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

¹ Research Laboratory I, Pharmaceutical Research Unit, Research and Development Division, Mitsubishi Pharma, Yokohama, Japan
² Research Laboratory II, Pharmaceutical Research Unit, Research and Development Division, Mitsubishi Pharma, Yokohama, Japan

Address correspondence and reprint requests to Bunpei Kakinoki, Research Laboratory I, Pharmaceutical Research Unit, Research and Development Division, Mitsubishi Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan. E-mail address: kakinoki.bunpei{at}mf.m-pharma.co.jp

Abbreviations: MCV, motor nerve conduction velocity; NGF, nerve growth factor; PGP9.5, protein gene product 9.5; PKC, protein kinase C; SCV, sensory nerve conduction velocity; STZ, streptozotocin; Trk, tyrosine receptor kinase

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.

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