The photoreceptor cell death associated with the various genetic forms of retinitis pigmentosa (RP) is currently untreatable and leads to partial or complete vision loss. Carnosic acid (CA) upregulates endogenous antioxidant enzymes and has proven neuroprotective in studies of neurodegenerative models affecting the brain. In this study, we examined the potential effect of CA on photoreceptor death in the Pde6b rd10 mouse model of RP. Our data shows that CA provided morphological and functional preservation of photoreceptors. CA appears to exert its neuroprotective effects through inhibition of oxidative stress and endoplasmic reticulum stress.Retinitis pigmentosa (RP) is a class of inherited diseases which are characterized by the gradual degeneration of rod photoreceptors followed by cone photoreceptor cell dysfunction and death 1 . RP is a significant cause of vision loss, and affects approximately 1 in 3,700 people 2 . The initial symptoms of RP impact the peripheral retina. RP in late stages will involve central vision and may result in legal blindness 3 . Although effective treatments for RP should start early in life, there are currently no effective medications available for controlling the development of RP due to the limited therapeutic benefits or potential side effects of currently available treatment options 4,5 . It is therefore important to search for novel therapeutics for RP treatment 6 .Photoreceptors work in a very challenging environment characterized by high oxygen supply 7 , excessive light exposure 8 , dim ambient light and active metabolism 9 . These stressors induce oxidative damage of the biological macromolecules that comprise photoreceptors 10 . Increasing evidence obtained from animal models of RP suggests that oxidative stress 11,12 , as well as endoplasmic reticulum (ER) stress 13 , may be the critical mechanisms underlying photoreceptor damage and death [14][15][16] . Consistent with this hypothesis, a number of studies have demonstrated that early administration of agents that inhibit oxidative stress could significantly decrease the rate of photoreceptor cell death in animal models of RP 11,17,18 .Carnosic acid (CA) is a potent antioxidant isolated from Rosmarinus officinalis. CA can readily cross the blood-brain barrier 19 and exert its protective effects after conversion from its catechol form to an electrophilic quinone form. This conversion allows CA to bind to Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm and subsequently release protective transcription factors 20,21 . Unlike other antioxidants, CA does not deplete the endogenous antioxidant glutathione 20 .The Pde6b rd10 (rd10) mouse is a well-characterized model of RP 22,23 . The rd10 mouse carries a missense mutation in exon 13 of the beta subunit of the rod phosphodiesterase gene (Pde6b) 22,23 , mutations in which also cause human RP 24,25 . In rd10 mice, rod cell death begins around postnatal day (P) 18 26 , and is near complete by P35 27 . In this study, we demonstrate that CA slows rod degeneration in ...

In diabetes, there are two major physiological aberrations: (i) Loss of insulin signaling due to absence of insulin (type 1 diabetes) or insulin resistance (type 2 diabetes) and (ii) increased blood glucose levels. The retina has a high proclivity to damage following diabetes, and much of the pathology seen in diabetic retinopathy has been ascribed to hyperglycemia and downstream cascades activated by increased blood glucose. However, less attention has been focused on the direct role of insulin on retinal physiology, likely due to the fact that uptake of glucose in retinal cells is not insulin-dependent. The retinal pigment epithelium (RPE) is instrumental in maintaining the structural and functional integrity of the retina. Recent studies have suggested that RPE dysfunction is a precursor of, and contributes to, the development of diabetic retinopathy. To evaluate the role of insulin on RPE cell function directly, we generated a RPE specific insulin receptor (IR) knockout (RPEIRKO) mouse using the Cre-loxP system. Using this mouse, we sought to determine the impact of insulin-mediated signaling in the RPE on retinal function under physiological control conditions as well as in streptozotocin (STZ)induced diabetes. We demonstrate that loss of RPE-specific IR expression resulted in lower a-and bwave electroretinogram amplitudes in diabetic mice as compared to diabetic mice that expressed IR on the RPE. Interestingly, RPEIRKO mice did not exhibit significant differences in the amplitude of the RPEdependent electroretinogram c-wave as compared to diabetic controls. However, loss of