Diosgenin from Dioscorea nipponica Ameliorates Diabetic Neuropathy by Inducing Nerve Growth Factor

Abstract

The increasing prevalence of diabetes heightens concerns over diabetic complications such as neuropathy. Diabetic neuropathy is one of the most debilitating complications of type 1 and type 2 diabetes.1) The histopathology of the condition is characterized by axonal degeneration, demyelination, and atrophy in association with failed axonal regeneration, remyelination, and impaired synaptogenesis. 2)Previous reports have suggested that reduced availability of nerve growth factor (NGF) plays a significant role in the pathogenesis of diabetic polyneuropathy.3) Retrograde axonal transport of NGF is impaired in animals with diabetes mellitus (DM), 4) and its transcription in neuronal target tissues is reduced.5) NGF itself has been considered an option for the treatment of diabetic peripheral neuropathy. Although systemic administration of exogenous recombinant human NGF was found to prevent neuropathy in a phase II clinical trial, 6) unfortunately efficacy of NGF was not demonstrated in a completed phase III trial due to its limited delivery to the nervous system and adverse effects after subcutaneous injection.7) An alternative therapeutic approach is the use of small molecules to induce or enhance neurotropic factor production. Saito and colleagues reported that the orally active small molecule MCC-257, a sialic acid derivative, elevated NGF levels in the sciatic nerve and improved nerve conduction velocity in a diabetic rodent model. 8) Also, retinoic acid can revert functional and ultrastructural changes and induce neural regeneration after the establishment of diabetic neuropathy, possibly because of increased NGF concentrations in nerve terminals. 9)Our study focused on diosgenin (DG), a major steroidal sapogenin isolated from Dioscoreaceae. DG is the primary spirostane-type sapogenin found in several plants, including fenugreek, Costus speciosus, and the Dioscorea species. 10) DG has been shown to be useful in maintaining healthy blood cholesterol levels, 11) and is a precursor for several hormones such as dehydroepiandrosterone.12)The present study examined the neuroprotective effect of DG on diabetic peripheral neuropathy through increasing NGF levels in a diabetic rodent model. MATERIALS AND METHODS Isolation of Diosgenin from Dioscorea nipponicaRhizomes of Dioscorea nipponica (DN) MAKINO (Dioscoreaceae), referred to as Cheonsangyong in China and as Buchema in Korea, were obtained from the Kyungdong Herb Market in Seoul, Korea. They were identified by Dr. C. S. Yook, Department of Pharmacy, Kyung Hee University. Dried DN rhizomes (1 kg) were extracted 3 times using 85% methanol under ultrasonic apparatus for each 2 h and evaporated to dryness. Such an extraction process was repeated twice. The residue (147 g) was then partitioned between water-saturated n-butanol and water, and the n-butanol layer was separated, which was repeated 5 times, and evaporated to dryness. The yield was 3.4%. The residue was subsequently taken up into 2.5 N HCl for 4 h at 94°C, extracted using CHCl 3 , filtered, and evaporated to...

Protective effect of mulberry flavonoids on sciatic nerve in alloxan-induced diabetic rats

“…Axon demyelination and loss were also presented in the sciatic nerve of diabetic mice by electron microscopy examination (Kang et al, 2011). The proper function and maintenance of axons depended on myelin formation (Lappe-Siefke et al, 2003).…”

Exogenous neuregulin-1 attenuates STZ-induced diabetic peripheral neuropathic pain in rats

“…Previous evidences showed that NGF played a significant role in the pathogenesis of diabetic polyneuropathy, and itself had been considered an option for the treatment of diabetic peripheral pain 12 . In our study, we confirmed the expression of NRG1 and NGF in spinal cord of rats.…”

“…Retrograde axonal transport of NGF is impaired in animals with DM, and its transcription in neuronal target tissues is reduced. Pathological conditions that alter NGF expression may result in neuronal dysfunction and death 12 . A previous study showed that the concentration of NGF in the sciatic nerves of STZ-induced diabetic rats decreased 3 weeks after STZ injection 23 .…”

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

“…In particular, D. japonica has inhibitory activities on polyuria and diabetes (Kim, 1998) and D. nipponica has antiobesity properties (Jung et al, 2003). Previously, we reported that furostanol saponins isolated from D. japonica upregulated NGF contents in rat glioma C6 cells (Kim et al, 2011a) and diosgenin from D. nipponica ameliorated diabetic neuropathy by increasing the endogenous NGF levels in streptozotocin (STZ)-induced diabetic mice (Kang et al, 2011). Therefore, we proposed that these two Dioscorea species might improve various symptoms of diabetic neuropathy via NGF regulation.…”

“…The NCV tests were performed using the methods reported by Kang (Kang et al, 2011). Animals were anesthetized using a combination of 1.5% isofluorane (Choongwae Pharma Co., Seoul, Korea) with 70% N 2 O and 30% O 2 gas using a gas anesthesia machine (Tabletop research anesthesia machine sets, SurgiVet, USA).…”