Rolipram, a phosphodiesterase-4-selective inhibitor, promotes the survival of cultured rat dopaminergic neurons.
We evaluated the effects of rolipram, a selective inhibitor of phosphodiesterase (PDE) 4, on the survival of dopaminergic neurons in 13-day culture. Rolipram did not affect the survival of dopaminergic neurons in the absence of forskolin, but significantly enhanced the survival of dopaminergic neurons in the presence of 10(-5) M forskolin in a concentration-dependent manner (10(-8) - 10(-5) M). Rolipram also enhanced the neurotrophic effect of forskolin on total neurons including dopaminergic and non-dopaminergic neurons at a high concentration (10(-5) M), but did not affect the survival of cells containing glutamate or gamma-aminobutylic acid. A non-selective PDE inhibitor, 1-isobutyl-3-methylxanthine, caused a marked increase of dopaminergic neurons, whereas selective inhibitors of PDE2 and PDE3 showed far weaker effects. A PDE1 inhibitor, on the other hand, caused non-specific cell death in the presence or absence of forskolin. These findings suggest that rolipram has a potential to enhance the survival of dopaminergic neurons selectively by way of PDE4 inhibition.
Yamashita
N
N
Drug Discovery, Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Yokahama, Japan.
Hayashi
A
A
Baba
J
J
Sawa
A
A
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004298:Dopamine; D008636:Mesencephalon / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D020889:Rolipram
D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; D004298:Dopamine