Abstract
The high-density corneal innervation plays a pivotal role in sustaining the integrity of the ocular surface. We have previously demonstrated that pigment epithelium-derived factor (PEDF) plus docosahexaenoic acid (DHA) promotes corneal nerve regeneration; here, we report the mechanism involved and the discovery of a stereospecific Resolvin D6-isomer (RvD6si) that drives the process. RvD6si promotes corneal wound healing and functional recovery by restoring corneal innervation after injury. RvD6si applied to the eye surface elicits a specific transcriptome signature in the trigeminal ganglion (TG) that includes Rictor, the rapamycin-insensitive complex-2 of mTOR (mTORC2), and genes involved in axon growth, whereas genes related to neuropathic pain are decreased. As a result, attenuation of ocular neuropathic pain and dry eye will take place. Thus, RvD6si opens up new therapeutic avenues for pathologies that affect corneal innervation.
Highlights
The high-density corneal innervation plays a pivotal role in sustaining the integrity of the ocular surface
A mechanistic link of pigment epithelium-derived factor (PEDF) + docosahexaenoic acid (DHA) action on corneal nerve regeneration has been uncovered with the activation of the iPLA2ζ and the increased expression of the neurotrophic factors, brain-derived growth factor (BDNF) and nerve growth factor (NGF), and the axon growth guidance semaphorin 7a (Sema7A) released in tears[25]
The total ion chromatogram (TIC) of 359 m/z represented all di-hydroxy DHA isomers in tears after 4 h of treatment, and three peaks were well defined with retention times (RT) 8.20, 8.74, and 9.20 min (Fig. 1B)
Summary
The high-density corneal innervation plays a pivotal role in sustaining the integrity of the ocular surface. Dry eye perturbs vision mainly during aging It occurs in rheumatoid arthritis, diabetes, thyroid gland pathologies, environmental conditions (e.g., exposure to smoke or pollutants), long-term use of contact lenses, and after refractive surgery. Corneal innervation is required to maintain the integrity of the ocular surface[1], and nerve damage decreases tear production, blinking reflex, and perturbs epithelial wound healing, resulting in loss of transparency and vision[2,3,4,5]. For this reason, there is a strong relationship between dry eye and corneal nerve damage. We demonstrate that the topical application of RvD6si is cornea protective, revealing novel mechanisms and potential therapeutic avenues for dry eye and ocular neuropathic pain
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