Protective effects of the sigma agonist Pre-084 in the rat retina

Abstract

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 s1 receptor agonists in these processes. Methods: AB and the s1 receptor agonist Pre-084 were injected intravitreally in the anaesthetised rat. In additional experiments, the s1 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 s 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 s 1 receptor agonists could represent potential pharmacological tools for restraining AB related retinal damage.

SN79, a sigma receptor antagonist, attenuates methamphetamine-induced astrogliosis through a blockade of OSMR/gp130 signaling and STAT3 phosphorylation

“…Although SN79 treatment was found to mitigate METH-induced increases in STAT3 phosphorylation, it may be possible that modulation of ERK1/2 and JNK pathways are contributing to increases in SOCS3 (Baker et al 2008), thereby leading to the blockade of STAT3 phosphorylation seen in the current report. Supporting this hypothesis are previous studies showing the modulation of ERK1/2 and JNK signaling by various sigma receptor ligands (Cantarella et al 2007; Nishimura et al 2008; Son and Kwon 2010; Tan et al 2010; Tuerxun et al 2010), although their effects specifically within astrocytes on these signaling pathways are currently unknown.…”

The pharmacology of sigma-1 receptors

“…As β-amyloid is toxic to the retina, the sigma-1 receptor agonist, PRE-084, was used to examine if it might protect retinas against β-amyloid-induced retinal degeneration. Indeed, PRE-084 was protective i retinal neurons and was effective in abrogating the β-amyloid-induced biochemical changes, including the overexpression of TRAIL and the apoptotic protein, Bax, and the phosphorylation of JNK (Cantarella et al, 2007). Further, the effect of PRE-084 was blocked by BD1047 (Cantarella et al, 2007).…”

“…Indeed, PRE-084 was protective i retinal neurons and was effective in abrogating the β-amyloid-induced biochemical changes, including the overexpression of TRAIL and the apoptotic protein, Bax, and the phosphorylation of JNK (Cantarella et al, 2007). Further, the effect of PRE-084 was blocked by BD1047 (Cantarella et al, 2007). Another laboratory used primary ganglion cells isolated from rat retinas and found that (+)pentazocine prevented the excitotoxicity to cells (Dun et al, 2007).…”

Progesterone Receptor Membrane Component 1 (PGRMC1) Expression in Murine Retina

“…Topical administration of σR1-site agonists lowers intraocular pressure and might provide control of ocular hypertension (22, 23). Profound retinal neuroprotection has been demonstrated using σR1 ligands in vitro (24-27) and in vivo (28, 29). …”