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Glaucoma, mainly caused by high intraocular pressure (IOP), is characterized by apoptotic death of retinal ganglion cells (RGCs). We investigated the possible involvement of cyclin-dependent kinase 5 (Cdk5) and its activator p35, which have been implicated in a variety of neurological disorders, in RGC apoptosis in a rat experimental glaucoma model reproduced by blocking episcleral veins. Cholera toxin B subunit (CTB) retrogradely labeled RGCs displayed a dramatic reduction in number both in the central and peripheral retina on day 14 (D14) (P<0.05 vs control), D21 (P<0.01 vs control) and D28 (P<0.001 vs control) after operation. Terminal dUTP nick end labeling (TUNEL)-positive cells were detected on D14 both in the central and peripheral regions, and numerous TUNEL-positive cells were found on D21 and D28 in both the regions (P all<0.001 vs control). As compared with the control eyes, the expression level of Cdk5 was significantly increased on D21 (P<0.001), whereas that of p35 displayed a marked increase on D14 (P<0.01) and D21 (P<0.001). Meanwhile, both NR2A and p-NR2AS1232 increased from D14 onwards (P<0.01 to 0.001). Co-immunoprecipitation indicated a direct interaction between Cdk5 and p-NR2AS1232. Intraperitoneal injection of the Cdk5 inhibitor roscovitine remarkably inhibited RGC apoptosis (P<0.001 vs vehicle group) and increased the number of CTB-labeled RGCs (P<0.05 to 0.01 vs vehicle group) in whole flat-mounted retinas, which was accompanied by a significant decrease in expression levels of p35 and p-NR2AS1232 (P all<0.01 vs vehicle group). Our results suggest that elevation of p-NR2AS1232 by Cdk5/p35 contributes to RGC apoptotic death in experimental glaucoma rats, which could be effectively ameliorated by inhibiting Cdk5/p35.