piperidines and Corneal-Injuries

Neurotrophic keratopathy is a corneal epitheliopathy induced by trigeminal denervation that can be treated with eyedrops containing the neuropeptide substance P (or the peptide FGLM-NH2 derived therefrom) and insulin-like growth factor 1 (or the peptide SSSR derived therefrom). Here, we examine the mechanism by which substance P (or FGLM-NH2) promotes corneal epithelial wound healing in a mouse model of neurotrophic keratopathy.. The left eye of mice subjected to trigeminal nerve axotomy in the right eye served as a model of neurotrophic keratopathy. Corneal epithelial wound healing was monitored by fluorescein staining and slit-lamp examination. The distribution of substance P, neurokinin-1 receptor (NK-1R), and phosphorylated Akt was examined by immunohistofluorescence analysis. Cytokine and chemokine concentrations in intraocular fluid were measured with a multiplex assay.. Topical administration of FGLM-NH2 and SSSR promoted corneal epithelial wound healing in the neurotrophic keratopathy model in a manner sensitive to the NK-1R antagonist L-733,060. Expression of substance P and NK-1R in the superficial layer of the corneal epithelium decreased and increased, respectively, in model mice compared with healthy mice. FGLM-NH2 and SSSR treatment suppressed the production of interleukin-1α, macrophage inflammatory protein 1α (MIP-1α) and MIP-1β induced by corneal epithelial injury in the model mice. It also increased the amount of phosphorylated Akt in the corneal epithelium during wound healing in a manner sensitive to prior L-733,060 administration.. The substance P-NK-1R axis promotes corneal epithelial wound healing in a neurotrophic keratopathy model in association with upregulation of Akt signaling and attenuation of changes in the cytokine-chemokine network.

Topics: Animals; Corneal Injuries; Epithelium, Corneal; Insulin-Like Growth Factor I; Mice; Neurokinin-1 Receptor Antagonists; Neurotransmitter Agents; Piperidines; Proto-Oncogene Proteins c-akt; Receptors, Neurokinin-1; Signal Transduction; Substance P; Wound Healing

To determine whether the inhibition of Substance P (SP) activity can reduce corneal neovascularization (CNV) by means of local administration of high-affinity, competitive, tachykinin 1 receptor (NK1R) antagonists Lanepitant and Befetupitant.. We performed a safety and efficacy study by using (1) two different C57BL/6 mouse models of CNV: alkali burn and sutures; (2) different concentrations; and (3) different routes of administration: topical or subconjunctival. Clinical examination endpoints, SP levels, CNV index, and leukocyte infiltration were measured.. Substance P increased after injury in the corneal epithelium of both CNV models, and later in the suture model. Topical Lanepitant was nontoxic to the ocular surface and effective in reducing hemangiogenesis and lymphangiogenesis, corneal SP levels, and leukocyte infiltration, as soon as 4 days later in the alkali burn model. Topical Lanepitant, up to 7 days, was ineffective in the suture model. However, subconjunctival Lanepitant was effective in reducing lymphatic CNV, leukocyte infiltration, and SP levels in the suture model, after 10 days. Additionally, in the alkali burn model, subconjunctival Lanepitant significantly reduced blood CNV, corneal perforation rate, opacity, and leukocyte infiltration, and improved tear secretion. Finally, topical application of Befetupitant reduced CNV in the alkali burn model but was toxic owing to the vehicle (dimethyl sulfoxide [DMSO]); hence, Befetupitant was not tested in the suture model.. The NK1R antagonist Lanepitant is safe for the ocular surface and effective in reducing both corneal hemangiogenesis and lymphangiogenesis, and leukocyte infiltration. We suggest that inhibition of NK1R may represent an adjunctive tool in the treatment of CNV.

Topics: Administration, Topical; Animals; Burns, Chemical; Conjunctiva; Cornea; Corneal Injuries; Corneal Neovascularization; Disease Models, Animal; Eye Burns; Female; Follow-Up Studies; Immunohistochemistry; Indoles; Injections; Mice; Mice, Inbred C57BL; Neurokinin-1 Receptor Antagonists; Ophthalmic Solutions; Piperidines; Pyridines; Receptors, Neurokinin-1; Sutures; Tomography, Optical Coherence; Treatment Outcome

The authors determined the effect of topically applied substance P (SP) on the rate of corneal epithelial wound closure in the rabbit.. Uniform circular lesions, 6.5 mm in diameter, were made bilaterally in the corneal epithelium of 24 rabbits using N-heptanol. Substance P was applied repeatedly to one eye, and the SP1-7 fragment was applied to the contralateral (control) eye until wound closure was obtained. Three concentrations of peptide solution (5 x 10(-5) M, 5 x 10(-4) M, and 5 x 10(-3) M) were tested in separate groups of eight animals each. An additional eight animals received topical applications (5 x 10(-7) M) of the neurokinin-1 (NK1)-specific SP receptor antagonist CP-99,994-01 or its ineffective enantiomer CP-100,263-01. The mean rates of wound healing for each group of experimental and control eyes were determined by linear regression and analyzed by analysis of variance.. There were no statistically significant differences in the mean rates of wound closure (range, 0.083 to 0.106 mm/hour) between experimental- and control-treated corneas for any of the four groups tested.. The topical application of SP or its NK1 receptor antagonist has no significant effect on the rate of corneal epithelial wound closure in the rabbit.

Topics: Administration, Topical; Animals; Cornea; Corneal Injuries; Epithelium; Male; Neurokinin A; Ophthalmic Solutions; Piperidines; Rabbits; Receptors, Neurokinin-1; Stereoisomerism; Substance P; Wound Healing