Rod photoreceptor cell death is induced by okadaic acid through activation of PKC and L-type voltage-dependent Ca2+ channels and prevented by IGF-1.
Retinal dystrophies involve extensive photoreceptor apoptosis. Neuroprotective effects of insulin-like growth factor (IGF)-1 have been demonstrated in various tissues, including the retina. The aim of this study was to investigate: (i) the action of IGF-1 upon selective photoreceptor death induced by okadaic acid (OA); and (ii) signaling pathways related to both OA-induced cell death and IGF-1 neuroprotective effect. Retinal explants were incubated with 5nM OA, a protein phosphatase type 1 and type 2A inhibitor, which induces cell death detected by the identification of pyknotic morphology of photoreceptors immunostained for rhodopsin. OA increased both the number of pyknotic Rho 4D2(+) profiles, and Ca(2+) influx, measured through the incorporation of (45)CaCl(2), in a dose- and time-dependent way, while treatment with 10ng/mL IGF-1 abrogated both effects. Treatment with phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C, modulated OA effects, indicating the involvement of PKC. Furthermore, either 10microM chelerythrine chloride, an inhibitor of PKC, or 10microM nifedipine, a L-voltage-sensitive Ca(2+) channel blocker, inhibited both Ca(2+) influx and cell death induced by OA. The data show that okadaic acid induces rod photoreceptor cell death in retinal tissue through activation of PKC and ensuing Ca(2+) influx through L-type Ca(2+) channels, which is counteracted by a neuroprotective effect of IGF-1.
Adão-Novaes
Juliana
J
Programa de Neurobiologia, Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil.
de Cássia Belem Guterrres
Céulem
C
Linden
Rafael
R
Sholl-Franco
Alfred
A
D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects*; D004789:Enzyme Activation; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D019319:Okadaic Acid / Q000633:toxicity*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology / Q000187:drug effects*
D020746:Calcium Channels, L-Type; D019319:Okadaic Acid; D007334:Insulin-Like Growth Factor I; D011493:Protein Kinase C