Sigma 1 receptor stimulation protects against oxidative damage through suppression of the ER stress responses in the human lens

Stimulation of sigma-1 receptors is reported to protect against oxidative stress. The present study uses cells and tissue from the human lens to elucidate the relationship between the sigma 1 receptor, ER stress and oxidative stress-induced damage. Exposure of the human lens cell line FHL124 to increasing concentrations of HO led to reduced cell viability and increased apoptosis. In response to 30µM HO, levels of the ER stress proteins BiP, ATF6 and pEIF2a were significantly increased within 4h of exposure. Expression of the sigma 1 receptor was markedly increased in response to HO. Application of 10 and 30µM (+)-pentazocine, a sigma 1 receptor agonist, significantly inhibited the HO induced cell death. (+)-Pentazocine also suppressed the oxidative stress induced reduction of pro-caspase 12 and suppressed the induction of the ER stress proteins BiP and EIF2a. When applied to cultured human lenses, (+)-pentazocine protected against apoptotic cell death, LDH release and against HO induced opacification. These data demonstrate that stimulation of the sigma 1 receptor provides significant protection from oxidative damage and is, therefore, a putative therapeutic approach to delay the onset of diseases that may be triggered by oxidative damage, including cataract formation.