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Neurotrophic factors and corneal nerve regeneration.

ABSTRACT: The cornea has unique features that make it a useful model for regenerative medicine studies. It is an avascular, transparent, densely innervated tissue and any pathological changes can be easily detected by slit lamp examination. Corneal sensitivity is provided by the ophthalmic branch of the trigeminal nerve that elicits protective reflexes such as blinking and tearing and exerts trophic support by releasing neuromediators and growth factors. Corneal nerves are easily evaluated for both function and morphology using standard instruments such as corneal esthesiometer and in vivo confocal microscope. All local and systemic conditions that are associated with damage of the trigeminal nerve cause the development of neurotrophic keratitis, a rare degenerative disease. Neurotrophic keratitis is characterized by impairment of corneal sensitivity associated with development of persistent epithelial defects that may progress to corneal ulcer, melting and perforation. Current neurotrophic keratitis treatments aim at supporting corneal healing and preventing progression of corneal damage. Novel compounds able to stimulate corneal nerve recovery are in advanced development stage. Among them, nerve growth factor eye drops showed to be safe and effective in stimulating corneal healing and improving corneal sensitivity in patients with neurotrophic keratitis. Neurotrophic keratitis represents an useful model to evaluate in clinical practice novel neuro-regenerative drugs.

SUBMITTER: Sacchetti M

PROVIDER: S-EPMC5607810 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Neurotrophic factors and corneal nerve regeneration.

Sacchetti Marta M Lambiase Alessandro A

Neural regeneration research 20170801 8

The cornea has unique features that make it a useful model for regenerative medicine studies. It is an avascular, transparent, densely innervated tissue and any pathological changes can be easily detected by slit lamp examination. Corneal sensitivity is provided by the ophthalmic branch of the trigeminal nerve that elicits protective reflexes such as blinking and tearing and exerts trophic support by releasing neuromediators and growth factors. Corneal nerves are easily evaluated for both functi ...[more]

PMID: 28966630

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Project description:Neurotrophic Keratopathy (NK) is a neurodegenerative corneal disease that results in diminished corneal sensation. Previous studies have found that Cenegermin 0.002%, a recombinant human nerve growth factor (rhNGF), improves corneal epithelial healing in stage 2 and 3 NK patients. However, rhNGF effect on corneal sensation and nerve regeneration has not been well established. Thus, this study aims to analyze the effect of rhNGF on corneal nerve regeneration using in vivo confocal microscopy (IVCM) and on corneal sensitivity in NK patients. This is a retrospective, longitudinal, case-control study that included patients with NK, treated with rhNGF for at least 4 weeks, with pre- and post-treatment IVCM images available for analysis. Chart reviews were conducted documenting prior medical and surgical history, clinical signs and symptoms, and corneal sensation using Cochet-Bonnet esthesiometry. Corneal nerve parameters were assessed by IVCM. Sex- and age-matched reference controls were selected from a database of healthy subjects for comparison. The study included 25 patients, with 22 (88%) stage 1, two (8%) stage 2, and 1 (4%) stage 3 NK patients, with a median age of 64 years (range: 30-93 years). Total, main, and branch nerve densities [median (range) in mm/mm2] were lower in the NK group pre-treatment [2.3 (0.0-21.1); 1.7 (0.0-13.0); 0.5 (0.0-10.2); respectively] vs. controls [22.3 (14.9-29.0); 10.1 (3.2-15.4); and 12.1 (6.2-18.4), (p < 0.0001 for all), respectively]. Post-treatment nerve densities increased compared to pre-treatment to 5.3 (0.0-19.4, p = 0.0083) for total, 3.5 (0.0-13.2, p = 0.0059) for main, and 2.0 (0.0-10.4, p = 0.0251) for branch nerves, but remained lower than controls (p < 0.0001 for all). Corneal sensation increased from 2.3 ± 1.1 cm pre-treatment to 4.1 ± 1.4 cm post-treatment (p = 0.001). Median best corrected visual acuity significantly increased following rhNGF treatment from 0.4 (0.0-1.6) to 0.12 (-0.1 to 1.6) (p = 0.007). Patients with NK treated with at least 4 weeks of rhNGF, showed a significant increase in corneal nerve densities after treatment. A significant increase in corneal sensation, as well as best corrected visual acuity, was observed following treatment.

Project description:PurposeNeurotrophic keratopathy is a degenerative disease characterized by damage to the corneal nerves leading to corneal hypoesthesia and anaesthesia. The resultant progressive visual deterioration is refractory to existing conventional treatment options. Corneal neurotization is a novel and effective surgical procedure that directly targets the underlying pathology of nerve loss by stimulating new corneal nerve growth. This study reports the outcomes and the pre- and postoperative in vivo confocal microscopy findings of the first published Australian case of indirect, minimally invasive, corneal neurotization using an ipsilateral sural nerve autograft.ObservationsAn 11-year-old boy developed corneal hypoesthesia in the left eye following surgical debulking of a cerebellopontine angle arachnoid cyst. He was diagnosed with Mackie Stage 1 neurotrophic keratopathy. Due to his hypoesthesia, he had developed recurrent microbial keratitis and corneal ulceration secondary to foreign bodies sustained during contact sports. At presentation, he reported photophobia and dry eye symptoms, corrected-distance visual acuity was 6/18, Cochet-Bonnet aesthesiometer demonstrated reduced corneal sensation (5-15mm), Schirmer's I test was 15mm, and in vivo confocal microscopy showed a complete absence of a subepithelial corneal plexus. He underwent indirect, minimally invasive, corneal neurotization using the ipsilateral supratrochlear nerve and a sural nerve autograft. Subjective improvement in corneal sensation was noticed by the patient at 2 months. Objective improvement, measured on Cochet-Bonnet aesthesiometer, was first observed at 6 months with steady stepwise improvement to 20-35mm at 21 months. Importantly, due to the increase in corneal sensation, the patient did not develop any further corneal complications. At 12 months, dry eye symptoms resolved and Schirmer's I test improved to 30mm. At 15 months, corrected-distance visual acuity improved to 6/5 and in vivo confocal microscopy demonstrated evidence of corneal reinnervation with nerves running through the subepithelial space surrounded by healthy and active keratocytes.Conclusions and importanceCorneal neurotization represents an exciting development in the armamentarium for the treatment of neurotrophic keratopathy and can be considered for younger patients with early-stage disease.

Project description:The efficacy of electroacupuncture in the treatment of peripheral facial paralysis is known, but the specific mechanism has not been clarified. Glial cell-derived neurotrophic factor (GDNF) has been shown to protect neurons by binding to N-cadherin. Our previous results have shown that electroacupuncture could increase the expression of N-cadherin mRNA in facial neurons and promote facial nerve regeneration. In this study, the potential mechanisms by which electroacupuncture promotes nerve regeneration were elucidated through assessing the effects of electroacupuncture on GDNF and N-cadherin expression in facial motoneurons of rabbits with peripheral facial nerve crush injury. New Zealand rabbits were randomly divided into a normal group (normal control, n = 21), injury group (n = 45) and electroacupuncture group (n = 45). Model rabbits underwent facial nerve crush injury only. Rabbits in the electroacupuncture group received facial nerve injury, and then underwent electroacupuncture at Yifeng (TE17), Jiache (ST6), Sibai (ST2), Dicang (ST4), Yangbai (GB14), Quanliao (SI18), and Hegu (LI4; only acupuncture, no electrical stimulation). The results showed that in behavioral assessments, the total scores of blink reflex, vibrissae movement, and position of apex nasi, were markedly lower in the EA group than those in the injury group. Hematoxylin-eosin staining of the right buccinator muscle of each group showed that the cross-sectional area of buccinator was larger in the electroacupuncture group than in the injury group on days 1, 14 and 21 post-surgery. Toluidine blue staining of the right facial nerve tissue of each group revealed that on day 14 post-surgery, there was less axonal demyelination and fewer inflammatory cells in the electroacupuncture group compared with the injury group. Quantitative real time-polymerase chain reaction showed that compared with the injury group, N-cadherin mRNA levels on days 4, 7, 14 and 21 and GDNF mRNA levels on days 4, 7 and 14 were significantly higher in the electroacupuncture group. Western blot assay displayed that compared with the injury group, the expression of GDNF protein levels on days 7, 14 and 21 were significantly upregulated in the electroacupuncture group. The histology with hematoxylin-eosin staining and Nissl staining of brainstem tissues containing facial neurons in the middle and lower part of the pons exhibited that on day 7 post-surgery, there were significantly fewer apoptotic neurons in the electroacupuncture group than in the injury group. By day 21, there was no significantly difference in the number of neurons between the electroacupuncture and normal groups. Taken together, these results have confirmed that electroacupuncture promotes regeneration of peripheral facial nerve injury in rabbits, inhibits neuronal apoptosis, and reduces peripheral inflammatory response, resulting in the recovery of facial muscle function. This is achieved by up-regulating the expression of GDNF and N-cadherin in central facial neurons.

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Neurotrophic factors and corneal nerve regeneration.

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Neurotrophic factors and corneal nerve regeneration.

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