Protective effects of the sigma agonist Pre-084 in the rat retina.
OBJECTIVE
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.
Cantarella
Giuseppina
G
Department of Experimental and Clinical Pharmacology, University of Catania School of Medicine, Viale Andrea Doria 6, 95125 Catania, Italy.
Bucolo
Claudio
C
Di Benedetto
Giulia
G
Pezzino
Salvatore
S
Lempereur
Laurence
L
Calvagna
Rosa
R
Clementi
Silvia
S
Pavone
Piero
P
Fiore
Lucia
L
Bernardini
Renato
R
D016229:Amyloid beta-Peptides / Q000008:administration & dosage*; D000818:Animals; D005029:Ethylenediamines / Q000008:administration & dosage; D007267:Injections; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D023421:Models, Animal; D009025:Morpholines / Q000008:administration & dosage*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000032:analysis; D017480:Receptors, sigma / Q000819:agonists* / Q000037:antagonists & inhibitors; D012160:Retina / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000032:analysis; D014822:Vitreous Body; D051028:bcl-2-Associated X Protein / Q000032:analysis
D016229:Amyloid beta-Peptides; D005029:Ethylenediamines; D009025:Morpholines; D018696:Neuroprotective Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D017480:Receptors, sigma; D053221:TNF-Related Apoptosis-Inducing Ligand; C505655:Tnfsf10 protein, rat; D051028:bcl-2-Associated X Protein; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; D048670:MAP Kinase Kinase 4