A caspase-3-dependent pathway is predominantly activated by the excitotoxin pregnenolone sulfate and requires early and late cytochrome c release and cell-specific caspase-2 activation in the retinal cell death.
This study investigates the implication of mitochondria- and caspase-dependent pathways in the death of retinal neurones exposed to the neurosteroid pregnenolone sulfate (PS) shown to evoke apoptosis and contribute to amplification and propagation of excitotoxicity. After a brief PS challenge of intact retinas, caspase-3 and caspase-2 activation and cytochrome c release occur early and independent of changes in the oxidative state measured by superoxide dismutase activity. The temporal and spatial relationship of these events suggests that a caspase-3-dependent pathway is activated in response to cytochrome c release and requires caspase-2 activation and a late cytochrome c release in specific cellular subsets of retinal layers. The protection by caspase inhibitors indicates a predominant role of the pathway in PS-induced retinal apoptosis, although a limited use of caspase inhibitors is upheld on a conceivable shift from apoptosis toward necrosis. Conversely, 3alpha-hydroxy-5beta-pregnan-20-one sulfate and 17beta-oestradiol provide complete prevention of PS-induced retinal death.
Cascio
C
C
Istituto di Biologia dello Sviluppo and Laboratorio di Elettromicroscopia, Istituto di Metodologia Diagnostica Avanzata, CNR, Palermo, Italy.
Guarneri
R
R
Russo
D
D
De Leo
G
G
Guarneri
M
M
Piccoli
F
F
Guarneri
P
P
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053143:Caspase 2; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D003574:Cytochrome c Group / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity; D010084:Oxidation-Reduction / Q000187:drug effects; D011280:Pregnanolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D011284:Pregnenolone / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; C018370:pregnenolone sulfate; D004958:Estradiol; D011284:Pregnenolone; C019427:3-hydroxypregnan-3-one 3-sulfate; D011280:Pregnanolone; C505410:Casp3 protein, rat; D053143:Caspase 2; D053148:Caspase 3; D020169:Caspases