AIM: With the rationale that amyloid beta (AB) is toxic to the retina, we here assessed the role of TRAIL, a mediator of AB toxicity and related signal transduction, in a rat model. We also attempted to demonstrate possible protective effects of sigma 1 receptor agonists in these processes. METHODS: AB and the sigma 1 receptor agonist Pre-084 were injected intravitreally in the anaesthetised rat. In additional experiments, the sigma 1 receptor antagonist BD1047 was administered to assess specificity of the effects of Pre-084. Western blot analysis was performed on retinas to evaluate the expression of TRAIL and TRAIL receptors in the retina, as well as of Bax and phosphorylated JNK following the different treatments. Lactic dehydrogenase (LDH) levels were measured as a cytotoxicity marker. RESULTS: All TRAIL receptors were expressed in rat retinas. Intravitreal injection of AB in rat eyes induced overexpression of TRAIL and the proapoptotic protein Bax, as well as phosphorylation of JNK. All these effects of AB were abrogated by pretreatment with the sigma(1) receptor agonist Pre-084. CONCLUSIONS: It is likely that TRAIL is a mediator of AB effects on the retina. In light of their specific inhibitory effects upon TRAIL expression, it is plausible to hypothesise that sigma(1) receptor agonists could represent potential pharmacological tools for restraining AB related retinal damage.
AIM: With the rationale that amyloid beta (AB) is toxic to the retina, we here assessed the role of TRAIL, a mediator of AB toxicity and related signal transduction, in a rat model. We also attempted to demonstrate possible protective effects of sigma 1 receptor agonists in these processes. METHODS: AB and the sigma 1 receptor agonist Pre-084 were injected intravitreally in the anaesthetised rat. In additional experiments, the sigma 1 receptor antagonist BD1047 was administered to assess specificity of the effects of Pre-084. Western blot analysis was performed on retinas to evaluate the expression of TRAIL and TRAIL receptors in the retina, as well as of Bax and phosphorylated JNK following the different treatments. Lactic dehydrogenase (LDH) levels were measured as a cytotoxicity marker. RESULTS: All TRAIL receptors were expressed in rat retinas. Intravitreal injection of AB in rat eyes induced overexpression of TRAIL and the proapoptotic protein Bax, as well as phosphorylation of JNK. All these effects of AB were abrogated by pretreatment with the sigma(1) receptor agonist Pre-084. CONCLUSIONS: It is likely that TRAIL is a mediator of AB effects on the retina. In light of their specific inhibitory effects upon TRAIL expression, it is plausible to hypothesise that sigma(1) receptor agonists could represent potential pharmacological tools for restraining AB related retinal damage.
Authors: Heidi LeBlanc; David Lawrence; Eugene Varfolomeev; Klara Totpal; John Morlan; Peter Schow; Sharon Fong; Ralph Schwall; Dominick Sinicropi; Avi Ashkenazi Journal: Nat Med Date: 2002-03 Impact factor: 53.440
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