title: Elevation of p-NR2A(S1232) by Cdk5/p35 contributes to retinal ganglion cell apoptosis in a rat experimental glaucoma model.
abstract: 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-NR2A(S1232) increased from D14 onwards (P<0.01 to 0.001). Co-immunoprecipitation indicated a direct interaction between Cdk5 and p-NR2A(S1232). 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-NR2A(S1232) (P all<0.01 vs. vehicle group). Our results suggest that elevation of p-NR2A(S1232) by Cdk5/p35 contributes to RGC apoptotic death in experimental glaucoma rats, which could be effectively ameliorated by inhibiting Cdk5/p35.
authors.affiliation: Institutes of Brain Science, Institute of Neurobiology and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Yanying
authors.initials: Y
authors.lastname: Miao
authors.forename: Xiao-Han
authors.initials: XH
authors.lastname: Wang
authors.forename: Zhongfeng
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000502:physiology*; D004195:Disease Models, Animal; D005901:Glaucoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis / Q000378:metabolism*; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000502:physiology*
chemical_list: C120997:NR2A NMDA receptor; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C089495:neuronal Cdk5 activator (p25-p35); D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat