and temporal regions) damage when administered intracerebroventricularly (i.c.v) in adult mice. In this study, we explored differential gene expression profiles following exposure of human glial (Hs 683) cell lines to CDX at various time intervals using Affymetrix-GeneChips. By means of MAS and GeneSpring analyses, 105 genes whose expression was significantly (P<0.01) altered by at least 3-fold were selected. Results of the genome analysis reveal that the potential role of CDX at molecular level involves the regulation of genes in signal transduction, ubiquitin-inflammation, mitochondrial-dysfunction, and damage-response pathways. In addition, using QRT-PCR and rationally designed specific CDX-binding peptide (P-NT.II), we identified the genes - IL7R, IL13RA2, IL-1β, TNFRSF12A, GADD45A, CD44 and IFI44 - that might play an important role in CDX-induced glial inflammation, DNA-damage and degeneration. These findings reveal new insight into the molecular mechanisms of glial-driven neurodegeneration after exposure to neurotoxins.
KW - Glial-degeneration and real-time PCR
KW - Inflammation
KW - Microarray
KW - TUNEL-assay
KW - Three-finger toxins
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U2 - 10.1016/j.toxicon.2005.08.017
DO - 10.1016/j.toxicon.2005.08.017
M3 - Article
C2 - 16309724
AN - SCOPUS:28444464017
SN - 0041-0101
VL - 46
SP - 883
EP - 899
JO - Toxicon
JF - Toxicon
IS - 8
ER -