Inhibition of ceramide biosynthesis preserves photoreceptor structure and function in a mouse model of retinitis pigmentosa

Abstract

Retinitis pigmentosa (RP) is a genetic disease causing progressive apoptotic death of photoreceptors and, ultimately, incurable blindness. Using the retinal degeneration 10 (rd10) mouse model of RP, we investigated the role of ceramide, a proapoptotic sphingolipid, in retinal degeneration. We also tested the possibility that photoreceptor loss can be slowed or blocked by interfering with the ceramide signaling pathway of apoptosis in vivo. Retinal ceramide levels increased in rd10 mice during the period of maximum photoreceptor death. Single intraocular injections of myriocin, a powerful inhibitor of serine palmitoyl-CoA transferase, the ratelimiting enzyme of ceramide biosynthesis, lowered retinal ceramide levels to normal values and rescued photoreceptors from apoptotic death. Noninvasive treatment was achieved using eye drops consisting of a suspension of solid lipid nanoparticles loaded with myriocin. Short-term noninvasive treatment lowered retinal ceramide in a manner similar to intraocular injections, indicating that nanoparticles functioned as a vector permitting transcorneal drug administration. Prolonged treatment (10-20 d) with solid lipid nanoparticles increased photoreceptor survival, preserved photoreceptor morphology, and extended the ability of the retina to respond to light as assessed by electroretinography. In conclusion, pharmacological targeting of ceramide biosynthesis slowed the progression of RP in a mouse model, and therefore may represent a therapeutic approach to treating this disease in humans. Transcorneal administration of drugs carried in solid lipid nanoparticles, as experimented in this study, may facilitate continuous, noninvasive treatment of patients with RP and other retinal pathologies.sphingolipid | apoptosis | electroretinography | morphology

Sphingolipid profile alters in retinal dystrophic P23H-1 rats and systemic FTY720 can delay retinal degeneration

“…The processes of apoptotic cell death is integral to major retinal diseases including RP, Stargardt's disease, Leber's congenital amaurosis, and AMD (38)(39)(40)(41). Recent evidence suggests a strong correlation between Cer signaling and survival and homeostasis of photoreceptor and RPE cells (8,(42)(43)(44)(45)(46)(47)(48). In this study, we found significant alterations in the sphingolipid profile in P23H-1 rat retina at early age points (P22) when their photoreceptors begin to degenerate.…”

Spatial organization of lipids in the human retina and optic nerve by MALDI imaging mass spectrometry

“…This side reaction product can progressively accumulate with age in the RPE and may contribute to retinal degenerative diseases such as AMD ( 14,15 ). Additionally, the production of ceramides, which are bioactive sphingolipids that are critical mediators for initiating oxidative stress-induced apoptotic cell death of both photoreceptors and RPE cells, may lead to several ret inal diseases including retinitis pigmentosa and AMD (16)(17)(18)(19).…”

Determination of the serine palmitoyl transferase inhibitor myriocin by electrospray and Q‐trap mass spectrometry

“…To carried out under Avertine general anaesthesia, as described in (Strettoi et al, 2010). An identical volume of DMSO vehicle was injected into the opposite eye of the same animal to obtain control samples for analytical development.…”

“…This preparation was supplied at a nominal concentration 1 mM (Gasco & Gasco, 2007), and previously characterized by TLC (Strettoi et al, 2010). Three aliquots from six independent vials were processed as described in Material and Methods, and injected in triplicate.…”

“…In particular, it seems to be is a promising candidate to treat diseases such as diabetes (Ussher et al, 2011; Kurek et al, 2017) retinitis pigmentosa (Piano et al, 2013;Strettoi et al, 2010), cystic fibrosis (Caretti et al, 2014;Caretti et al, 2016) and myocardial infarction (Reforgiato et al, 2016). Myriocin is active at few nanomoles dose (1-5 microg) as a powerful immunosuppressant, and may have clinical potential in organ transplantation and for the treatment of autoimmune diseases (Fujita et al, 1994).…”