Docosanoid signaling modulates corneal nerve regeneration: effect on tear secretion, wound healing, and neuropathic pain

The cornea is densely innervated, mainly by sensory nerves of the ophthalmic branch of the trigeminal ganglia (TG). These nerves are important to maintain corneal homeostasis, and nerve damage can lead to a decrease in wound healing, an increase in corneal ulceration and dry eye disease (DED), and neuropathic pain. Pathologies, such as diabetes, aging, viral and bacterial infection, as well as prolonged use of contact lenses and surgeries to correct vision can produce nerve damage. There are no effective therapies to alleviate DED (a multifunctional disease) and several clinical trials using ω-3 supplementation show unclear and sometimes negative results. Using animal models of corneal nerve damage, we show that treating corneas with pigment epithelium-derived factor (PEDF) plus docosahexaenoic acid (DHA) increases nerve regeneration, wound healing, and tear secretion. The mechanism involves the activation of a calcium-independent phospholipase A2 (iPLA2ζ) that releases the incorporated DHA from phospholipids and enhances the synthesis of docosanoids neuroprotectin D1 (NPD1) and a new resolvin stereoisomer RvD6i. NPD1 stimulates the synthesis of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and of semaphorin 7A (Sema7A). RvD6i treatment of injured corneas modulates gene expression in the TG resulting in enhanced neurogenesis; decreased neuropathic pain and increased sensitivity. Taken together, these results represent a promising therapeutic option to re-establish the homeostasis of the cornea.

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Novel RvD6 stereoisomer induces corneal nerve regeneration and wound healing post-injury by modulating trigeminal transcriptomic signature

Scientific Reports ◽

10.1038/s41598-020-61390-8 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 3

Author(s):

Thang L. Pham ◽

Azucena H. Kakazu ◽

Jiucheng He ◽

Bokkyoo Jun ◽

Nicolas G. Bazan ◽

...

Keyword(s):

Wound Healing ◽

Nerve Regeneration ◽

Post Injury ◽

Transcriptomic Signature ◽

Corneal Nerve

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Defining a mechanistic link between pigment epithelium–derived factor, docosahexaenoic acid, and corneal nerve regeneration

Journal of Biological Chemistry ◽

10.1074/jbc.m117.801472 ◽

2017 ◽

Vol 292 (45) ◽

pp. 18486-18499 ◽

Cited By ~ 26

Author(s):

Thang Luong Pham ◽

Jiucheng He ◽

Azucena H. Kakazu ◽

Bokkyoo Jun ◽

Nicolas G. Bazan ◽

...

Keyword(s):

Docosahexaenoic Acid ◽

Nerve Regeneration ◽

Pigment Epithelium ◽

Pigment Epithelium Derived Factor ◽

Corneal Nerve

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The effect of human platelet lysate on corneal nerve regeneration

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2019-314408 ◽

2019 ◽

pp. bjophthalmol-2019-314408 ◽

Cited By ~ 1

Author(s):

Chin-Te Huang ◽

Hsiao-Sang Chu ◽

Kuo-Chi Hung ◽

Lily Wei Chen ◽

Mei-Yun Chen ◽

...

Keyword(s):

Wound Healing ◽

Nerve Regeneration ◽

Neurotrophic Factors ◽

Ganglion Cells ◽

Human Platelet ◽

Platelet Lysate ◽

Human Platelet Lysate ◽

Corneal Nerve

AimThis study aimed to test whether human platelet lysate (HPL) has neurotrophic ability for corneal nerve regeneration.MethodsWe measured the neurotrophic factors in human peripheral serum (HPS) and two commercially available HPLs, UltraGRO and PLTMax. In vitro, we compared the growth rates, neuronal differentiation and immunostaining of neuron markers in mouse neuroblastoma cell line (Neuro-2a) and primary culture of mouse trigeminal ganglion cells that were cultivated in different concentrations of fetal bovine serum, HPS and HPL. In vivo, we created corneal wounds on Sprague Dawley rats with a rotating burr and evaluated the effects of topical HPL on wound healing and corneal nerve regeneration by in vivo confocal microscopy and corneal aesthesiometry.ResultsHPLs had significantly higher concentrations of various neurotrophic factors compared with HPS (p<0.05). In Neuro-2a cells, 3% HPL was better at promoting neuronal growth and differentiation compared with HPS at the same concentration. HPL was also found to have superior neurotrophic effects compared with HPS in primary cultures of mouse trigeminal ganglion cells. In vivo, HPL-treated eyes had better corneal epithelial wound healing rate, nerve regeneration length and corneal touch threshold compared with eyes treated with artificial tears (p<0.05).ConclusionHPL has significantly higher concentrations of neurotrophic factors compared with HPS. It showed not only in vitro but also in vivo corneal neurotrophic abilities. Our results suggest that HPL may have a potential role in the treatment of diseases related to corneal nerve damage or degeneration.

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Pigment Epithelium-Derived Factor Peptide Promotes Corneal Nerve Regeneration: An In Vivo and In Vitro Study

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.62.1.23 ◽

2021 ◽

Vol 62 (1) ◽

pp. 23

Author(s):

Shu-I Yeh ◽

Sung-Hsun Yu ◽

Hsiao-Sang Chu ◽

Chin-Te Huang ◽

Yeou-Ping Tsao ◽

...

Keyword(s):

Nerve Regeneration ◽

Pigment Epithelium ◽

In Vitro Study ◽

Vitro Study ◽

Pigment Epithelium Derived Factor ◽

Corneal Nerve

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A bioglass sustained-release scaffold with ECM-like structure for enhanced diabetic wound healing

Nanomedicine ◽

10.2217/nnm-2020-0053 ◽

2020 ◽

Vol 15 (23) ◽

pp. 2241-2253

Author(s):

Pengju Zhang ◽

Yuqi Jiang ◽

Dan Liu ◽

Yan Liu ◽

Qinfei Ke ◽

...

Keyword(s):

Wound Healing ◽

Therapeutic Option ◽

Effective Strategy ◽

Diabetic Wound ◽

Nano Structure ◽

Wound Site ◽

Diabetic Wound Healing ◽

Coaxial Fibers ◽

Diabetic Wounds ◽

Endothelial Cell Adhesion

Aim: To develop an effective strategy for increasing angiogenesis at diabetic wound sites and thereby accelerating wound healing. Materials & methods: A micropatterned nanofibrous scaffold with bioglass nanoparticles encapsulated inside coaxial fibers was prepared by electrospinning. Results: Si ions could be released in a sustained manner from the scaffolds. The hierarchical micro-/nano-structure of the scaffold was found to act as a temporary extracellular matrix to promote endothelial cell adhesion and growth. The scaffold greatly improved angiogenesis and collagen deposition at the wound site, which shortened the healing period of diabetic wounds. Conclusion: This study provides a promising therapeutic option for chronic diabetic wounds with improved angiogenesis.

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Insulin resistance limits corneal nerve regeneration in patients with Type 2 diabetes undergoing intensive glycemic control

Journal of Diabetes Investigation ◽

10.1111/jdi.13582 ◽

2021 ◽

Author(s):

Georgios Ponirakis ◽

Muhammad A. Abdul‐Ghani ◽

Amin Jayyousi ◽

Mahmoud A. Zirie ◽

Salma Al‐Mohannadi ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Glycemic Control ◽

Nerve Regeneration ◽

Intensive Glycemic Control ◽

Corneal Nerve

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Monitoring New Long-Lasting Intravitreal Formulation for Glaucoma with Vitreous Images Using Optical Coherence Tomography

Pharmaceutics ◽

10.3390/pharmaceutics13020217 ◽

2021 ◽

Vol 13 (2) ◽

pp. 217

Author(s):

Maria Jesus Rodrigo ◽

Amaya Pérez del Palomar ◽

Alberto Montolío ◽

Silvia Mendez-Martinez ◽

Manuel Subias ◽

...

Keyword(s):

Optical Coherence Tomography ◽

Relative Intensity ◽

Therapeutic Option ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Aggregate Size ◽

Daily Practice ◽

Optical Coherence ◽

Non Invasive ◽

Invasive Method

Intravitreal injection is the gold standard therapeutic option for posterior segment pathologies, and long-lasting release is necessary to avoid reinjections. There is no effective intravitreal treatment for glaucoma or other optic neuropathies in daily practice, nor is there a non-invasive method to monitor drug levels in the vitreous. Here we show that a glaucoma treatment combining a hypotensive and neuroprotective intravitreal formulation (IF) of brimonidine–Laponite (BRI/LAP) can be monitored non-invasively using vitreoretinal interface imaging captured with optical coherence tomography (OCT) over 24 weeks of follow-up. Qualitative and quantitative characterisation was achieved by analysing the changes in vitreous (VIT) signal intensity, expressed as a ratio of retinal pigment epithelium (RPE) intensity. Vitreous hyperreflective aggregates mixed in the vitreous and tended to settle on the retinal surface. Relative intensity and aggregate size progressively decreased over 24 weeks in treated rat eyes as the BRI/LAP IF degraded. VIT/RPE relative intensity and total aggregate area correlated with brimonidine levels measured in the eye. The OCT-derived VIT/RPE relative intensity may be a useful and objective marker for non-invasive monitoring of BRI/LAP IF.

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The effect of Rho Kinase inhibition on corneal nerve regeneration in vitro and in vivo

The Ocular Surface ◽

10.1016/j.jtos.2021.08.011 ◽

2021 ◽

Author(s):

Sonja Mertsch ◽

Inga Neumann ◽

Cosima Rose ◽

Marc Schargus ◽

Gerd Geerling ◽

...

Keyword(s):

Nerve Regeneration ◽

Rho Kinase ◽

Kinase Inhibition ◽

Corneal Nerve ◽

Regeneration In Vitro

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HCN2 ion channels: basic science opens up possibilities for therapeutic intervention in neuropathic pain

Biochemical Journal ◽

10.1042/bcj20160287 ◽

2016 ◽

Vol 473 (18) ◽

pp. 2717-2736 ◽

Cited By ~ 23

Author(s):

Christoforos Tsantoulas ◽

Elizabeth R. Mooney ◽

Peter A. McNaughton

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

Ion Channels ◽

Warning Signal ◽

Sensory Nerves ◽

Nociceptive Neurons ◽

Pain Syndromes ◽

Medical Need ◽

Pathological Pain ◽

Genetic Deletion

Nociception — the ability to detect painful stimuli — is an invaluable sense that warns against present or imminent damage. In patients with chronic pain, however, this warning signal persists in the absence of any genuine threat and affects all aspects of everyday life. Neuropathic pain, a form of chronic pain caused by damage to sensory nerves themselves, is dishearteningly refractory to drugs that may work in other types of pain and is a major unmet medical need begging for novel analgesics. Hyperpolarisation-activated cyclic nucleotide (HCN)-modulated ion channels are best known for their fundamental pacemaker role in the heart; here, we review data demonstrating that the HCN2 isoform acts in an analogous way as a ‘pacemaker for pain’, in that its activity in nociceptive neurons is critical for the maintenance of electrical activity and for the sensation of chronic pain in pathological pain states. Pharmacological block or genetic deletion of HCN2 in sensory neurons provides robust pain relief in a variety of animal models of inflammatory and neuropathic pain, without any effect on normal sensation of acute pain. We discuss the implications of these findings for our understanding of neuropathic pain pathogenesis, and we outline possible future opportunities for the development of efficacious and safe pharmacotherapies in a range of chronic pain syndromes.

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