Cell Death Pathways in Mutant Rhodopsin Rat Models Identifies Genotype-Specific Targets Controlling Retinal Degeneration.

Retinitis pigmentosa (RP) is a group of inherited neurological disorders characterized by rod photoreceptor cell death, followed by secondary cone cell death leading to progressive blindness. Currently, there are no viable treatment options for RP. Due to incomplete knowledge of the molecular signaling pathways associated with RP pathogenesis, designing therapeutic strategies remains a challenge. In particular, preventing secondary cone photoreceptor cell loss is a key goal in designing potential therapies. In this study, we identified the main drivers of rod cell death and secondary cone loss in the transgenic S334ter rhodopsin rat model, tested the efficacy of specific cell death inhibitors on retinal function, and compared the effect of combining drugs to target multiple pathways in the S334ter and P23H rhodopsin rat models. The primary driver of early rod cell death in the S334ter model was a caspase-dependent process, whereas cone cell death occurred though RIP3-dependent necroptosis. In comparison, rod cell death in the P23H model was via necroptotic signaling, whereas cone cell loss occurred through inflammasome activation. Combination therapy of four drugs worked better than the individual drugs in the P23H model but not in the S334ter model. These differences imply that treatment modalities need to be tailored for each genotype. Taken together, our data demonstrate that rationally designed genotype-specific drug combinations will be an important requisite to effectively target primary rod cell loss and more importantly secondary cone survival.

Potential Synergies of ß-Hydroxybutyrate and Butyrate on the Modulation of Metabolism, Inflammation, Cognition, and General Health.

The low-carbohydrate high-fat diet (LCHFD), also known as the ketogenic diet, has cycled in and out of popularity for decades as a therapeutic program to treat metabolic syndrome, weight mismanagement, and drug-resistant disorders as complex as epilepsy, cancer, dementia, and depression. Despite the benefits of this diet, health care professionals still question its safety due to the elevated serum ketones it induces and the limited dietary fiber. To compound the controversy, patient compliance with the program is poor due to the restrictive nature of the diet and symptoms related to energy deficit and gastrointestinal adversity during the introductory and energy substrate transition phase of the diet. The studies presented here demonstrate safety and efficacy of the diet including the scientific support and rationale for the administration of exogenous ketone bodies and ketone sources as a complement to the restrictive dietary protocol or as an alternative to the diet. This review also highlights the synergy provided by exogenous ketone, ß-hydroxybutyrate (BHB), accompanied by the short chain fatty acid, butyrate (BA) in the context of cellular and physiological outcomes. More work is needed to unveil the molecular mechanisms by which this program provides health benefits.

Anti-ageing glycoprotein promotes long-term survival of transplanted neurosensory precursor cells.

Cell therapy, to replace lost tissue, is a promising approach for the treatment of various neurodegenerative diseases. Many studies suggest, however, that the percentage of transplanted cells that survive and undergo functional integration remains low as a result of immune rejection, suboptimal precursor cell type, trauma during cell transplantation, toxic compounds released by dying tissues or nutritional deficiencies. We recently developed an ex vivo system to facilitate identification of factors contributing to the death of transplanted neuronal (photoreceptor) cells and compounds that block these toxic effects. In this system, photoreceptor precursor cells (PPCs) are sandwiched between a neurosensory retinal explant and retinal pigment epithelium derived from human embryonic stem cells. Explant medium was collected to identify toxic components and PPC survival was assessed by flow cytometry. We also assessed the potential for AAGP™, a cryopreservative molecule, to improve PPC survival. We identified elevated prostaglandin E2 (PGE2) in the explant medium and demonstrated that AAGP™ reduced PGE2 levels by 2.6-fold. A pro-inflammatory stress assay suggested that this may result from AAGP™ inhibition of cyclo-oxygenase-2 (COX-2) expression. We confirmed that PGE2 reduced the viability of cultured PPCs by 44% and found that the survival rate of PPCs pretreated with AAGP™ was 2.8-fold higher than in untreated PPCs. These data suggest that PGE2 release from necrotic tissue may be one factor that reduces the survival of transplanted precursor cells and that the pro-survival molecule AAGP™ may improve long-term transplanted cell viability. Copyright © 2016 John Wiley & Sons, Ltd.