Regulation of caspase activation in axotomized retinal ganglion cells.
Transection of the optic nerve initiates massive death of retinal ganglion cells (RGCs). Interestingly, despite the severity of the injury, RGC loss was not observed until several days after axotomy. The mechanisms responsible for this initial lack of RGC death remained unknown. In the current study, immunohistochemical analysis revealed that caspases-3 and -9 activation in the RGCs were not detected until day 3 post-axotomy, coinciding with the onset of axotomy-induced RGC loss. Interestingly, elevated Akt phosphorylation was observed in axotomized retinas during the absence of caspase activation. Inhibiting the increase in Akt phosphorylation by intravitreal injection of wortmannin and LY294002, inhibitors of PI3K, resulted in premature nuclear fragmentation, caspases-3 and -9 activation in the ganglion cell layer. Our findings thus indicate that the PI3K/Akt pathway may serve as an endogenous regulator of caspase activation in axotomized RGCs, thereby, contributing to the late onset of RGC death following axotomy.
Cheung
Zelda H
ZH
Department of Anatomy, Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Chan
Yuen-Man
YM
Siu
Flora K W
FK
Yip
Henry K
HK
Wu
Wutian
W
Leung
Mason C P
MC
So
Kwok-Fai
KF
D000818:Animals; D019771:Axotomy / Q000379:methods; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D006224:Cricetinae; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008647:Mesocricetus; D009025:Morpholines / Q000494:pharmacology; D020221:Optic Nerve Injuries / Q000201:enzymology; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000201:enzymology*
D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases