Early Loss of Innervation of Cornea Epithelium in Streptozotocin-Induced Type 1 Diabetic Rats: Improvement with Ilepatril Treatment

Davidson, Eric P.; Coppey, Lawrence J.; Yorek, Mark A.

doi:10.1167/iovs.12-10826

Cited by 57 publications

(59 citation statements)

References 35 publications

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“…It has been demonstrated in both human and animal subjects that diabetes alters the structure of corneal nerves, and this may be an early marker for diabetic PN. 2–6,12,18–25 We propose that a diabetes-induced loss in corneal nerve density will translate into a decrease in cornea sensitivity in response to corneal stimulation through hypertonicity that can be evaluated by capturing and measuring behavioral changes in facial and/or ocular movement. Quantifying these behavioral changes could provide an objective screening tool for detection of PN that can be easily performed during a routine eye examination.…”

Section: Discussionmentioning

confidence: 99%

Corneal Sensitivity to Hyperosmolar Eye Drops: A Novel Behavioral Assay to Assess Diabetic Peripheral Neuropathy

Yorek

Davidson

Poolman

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PurposeDiagnosis of peripheral neuropathy (PN), which affects approximately 50% of the diabetic population, is subjective, with many patients seeking a diagnosis only after presenting with symptoms. Recently, in vivo confocal microscopy of subepithelial corneal nerve density has been promoted as a surrogate marker for early detection of PN, but imaging of corneal nerves requires sophisticated instrumentation, expertise in confocal imaging, cooperative patients, and automated analysis tools to derive corneal nerve density. As an alternative, we developed a simple screening method that is based on the sensitivity of corneal nerves to cause reflex eyelid squinting in response to hyperosmolar eye drops.MethodsEyes of control and type 2 diabetic rats were given an eye drop of a 290- to 900-mOsm solution, and the ocular response was video recorded. Other neuropathic end points including nerve conduction velocity and subepithelial cornea nerve density were determined.ResultsMotor and sensory nerve conduction velocity and total nerve fiber length of corneal nerves in the subepithelial layer were significantly decreased in diabetic rats. Applying the hyperosmotic solutions to the ocular surface caused an osmolarity-dependent increase in squinting of the treated eye in control rats. Squinting was almost totally blocked by preapplication of proparacaine or N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide, a transient receptor potential melastatin-8 channel blocker. Squinting in response to the 900-mOsm solution was significantly reduced in diabetic rats.ConclusionsPreclinical studies show that evaluation of corneal sensitivity may be an alternative method for the early detection of PN and has potential for translation to clinical studies.

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Section: Discussionmentioning

confidence: 99%

Corneal Sensitivity to Hyperosmolar Eye Drops: A Novel Behavioral Assay to Assess Diabetic Peripheral Neuropathy

Yorek

Davidson

Poolman

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…Indeed, examination of the corneal sub-basal nerve plexus has already been used to assess therapeutic efficacy of a vasopeptidase inhibitor in treating DN in an animal model of diabetes. 16 …”

Section: Introductionmentioning

confidence: 99%

Differential reduction in corneal nerve fiber length in patients with type 1 or type 2 diabetes mellitus

Stem

Hussain

Lentz

et al. 2014

Journal of Diabetes and its Complications

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Aim To examine the relationship between corneal nerve fiber length (CNFL) and diabetic neuropathy (DN) status in patients with type 1 or type 2 diabetes mellitus (DM) Methods In this cross-sectional study, we examined 25 diabetic patients without DN, 10 patients with mild DN, 8 patients with severe DN, and 9 controls without diabetes. DN status was assigned based on a combination of clinical symptoms, signs, and electrophysiological testing. Patients underwent corneal confocal microscopy (CCM) of the sub-basal nerve plexus. Post-hoc analysis of the CCM images was performed to quantify the average CNFL, and ANOVA was used to assess for differences in CNFL. Results All 25 subjects without DN had type 1 DM, and subjects with DN had type 2 DM. Participants with severe DN had significantly lower CNFL (12.5 ± 6.1 mm/mm2) compared to controls (20.7 ± 2.2 mm/mm2) (p=0.009). However, lower CNFL was also found in participants with type 1 DM who did not have DN (15.1 ± 4.7 mm/mm2) relative to controls (p=0.033). Conclusions CCM of the sub-basal nerve plexus may be an indicator of early peripheral nerve degeneration in type 1 DM. Type of diabetes, in addition to degree of neuropathy, may influence the extent of corneal nerve damage.

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“…Davidson et al reported a 50% loss of corneal nerve fibers after 12 weeks of high fat diet in low-dose streptozotocin-induced diabetic rats [64]. Yin et al described corneal changes in streptozotocin-induced type 1 diabetic rats.…”

Section: Corneal Sensitivity In Diabetesmentioning

confidence: 99%

Neuronal Changes in the Diabetic Cornea: Perspectives for Neuroprotection

Bikbova

Oshitari

Baba

et al. 2016

BioMed Research International

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Diabetic neuropathy is associated with neurotrophic ulcerations of the skin and cornea. Decreased corneal sensitivity and impaired innervation lead to weakened epithelial wound healing predisposing patients to ocular complications such as corneal infections, stromal opacification, and surface irregularity. This review presents recent findings on impaired corneal innervation in diabetic individuals, and the findings suggest that corneal neuropathy might be an early indicator of diabetic neuropathy. Additionally, the recent findings for neuroprotective and regenerative therapy for diabetic keratopathy are presented.

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Early Loss of Innervation of Cornea Epithelium in Streptozotocin-Induced Type 1 Diabetic Rats: Improvement with Ilepatril Treatment

Cited by 57 publications

References 35 publications

Corneal Sensitivity to Hyperosmolar Eye Drops: A Novel Behavioral Assay to Assess Diabetic Peripheral Neuropathy

Corneal Sensitivity to Hyperosmolar Eye Drops: A Novel Behavioral Assay to Assess Diabetic Peripheral Neuropathy

Differential reduction in corneal nerve fiber length in patients with type 1 or type 2 diabetes mellitus

Neuronal Changes in the Diabetic Cornea: Perspectives for Neuroprotection

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