Cell-specific caspase expression by different neuronal phenotypes in transient retinal ischemia

J Neurochem. 2001 Apr;77(2):466-75. doi: 10.1046/j.1471-4159.2001.00258.x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Chloromethyl Ketones / administration & dosage
  • Amino Acid Chloromethyl Ketones / pharmacology
  • Amino Acid Chloromethyl Ketones / therapeutic use
  • Animals
  • Apoptosis / drug effects
  • Caspases / biosynthesis*
  • Caspases / genetics
  • Cysteine Proteinase Inhibitors / administration & dosage
  • Cysteine Proteinase Inhibitors / pharmacology
  • Cysteine Proteinase Inhibitors / therapeutic use
  • Drug Administration Schedule
  • Electroretinography
  • Enzyme Induction
  • Eye Proteins / biosynthesis*
  • Eye Proteins / genetics
  • Interneurons / enzymology
  • Ischemia / enzymology*
  • Ischemia / etiology
  • Ischemia / pathology
  • Male
  • Neurons / enzymology*
  • Neurons / pathology
  • Ocular Hypertension / complications
  • Oligodeoxyribonucleotides, Antisense / pharmacology
  • Phenotype
  • Premedication
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / enzymology
  • Reperfusion Injury / pathology
  • Retinal Diseases / enzymology*
  • Retinal Diseases / pathology
  • Retinal Ganglion Cells / enzymology
  • Tosylphenylalanyl Chloromethyl Ketone / analogs & derivatives
  • Tosylphenylalanyl Chloromethyl Ketone / pharmacology

Substances

  • Amino Acid Chloromethyl Ketones
  • Cysteine Proteinase Inhibitors
  • Eye Proteins
  • Oligodeoxyribonucleotides, Antisense
  • butyloxycarbonyl-aspartyl-fluoromethyl ketone
  • tyrosyl-valyl-alanyl-aspartic acid fluoromethyl ketone
  • Tosylphenylalanyl Chloromethyl Ketone
  • Caspases