title: Effects of roscovitine, a cell cyclin [correction of cycling]-dependent kinase inhibitor, on intraocular pressure of rabbit and retinal ganglion cell damage.
abstract: Glaucoma is characterized by increased intraocular pressure (IOP) and the death of retinal ganglion cells. Previously, we reported that roscovitine, a cell cyclin-dependent kinase (CDK) inhibitor, strongly induced relaxation of porcine trabecular meshwork cells, implicating an interaction with lowered IOP. In addition, the activity of CDKs is known to increase in response to high IOP, which is linked to retinal ganglion cell damage. However, the effects of roscovitine on IOP and retinal damage have not been investigated. Roscovitine has racemic isomers that differ in their inhibition of CDKs. Therefore, we investigated the effects of both the R-isomer and the S-isomer on the IOP of rabbits and on the death of cultured retinal ganglion cells. In the in vivo rabbit experiment, instillation of both isomers significantly lowered the IOP. In the in vitro cell experiment, the R-isomer amplified the effects of tunicamycin, an endoplasmic reticulum stress inducer, and increased oxygen-glucose deprivation-induced cell death, whereas S-isomer significantly inhibited this cell death. Therefore, both isomers of roscovitine can lower the IOP, but from the perspective of neuroprotective effects, the S-isomer was superior to the R-isomer. The S-isomer of roscovitine may be useful as an agent for lowering IOP and its neuroprotective effects.
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Kasai
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Imamura
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsuruma
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kurasawa
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Hirata
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Shimazawa
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
mesh_terms: D000287:Administration, Topical; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia; D002460:Cell Line; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D007429:Intraocular Pressure / Q000187:drug effects*; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011687:Purines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000473:pathology; D000077546:Roscovitine; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D018696:Neuroprotective Agents; D011687:Purines; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases; D005947:Glucose