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Tear neuropeptides for dry eye


Pre-LASIK (L) and post-LASIK (R)

Cecilia Chao

Dr Fiona Stapleton

Dr Blanka Golebiowski

School of Optometry and Vision Science, University of New South Wales


Nerve growth factor (NGF), substance P (SP) and calcitonin gene-related peptide (CGRP) are the key neuropeptides on the ocular surface and may be a remedy for dry eye in the near future. NGF at the ocular surface promotes nerve growth,1,2 and reinnervation after injury3 by preventing the death of neurons. NGF also regulates the level of neuropeptides, including SP and CGRP,1,4,5 on the ocular surface. The role of the neuropeptide SP and CGRP is not only limited to pain sensation at both cornea and conjunctiva, but also involved in epithelial wound healing, local inflammation, corneal reinnervation and maintaining ocular surface integrity.1,3,4,6-9

In general, neuropeptides are associated with cell and nerve function and subsequently maintain homeostasis in peripheral tissues, including the ocular surface.

NGF concentration in tissues rises when tissues or nerves are injured and returns to normal levels once the wound or nerves are healed.1,10-14 This explains the elevated NGF levels found in tears after LASIK refractive surgery.15

Administration of SP in vitro results in increased corneal epithelial cell numbers, and it is speculated that SP acts to enhance cell proliferation.16 Conversely, a reduction in corneal epithelial cell density (cells detached from the culture plate) was observed when CGRP was administered in vitro.16 It is likely that CGRP induces cell differentiation, which causes cells to detach and migrate, thus enabling wound healing.16

Our recent work has confirmed the importance of these neuropeptides in corneal nerve regeneration and maintenance of ocular surface integrity after LASIK refractive surgery (Chao et al 2014, under review). We found that tear SP concentration increases immediately after LASIK alongside the marked reduction of corneal nerve density, further supporting that SP has an important role in cell and nerve proliferation after injury.

In contrast, tear CGRP was positively associated with reinnervation (higher nerve fibre density and tortuosity) post-LASIK. This is consistent with the role of CGRP in reinnervation by cell differentiation after injury. Also, tear CGRP concentration was associated with better tear function (lower tear osmolarity and longer non-invasive tear break-up time) after LASIK. It is likely to be due to the restoration of nerve function.

Altered neuropeptide concentrations in tears commonly occur with dry eye and compromised ocular surface integrity. Higher tear NGF levels have been found in dry eye patients and in contact lens wearers with dry eye.14 Higher NGF levels in these patients are associated with greater dry eye severity,14,17 especially the degree of corneal staining and conjunctival hyperaemia.17 A reduction of tear CGRP concentration occurs in chronic dry eye and is associated with greater corneal staining and lower tear volume.17 Changes in SP levels were not significantly different in the same study.17

Other studies have also shown altered SP and CGRP levels in tears of contact lens wearers, dry eye patients with diabetes and post-refractive surgery patients,5,15,17-19 and have found altered levels of both neuropeptides to be associated with changes in corneal staining, corneal sensitivity and corneal sub-basal nerve density. Such findings suggest that administration of neuropeptides to the ocular surface could improve signs of dry eye, including neuropathic dry eye which results from diabetes or from corneal nerve damage due to mechanical/chemical injury such as that induced by refractive surgery.

The topical administration of neuropeptides to the ocular surface may ameliorate dry eye, including neuropathic dry eye, by facilitating corneal wound healing and reinnervation. NGF has previously been used in the management of peripheral (legs) diabetic neuropathy. Although this approach caused hyperalgesia at the injection site in the legs,20-23 this is less likely to be an issue for topical application (but not injection) at the ocular surface.

Topical NGF, SP (combined with insulin-like growth factor-1) and CGRP administration improves reinnervation and nerve function (restoration of sensory impairment), and promotes epithelial healing on damaged or injured ocular surface in both animals and humans.8,9,13,24-30 These neuropeptides may likewise be a promising treatment for dry eye, particularly ocular surface staining and dry eye symptoms resulting from nerve damage.

Tear neuropeptides are important in wound healing and integrity of the ocular surface, including maintenance of corneal nerves. They show promise as a future treatment of dry eye but clinical trials are required to confirm their merits.


Cecilia Chao was supported by the Australian Government through the International Postgraduate Research Scholarship scheme.

Conflict of interest disclosure

All authors have no proprietary or commercial interests in any concept or product discussed in this article.


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