Capsaicin-Induced Corneal Sensory Denervation and Healing Impairment Are Reversed by NGF Treatment

Lambìase, Alessandro; Aloe, Luigi; Mantelli, Flavio; Sacchetti, Marta; Perrella, Eleonora; Bianchi, Patrizia; Rocco, M. Di; Bombardieri, Stefano

doi:10.1167/iovs.12-10593

Cited by 43 publications

(37 citation statements)

References 34 publications

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“…As a consequence, the efficacy of topical treatment with murine NGF (mNGF) eye drops was evaluated both in animal models and in patients affected by neurotrophic and autoimmune corneal ulcers [12–15]. In all these cases, therapeutic efficacy was associated with a good safety profile [13–15].…”

Section: Introductionmentioning

confidence: 99%

Safety and Pharmacokinetics of Escalating Doses of Human Recombinant Nerve Growth Factor Eye Drops in a Double-Masked, Randomized Clinical Trial

et al. 2013

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Background and ObjectivesNerve growth factor (NGF) is a neurotrophin with therapeutic possibilities that extend from the nervous system to the eye. We tested the safety, maximal tolerated dose, pharmacokinetics, and antigenicity of a novel human recombinant NGF (rhNGF) eye-drop formulation in a phase I study.MethodsThis prospective, randomized, double-masked, vehicle-controlled trial, sponsored by Dompé SpA (registered as NCT01744704 at ClinicalTrials.gov), enrolled 74 healthy volunteers (24 females, 50 males, age 40.2 ± 11.8 years). Subjects were randomized in three cohorts to receive (1) a single eye-drop containing 0.0175, 0.175, or 0.7 μg rhNGF; (2) a single ascending dose of rhNGF eye drops three times a day for 1 day (total daily dose 2.1, 6.3, or 18.9 μg), or vehicle; or (3) a multiple ascending dose of rhNGF eye drops three times a day for 5 days (total dose 10.5, 31.5, or 94.5 μg), or vehicle. Outcome measures included blood chemistry, urinalyses, vital signs, electrocardiograms (ECGs), serum NGF antibodies, ocular and systemic adverse events (AEs), visual acuity, tear function, intraocular pressure, fundus oculi, and ocular symptoms.ResultsAdministration of rhNGF eye drops did not result in a significant increase of circulating NGF levels and no antidrug antibodies were detected in serum. No serious AEs were recorded, and a few mild, transient ocular AEs related to rhNGF administration were reported only at the highest concentration.ConclusionsrhNGF eye drops were well tolerated, with no detectable clinical evidence of systemic AEs. These results pave the way for the development of clinical trials on rhNGF in ophthalmology.

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Section: Introductionmentioning

confidence: 99%

Safety and Pharmacokinetics of Escalating Doses of Human Recombinant Nerve Growth Factor Eye Drops in a Double-Masked, Randomized Clinical Trial

et al. 2013

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“…Previous studies have described conflicting results related to the effects of manipulating the NGF pathway. Administration of NGF to the cornea has been shown to increase presence of corneal nerves and increase rates of epithelial proliferation [30], [32], [33], improve corneal healing after capsaicin administration and epithelial scraping [34], and increase wound closure [28]. Other studies have shown that NGF has no effect on wound closure [27].…”

Section: Discussionmentioning

confidence: 99%

Nerve Growth Factor Regulates Neurolymphatic Remodeling during Corneal Inflammation and Resolution

et al. 2014

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The cellular and physiologic mechanisms that regulate the resolution of inflammation remain poorly defined despite their widespread importance in improving inflammatory disease outcomes. We studied the resolution of two cardinal signs of inflammation–pain and swelling–by investigating molecular mechanisms that regulate neural and lymphatic vessel remodeling during the resolution of corneal inflammation. A mouse model of corneal inflammation and wound recovery was developed to study this process in vivo. Administration of nerve growth factor (NGF) increased pain sensation and inhibited neural remodeling and lymphatic vessel regression processes during wound recovery. A complementary in vivo approach, the corneal micropocket assay, revealed that NGF-laden pellets stimulated lymphangiogenesis and increased protein levels of VEGF-C. Adult human dermal lymphatic endothelial cells did not express canonical NGF receptors TrkA and p75NTR or activate downstream MAPK- or Akt-pathway effectors in the presence of NGF, although NGF treatment increased their migratory and tubulogenesis capacities in vitro. Blockade of the VEGF-R2/R3 signaling pathway ablated NGF-mediated lymphangiogenesis in vivo. These findings suggest a hierarchical relationship with NGF functioning upstream of the VEGF family members, particularly VEGF-C, to stimulate lymphangiogenesis. Taken together, these studies show that NGF stimulates lymphangiogenesis and that NGF may act as a pathogenic factor that negatively regulates the normal neural and lymphatic vascular remodeling events that accompany wound recovery.

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“…It has been shown that the levels of NGF are increased in the cornea after injury. This NGF increase is impaired in denervated cornea, which shows a delayed healing [49]. NGF treatment of denervated cornea improved corneal healing and increased the expression levels of the corneal stem cell marker p63 [50].…”

Section: Innervation and Corneamentioning

confidence: 94%

Roles of innervation in developing and regenerating orofacial tissues

Pagella

Jiménez-Rojo

Mitsiadis

2014

Cell. Mol. Life Sci.

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The head is innervated by 12 cranial nerves (I-XII) that regulate its sensory and motor functions. Cranial nerves are composed of sensory, motor, or mixed neuronal populations. Sensory neurons perceive generally somatic sensations such as pressure, pain, and temperature. These neurons are also involved in smell, vision, taste, and hearing. Motor neurons ensure the motility of all muscles and glands. Innervation plays an essential role in the development of the various orofacial structures during embryogenesis. Hypoplastic cranial nerves often lead to abnormal development of their target organs and tissues. For example, Möbius syndrome is a congenital disease characterized by defective innervation (i.e., abducens (VI) and facial (VII) nerves), deafness, tooth anomalies, and cleft palate. Hence, it is obvious that the peripheral nervous system is needed for both development and function of orofacial structures. Nerves have a limited capacity to regenerate. However, neural stem cells, which could be used as sources for neural tissue maintenance and repair, have been found in adult neuronal tissues. Similarly, various adult stem cell populations have been isolated from almost all organs of the human body. Stem cells are tightly regulated by their microenvironment, the stem cell niche. Deregulation of adult stem cell behavior results in the development of pathologies such as tumor formation or early tissue senescence. It is thus essential to understand the factors that regulate the functions and maintenance of stem cells. Yet, the potential importance of innervation in the regulation of stem cells and/or their niches in most organs and tissues is largely unexplored. This review focuses on the potential role of innervation in the development and homeostasis of orofacial structures and discusses its possible association with stem cell populations during tissue repair.

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Capsaicin-Induced Corneal Sensory Denervation and Healing Impairment Are Reversed by NGF Treatment

Cited by 43 publications

References 34 publications

Safety and Pharmacokinetics of Escalating Doses of Human Recombinant Nerve Growth Factor Eye Drops in a Double-Masked, Randomized Clinical Trial

Safety and Pharmacokinetics of Escalating Doses of Human Recombinant Nerve Growth Factor Eye Drops in a Double-Masked, Randomized Clinical Trial

Nerve Growth Factor Regulates Neurolymphatic Remodeling during Corneal Inflammation and Resolution

Roles of innervation in developing and regenerating orofacial tissues

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