Cell-specific caspase expression by different neuronal phenotypes in transient retinal ischemia.
Emerging evidence supports an important role for caspases in neuronal death following ischemia-reperfusion injury. This study assessed whether cell specific caspases participate in neuronal degeneration and whether caspase inhibition provides neuroprotection following transient retinal ischemia. We utilized a model of transient global retinal ischemia. The spatial and temporal pattern of the active forms of caspase 1, 2 and 3 expression was determined in retinal neurons following ischemic injury. Double-labeling with cell-specific markers identified which cells were expressing different caspases. In separate experiments, animals received various caspase inhibitors before the induction of ischemia. Sixty minutes of ischemia resulted in a delayed, selective neuronal death of the inner retinal layers at 7 days. Expression of caspase 1 was not detected at any time point. Maximal expression of caspase 2 was found at 24 h primarily in the inner nuclear and ganglion cell layers of the retina and localized to ganglion and amacrine neurons. Caspase 3 also peaked at 24 h in both the inner nuclear and outer nuclear layers and was predominantly expressed in photoreceptor cells and to a lesser extent in amacrine neurons. The pan caspase inhibitor, Boc-aspartyl fmk, or an antisense oligonucleotide inhibitor of caspase 2 led to significant histopathologic and functional improvement (electroretinogram) at 7 days. No protection was found with the caspase 1 selective inhibitor, Y-vad fmk. These observations suggest that ischemia-reperfusion injury activates different caspases depending on the neuronal phenotype in the retina and caspase inhibition leads to both histologic preservation and functional improvement. Caspases 2 and 3 may act in parallel in amacrine neurons following ischemia-reperfusion. These results in the retina may shed light on differential caspase specificity in global cerebral ischemia.
Singh
M
M
Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.
Savitz
S I
SI
Hoque
R
R
Gupta
G
G
Roth
S
S
Rosenbaum
P S
PS
Rosenbaum
D M
DM
D000590:Amino Acid Chloromethyl Ketones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000096:biosynthesis* / Q000235:genetics; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004596:Electroretinography; D004790:Enzyme Induction; D005136:Eye Proteins / Q000096:biosynthesis* / Q000235:genetics; D007395:Interneurons / Q000201:enzymology; D007511:Ischemia / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D008297:Male; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D009798:Ocular Hypertension / Q000150:complications; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010641:Phenotype; D011292:Premedication; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology; D012164:Retinal Diseases / Q000201:enzymology* / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000201:enzymology; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000031:analogs & derivatives / Q000494:pharmacology
D000590:Amino Acid Chloromethyl Ketones; D015853:Cysteine Proteinase Inhibitors; D005136:Eye Proteins; D020319:Oligodeoxyribonucleotides, Antisense; C417985:butyloxycarbonyl-aspartyl-fluoromethyl ketone; C425776:tyrosyl-valyl-alanyl-aspartic acid fluoromethyl ketone; D014108:Tosylphenylalanyl Chloromethyl Ketone; D020169:Caspases