TY - JOUR
T1 - 5,19-cyclo-9β,10ξ-androstane-3,17-dione promotes neurotrophic factor biosynthesis in 1321N1 human astrocytoma cells and improves passive avoidance learning impairment
AU - Obara, Yutaro
AU - Haganuma, Asami
AU - Murakami, Shinsuke
AU - Chiba, Toshiki
AU - Mori, Koichiro
AU - Nakagawasai, Osamu
AU - Tadano, Takeshi
AU - Kikuchi, Haruhisa
AU - Oshima, Yoshiteru
AU - Nakahata, Norimichi
N1 - Funding Information:
This work was supported in part by Grants-in-Aid from the Japan Society for the Promotion of Science (No. 18790039 and 10381 to Y.O. and No. 14370737 and 18058002 to N.N.).
PY - 2007/12/12
Y1 - 2007/12/12
N2 - Since neurotrophic factors are essential for neurons to form neuronal networks and maintain neuronal functions, neurotrophic factor-like substances or inducers of neurotrophic factors can be useful for the treatment of serious neuronal diseases such as Alzheimer's and Parkinson's diseases. In the present study, we examined an effect of 5,19-cyclo-9β,10ξ-androstane-3,17-dione (CAD) on neurotrophic factor synthesis in glial cells and scopolamine-induced impairment of learning in mice. 1321N1 human astrocytoma cells promoted secretion of certain neurotrophic factors in response to CAD with no cytotoxicity, which caused dramatic neurite outgrowth in rat pheochromocytoma (PC12) cells. In fact, CAD significantly enhanced nerve growth factor (NGF) secretion and its gene expression in 1321N1 cells, in a time and concentration-dependent manner. Because second messengers such as cAMP, inositol 1,4,5-trisphosphates and Ca2+ induce NGF gene expression, we measured activities of adenylyl cyclase and phospholipase C and intracellular Ca2+ concentration in 1321N1 cells. However, CAD changed neither second messenger levels. CAD enhanced the gene expression of proto-oncogene, c-fos that is one of the components of transcription factor (AP-1). In addition to those above, the in vivo effects of CAD were also examined. Although injection of muscarinic receptor antagonist scopolamine impaired passive avoidance learning in mice, pretreatment with CAD significantly reversed the adverse effect in a dose-dependent manner. Taking these results together, CAD has enormous therapeutic potential for serious neuronal diseases.
AB - Since neurotrophic factors are essential for neurons to form neuronal networks and maintain neuronal functions, neurotrophic factor-like substances or inducers of neurotrophic factors can be useful for the treatment of serious neuronal diseases such as Alzheimer's and Parkinson's diseases. In the present study, we examined an effect of 5,19-cyclo-9β,10ξ-androstane-3,17-dione (CAD) on neurotrophic factor synthesis in glial cells and scopolamine-induced impairment of learning in mice. 1321N1 human astrocytoma cells promoted secretion of certain neurotrophic factors in response to CAD with no cytotoxicity, which caused dramatic neurite outgrowth in rat pheochromocytoma (PC12) cells. In fact, CAD significantly enhanced nerve growth factor (NGF) secretion and its gene expression in 1321N1 cells, in a time and concentration-dependent manner. Because second messengers such as cAMP, inositol 1,4,5-trisphosphates and Ca2+ induce NGF gene expression, we measured activities of adenylyl cyclase and phospholipase C and intracellular Ca2+ concentration in 1321N1 cells. However, CAD changed neither second messenger levels. CAD enhanced the gene expression of proto-oncogene, c-fos that is one of the components of transcription factor (AP-1). In addition to those above, the in vivo effects of CAD were also examined. Although injection of muscarinic receptor antagonist scopolamine impaired passive avoidance learning in mice, pretreatment with CAD significantly reversed the adverse effect in a dose-dependent manner. Taking these results together, CAD has enormous therapeutic potential for serious neuronal diseases.
KW - 1321N1 human astrocytoma cell
KW - 5,19-cyclo-9β,10ξ-androstane-3,17-dione (CAD)
KW - Nerve growth factor (NGF)
KW - Neurotrophic factor
KW - PC12 cell
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U2 - 10.1016/j.brainres.2007.10.005
DO - 10.1016/j.brainres.2007.10.005
M3 - Article
C2 - 17980863
AN - SCOPUS:36349007097
VL - 1184
SP - 57
EP - 64
JO - Molecular Brain Research
JF - Molecular Brain Research
SN - 0006-8993
IS - 1
ER -