Orally Active Neurotrophin-Enhancing Agent Protects Against Dysfunctions of the Peripheral Nerves in Hyperglycemic Animals

Abstract

Biological substances with neurotrophic activities, such as nerve growth factor (NGF) and monosialoganglioside GM1, have been considered as agents for diabetic peripheral neuropathy. Because recent studies have suggested that decreased availability of these substances might contribute to the pathogenesis of diabetic peripheral neuropathy, some clinical trials of NGF for diabetic peripheral neuropathy have been conducted and have led to mixed conclusions. The major reasons were its limited delivery to the nervous system and adverse effects induced by subcutaneous injection, which was necessary because NGF is a polypeptide. The current study investigates whether an orally active sialic acid derivative, MCC-257, has neuroprotective properties in diabetic peripheral nerves. MCC-257 augmented NGF activity in cultured dorsal root ganglia and PC12 (pheochromocytoma 12) cells. Treatment with MCC-257 elevated NGF levels in the sciatic nerve, accompanied by improvement in nerve conduction velocity in strepotozotocin-induced diabetic animals. More importantly, MCC-257 ameliorated small fiber dysfunctions, including thermal hypoalgesia, substance P content, and histopthological innervation in the plantar skin of diabetic animals. Thus, the orally active neurotrophin enhancer provides a new option for the clinical treatment of diabetic peripheral neuropathy. Diabetes 55:616 -621, 2006

DA-9801 Promotes Neurite Outgrowth <i>via</i> ERK1/2-CREB Pathway in PC12 Cells

“…30) Sialic acid derivative MCC-257, known to potentiate the action of neurotrophins on central and peripheral neurons, protects the neuronal cells from a number of fatal conditions. 5,53) Upon exposure to NGF, PC12 cells cease division, extend neurites, become electrically excitable, and express neuronal markers. 28,29) In this study, DA-9801 increased both proliferation and neurite outgrowth in the presence of NGF.…”

“…[3][4][5] Hyperglycemia, a metabolic disruption known to increase oxidative stress in the peripheral nerves, is an important factor in the pathogenesis of DPN. 6) In patients with diabetes, as well as those with local nerve compression that needs to be treated to prevent or repair permanent nerve damage, treatment of the underlying cause might result in partial or full pain relief.…”

Dioscorea Extract (DA-9801) Modulates Markers of Peripheral Neuropathy in Type 2 Diabetic db/db Mice

“…Biomol Ther 22(5), 445-452 (2014) http://dx.doi.org/10.4062/biomolther.2014.051 sis, neuropathy-related abnormalities such as reduced nerve conduction velocity, atrophy of myelinated nerve fi bers and axons, and dysesthesia were statistically signifi cantly alleviated compared with that in untreated animals (Pearlstone et al, 1992;Apfel et al, 1994;Kakinoki et al, 2006).…”

The Protective Effects of DA-9801 (Dioscorea Extract) on the Peripheral Nerves in Streptozotocin-Induced Diabetic Rats

“…In addition, autoimmunity may play a role in the NGF deficiency in diabetes by mechanisms related to immune neutralization of available NGF (22). In experimental diabetic rats, following the treatment with NGF, decreased substance P levels are recovered in the peripheral nerves and this leads to the restoration of the nociceptive threshold to noxious thermal stimuli, the morphology of myelinated nerve fibers and neurogenic vasodilatation in STZinduced diabetic rats (23). According to a Phase II clinical trial, exogenous recombinant human NGF actually had a significant beneficial effect on diabetic peripheral neuropathy (24).…”