Stimulation of adenylyl cyclase and induction of brain-derived neurotrophic factor and TrkB mRNA by NKH477, a novel and potent forskolin derivative.
The present study was undertaken to examine whether NKH477, a novel and potent water-soluble forskolin derivative, stimulates adenylyl cyclase and regulates brain-derived neurotrophic factor (BDNF) and TrkB expression in the rat brain. Administration of NKH477 at a dose of 1.0 mg/kg, but not 0.1 mg/kg, increased levels of cyclic AMP (cAMP) in a time-dependent manner in frontal cortex and hippocampus. Repeated administration of NKH477 (1.0 mg/kg) for 7 or 14 days also increased levels of cAMP in these two brain regions, indicating that the response does not desensitize with chronic treatment. In addition, administration of NKH477 at the 1 mg/kg dose increased the expression of BDNF and TrkB mRNA in frontal cortex and hippocampus. This effect was observed after single, as well as repeated (7 or 14 days), administration of NKH477. These results demonstrate that NKH477 administration rapidly increases cAMP levels in brain and provides evidence that stimulation of this second messenger system increases the expression of BDNF and TrkB mRNA.
Morinobu
S
S
Department of Psychiatry, Shiga University of Medical Science, Otsu, Japan.
Fujimaki
K
K
Okuyama
N
N
Takahashi
M
M
Duman
R S
RS
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D001921:Brain / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D005576:Colforsin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D017403:In Situ Hybridization; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor / Q000235:genetics*; D013997:Time Factors
D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor; D005576:Colforsin; D000242:Cyclic AMP; D020794:Receptor Protein-Tyrosine Kinases; D000262:Adenylyl Cyclases