Abstract
Purpose:
Acid sphingomyelinase (ASM) is an enzyme that catalyzes the hydrolysis of sphingomyelin to the production of ceramide, which is an important modulator of inflammatory cytokine and apoptotic signaling. However, the role(s) of ASM in retinal neuronal degeneration have not been investigated. The purpose of this study is to investigate whether sphingolipid-signaling is involved in the retinal ischemic injury, and whether suppression of ASM can ameliorate the ischemic effect in the retina.
Methods:
Retinal ischemic injury was induced by elevating intraocular pressure to 120mmHg for 45 minutes. Sphingolipid species that mediate the ischemia induced stress-signaling were identified by liquid chromatography-mass spectrometry 24 hours following ischemic injury. To assess if reducing ASM expression can protect the retina from ischemic injury, ASM+/- mice and wild-type (WT) littermates were evaluated for changes in retinal function and morphology by electroretinogram (ERG), and microscopic examination at 7 days post ischemia.
Results:
The levels of ceramide and sphingosine displayed significant increases in ischemic retinas when compared with contralateral retinas. Functional retinal assessment revealed that ischemic injury in WT mice exhibited significantly decreased a- and b-wave amplitudes by 48±11% and 54±9% of baseline levels, respectively. In ASM+/- mice, the ERG a-and b-waves were reduced by 35±6% and 29±6% of baseline levels, respectively. Although ischemic injury was detected in ASM+/- mice, it was significantly less than that measured in WT mice. Morphometric analysis of ischemic eyes from WT mice demonstrated a 17% decreases in overall retina thickness and a significant loss (43% ) of cell bodies in the retinal ganglion cell layer, when compared to contralateral eyes. However, in ASM+/- mice, the ischemic injury did not produce any significant decrease in overall retina thickness. In addition, only 13% of ganglion cell body loss was observed in ischemic eyes from ASM+/- mice.
Conclusions:
These data provided evidence that sphingolipid metabolites play important roles in ischemic retinal injury. The ERG and retinal morphology results demonstrated that the reduction of ASM expression can partially protect the retina from retinal ischemic injury. Hence, Inhibition of ASM may present new opportunities for the treatment of retinal ischemic disorders.
Keywords: 572 ischemia •
695 retinal degenerations: cell biology •
615 neuroprotection