Abstract
Myriocin is an antibiotic derived from Mycelia sterilia, and is a potent inhibitor of serine palmitoyltransferase, the enzyme involved in the first step of sphingosine synthesis. Myriocin, inhibiting ceramide synthesis, has a great potential for treatment of diseases characterized by high ceramide levels in affected tissues, such as retinitis pigmentosa (RP). Drug delivery to the retina is a challenging task, which is generally by-passed through intravitreal injection, that represents a risky invasive procedure. We, therefore, developed and characterized an ophthalmic topical nanotechnological formulation based on a nanostructured lipid carrier (NLC) and containing myriocin. The ocular distribution of myriocin in the back of the eye was assessed both in rabbits and mice using LC-MS/MS. Moreover, rabbit retinal sphingolipid and ceramides levels, after myriocin-NLC (Myr-NLC) eye drops treatment, were assessed. The results demonstrated that Myr-NLC formulation is well tolerated and provided effective levels of myriocin in the back of the eye both in rabbits and mice. We found that Myr-NLC eye drops treatment was able to significantly decrease retinal sphingolipid levels. In conclusion, these data suggest that the Myr-NLC ophthalmic formulation is suitable for pharmaceutical development and warrants further clinical evaluation of this eye drops for the treatment of RP.
Highlights
Myriocin, a natural compound with immunosuppressive activity, worked as a template compound for the development of fingolimod, a drug approved for the treatment of multiple sclerosis
Fingolimod retained the immunosuppressant activity of myriocin but not the inhibitory activity on serine palmitoyltransferase (Zecri, 2016), the enzyme involved in the first step of sphingolipids synthesis
We carried out preliminary comparison of Myr-nanostructured lipid carrier (NLC) retinal distribution with myriocin aqueous suspension (PBS pH 7.4, [myriocin] 1⁄4 1 mg/ml) and a myriocin-loaded solid lipid nanoparticles (Myr-solid lipid nanoparticle (SLN)) formulation
Summary
A natural compound with immunosuppressive activity, worked as a template compound for the development of fingolimod, a drug approved for the treatment of multiple sclerosis. Fingolimod retained the immunosuppressant activity of myriocin but not the inhibitory activity on serine palmitoyltransferase (Zecri, 2016), the enzyme involved in the first step of sphingolipids (i.e. ceramides) synthesis. The mutation of ceramide kinase like gene (CERKL) was associated with autosomal recessive RP (RP26) (Tuson et al, 2004). CERKL lipid kinase activity has not been confirmed as well, but the role of CERKL in the regulation of the retinal sphingolipid metabolism was proven by Garanto et al (2013). The sphingolipid metabolism was found to be altered in the retinal degeneration 10 (rd10) mouse model of RP (Strettoi et al, 2010)
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