5,19-cyclo-9beta,10xi-androstane-3,17-dione promotes neurotrophic factor biosynthesis in 1321N1 human astrocytoma cells and improves passive avoidance learning impairment.
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-9beta,10xi-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 Ca(2+) induce NGF gene expression, we measured activities of adenylyl cyclase and phospholipase C and intracellular Ca(2+) 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.
Obara
Yutaro
Y
Department of Cellular Signaling, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Sendai, Japan. obaray@mail.pharm.tohoku.ac.jp
Haganuma
Asami
A
Murakami
Shinsuke
S
Chiba
Toshiki
T
Mori
Koichiro
K
Nakagawasai
Osamu
O
Tadano
Takeshi
T
Kikuchi
Haruhisa
H
Oshima
Yoshiteru
Y
Nakahata
Norimichi
N
D000738:Androsterone / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001254:Astrocytoma / Q000378:metabolism* / Q000473:pathology; D001362:Avoidance Learning / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D007859:Learning Disabilities / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D051379:Mice; D020932:Nerve Growth Factor / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects; D016716:PC12 Cells; D000090063:Proto-Oncogene Mas; D051381:Rats; D012601:Scopolamine; D013778:Tetrazolium Salts; D013844:Thiazoles
C527800:5,19-cyclo-9beta,10xi-androstane-3,17-dione; D004224:Diterpenes; D007295:Inositol Phosphates; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D013778:Tetrazolium Salts; D013844:Thiazoles; D020932:Nerve Growth Factor; D000738:Androsterone; D012601:Scopolamine; D000242:Cyclic AMP; C022616:thiazolyl blue