title: Phosphodiesterase inhibitors are neuroprotective to cultured spinal motor neurons.
abstract: We have previously reported that cyclic guanosine-3',5'-monophosphate (cGMP) protects spinal motor neurons against acute reactive oxygen species (ROS)-induced toxicity but not against chronic ROS-induced or glutamate (Glu)-induced toxicity. In this study, we investigated the effects of phosphodiesterase (PDE) inhibitors on the survival of cultured spinal motor neurons. Selective PDE5 inhibitors (dipyridamole, T-1032, and zaprinast) as well as a nonselective PDE inhibitor (aminophylline) protected motor and nonmotor neurons against both acute ROS-induced and chronic Glu-induced neurotoxicity, whereas selective inhibitors of PDE1-4 offered no protection. 8-Bromo-cGMP (8br-cGMP), a cGMP analogue, protected both motor and nonmotor neurons against acute ROS-induced toxicity but protected only nonmotor neurons against chronic Glu-induced toxicity. This neuroprotection was blocked by KT5823, a cGMP-dependent protein kinase (PKG) inhibitor. Immunohistochemical staining confirmed that PDE5 and PKG are located in almost all rat lumbar spinal neurons. Furthermore, semiquantitative analysis of the immunostaining intensity revealed that PDE5 was more abundant in motor neurons than in nonmotor neurons. Our results suggest that this difference in the amount of PDE5 may be responsible for the vulnerability of motor neurons to chronic excitotoxicity. In addition, the results of this study raise the possibility that PDE5 inhibitors might be used as a treatment for amyotrophic lateral sclerosis.
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Nakamizo
authors.forename: Jun
authors.initials: J
authors.lastname: Kawamata
authors.forename: Kohei
authors.initials: K
authors.lastname: Yoshida
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kawai
authors.forename: Rie
authors.initials: R
authors.lastname: Kanki
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sawada
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kihara
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yamashita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shibasaki
authors.forename: Akinori
authors.initials: A
authors.lastname: Akaike
authors.forename: Shun
authors.initials: S
authors.lastname: Shimohama
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018698:Glutamic Acid / Q000633:toxicity; D008297:Male; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000201:enzymology
chemical_list: D018696:Neuroprotective Agents; D010726:Phosphodiesterase Inhibitors; D018698:Glutamic Acid