Nobuyuki Yamashita, Akiko Hayashi, Jun Baba and Aiko Sawa (*)
Drug Discovery, Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222, Japan
(*) To whom correspondence should be addressed.
Abstract: 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.
Keywords: Rolipram, Phosphodiesterase 4, Forskolin, Dopaminergic neuron, Survival