Effect of glycemic control on corneal nerves and peripheral neuropathy in streptozotocin‐induced diabetic <scp>C57Bl</scp>/<scp>6J</scp> mice

Yorek, Mark A.; Obrosov, Alexander; Shevalye, Hanna; Lupachyk, Sergey; Harper, Matthew M.; Kardon, Randy H.

doi:10.1111/jns.12086

Cited by 44 publications

(66 citation statements)

References 38 publications

(64 reference statements)

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“…Previous and our studies have confirmed that streptozotocin injection-induced type 1 diabetic mice assumed typical characteristics of diabetic corneal neuropathy, including impaired corneal nerve regeneration with concomitant attenuated corneal sensory and trophic functions102021. Given the capacity of VEGF-B to restore the anatomic and function corneal innervations in normal mice, here we explored the contribution and mechanism of VEGF-B in diabetic corneal nerve fiber regeneration, corneal sensation and trophic function recovery by using type 1 diabetic mice and cultured trigeminal ganglion neurons.…”

supporting

confidence: 77%

VEGF-B promotes recovery of corneal innervations and trophic functions in diabetic mice

Zhao

et al. 2017

Sci Rep

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Vascular endothelial growth factor (VEGF)-B possesses the capacity of promoting injured peripheral nerve regeneration and restore their sensory and trophic functions. However, the contribution and mechanism of VEGF-B in diabetic peripheral neuropathy remains unclear. In the present study, we investigated the expression and role of VEGF-B in diabetic corneal neuropathy by using type 1 diabetic mice and cultured trigeminal ganglion (TG) neurons. Hyperglycemia attenuated the endogenous expression of VEGF-B in regenerated diabetic corneal epithelium, but not that of VEGF receptors in diabetic TG neurons and axons. Exogenous VEGF-B promoted diabetic corneal nerve fiber regeneration through the reactivation of PI-3K/Akt-GSK3β-mTOR signaling and the attenuation of neuronal mitochondria dysfunction via the VEGF receptor-1 and neuropilin-1. Moreover, VEGF-B improved corneal sensation and epithelial regeneration in both normal and diabetic mice, accompanied with the elevated corneal content of pigment epithelial-derived factor (PEDF). PEDF blockade partially abolished trophic function of VEGF-B in diabetic corneal re-innervation. In conclusion, hyperglycemia suppressed endogenous VEGF-B expression in regenerated corneal epithelium of diabetic mice, while exogenous VEGF-B promoted recovery of corneal innervations and trophic functions through reactivating PI-3K/Akt-GSK-3β-mTOR signaling, attenuating neuronal oxidative stress and elevating PEDF expression.

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supporting

confidence: 77%

VEGF-B promotes recovery of corneal innervations and trophic functions in diabetic mice

Zhao

et al. 2017

Sci Rep

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“…The cornea is the most densely innervated structure of the human body, containing Aδ and unmyelinated C fibers derived from the ophthalmic division of the trigeminal nerve21. CCM is gaining establishment as a valid measure of diabetic nerve damage in the clinic2223 that can also be used to monitor diabetic neurodegeneration in rodent models171824. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice

Trammell

Weidemann

Chadda

et al. 2016

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Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type 2 diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD+ metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with nicotinamide riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detection of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP+ and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR. The data justify testing of NR in human models of obesity, T2D and associated neuropathies.

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“…Sub-epithelial corneal nerves were imaged in vivo non-invasively using the Rostock cornea module of the Heidelberg Retina Tomograph (Heidelberg Engineering, Vista, CA) confocal microscope as previously described (Yorek et al, 2014; 2015). …”

Section: Methodsmentioning

confidence: 99%

Early vs. late intervention of high fat/low dose streptozotocin treated C57Bl/6J mice with enalapril, α-lipoic acid, menhaden oil or their combination: Effect on diabetic neuropathy related endpoints

et al. 2017

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We have previously demonstrated that enalapril, α-lipoic acid and menhaden (fish) oil has potential as a treatment for diabetic peripheral neuropathy. In this study we sought to determine the efficacy of these treatments individually or in combination on multiple neuropathic endpoints in a high fat fed low dose streptozotocin treated mouse, a model of type 2 diabetes, following early or late intervention. Four or twelve weeks after the onset of hyperglycemia, diabetic mice were treated with enalapril, α-lipoic acid, menhaden oil or their combination for 12 weeks. Afterwards, endpoints including glucose tolerance, motor and sensory nerve conduction velocity, thermal nociception, and intraepidermal and cornea nerve fiber density was determined. Glucose clearance was impaired in diabetic mice and significantly improved only with combination treatment and early intervention. Diabetes caused steatosis, slowing of motor and sensory nerve conduction velocity, thermal hypoalgesia and reduction in intraepidermal and cornea nerve fiber density. Treating diabetic mice with enalapril, α-lipoic acid or menhaden oil partially protected diabetic mice from these deficits, whereas the combination of these three treatments was more efficacious following early or late intervention. These studies suggest that a combination therapy may be more effective for treating neural complications of type 2 diabetes.

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Effect of glycemic control on corneal nerves and peripheral neuropathy in streptozotocin‐induced diabetic C57Bl/6J mice

Cited by 44 publications

References 38 publications

VEGF-B promotes recovery of corneal innervations and trophic functions in diabetic mice

VEGF-B promotes recovery of corneal innervations and trophic functions in diabetic mice

Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice

Early vs. late intervention of high fat/low dose streptozotocin treated C57Bl/6J mice with enalapril, α-lipoic acid, menhaden oil or their combination: Effect on diabetic neuropathy related endpoints

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