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

• Published in: Mechanisms of ageing and development Vol. 133; no. 11-12; pp. 665 - 674
• Main Authors: Wang, Lixin, Eldred, Julie A., Sidaway, Peter, Sanderson, Julie, Smith, Andrew J.O., Bowater, Richard P., Reddan, John R., Wormstone, I. Michael
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 01-11-2012; Elsevier
• Subjects: Apoptosis; Biological and medical sciences; Calcium - metabolism; Cataract; Cell Line; Cell Survival; Development. Metamorphosis. Moult. Ageing; Dose-Response Relationship, Drug; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum Chaperone BiP; ER stress; Eukaryotic Initiation Factor-2 - metabolism; Fundamental and applied biological sciences. Psychology; Heat-Shock Proteins - metabolism; Human; Humans; Hydrogen Peroxide - chemistry; In Situ Nick-End Labeling; L-Lactate Dehydrogenase - metabolism; Lens; Lens, Crystalline - metabolism; Oxidative Stress; Pentazocine - pharmacology; Receptors, sigma - metabolism; Sigma 1 receptor; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Human; ER stress; Oxidative stress; Cataract; Lens; Sigma 1 receptor; Senescence; Sigma receptor; Stimulation; Eye; Visual system; Eye disease; Vertebrata; Lens disease; Mammalia; Anterior segment disease
• ISSN: 0047-6374; 1872-6216
• DOI: 10.1016/j.mad.2012.09.005

► Oxidative insult increases sigma 1 receptor expression and ER stress in human lens cells. ► Stimulation of the sigma 1 receptor provides significant protection against oxidative damage. ► Sigma 1 receptor agonist protection suppresses, but does not ablate the ER stress response. ► Sigma 1 receptor agonists can prevent ER stress induced apoptosis.
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 H2O2 led to reduced cell viability and increased apoptosis. In response to 30μM H2O2, levels of the ER stress proteins BiP, ATF6 and pEIF2α were significantly increased within 4h of exposure. Expression of the sigma 1 receptor was markedly increased in response to H2O2. Application of 10 and 30μM (+)-pentazocine, a sigma 1 receptor agonist, significantly inhibited the H2O2 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 EIF2α. When applied to cultured human lenses, (+)-pentazocine protected against apoptotic cell death, LDH release and against H2O2 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.