Orally active neurotrophin-enhancing agent protects against dysfunctions of the peripheral nerves in hyperglycemic animals.
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 streptozotocin-induced diabetic animals. More importantly, MCC-257 ameliorated small fiber dysfunctions, including thermal hypoalgesia, substance P content, and histopathological 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.
Kakinoki
Bunpei
B
Research Laboratory I, Pharmaceutical Research Unit, Research and Development Division, Mitsubishi Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan. kakinoki.bunpei@mf.m-pharma.co.jp
Sekimoto
Sumito
S
Yuki
Satoshi
S
Ohgami
Tetsuya
T
Sejima
Mikiko
M
Yamagami
Keiji
K
Saito
Ken-ichi
K
D000284:Administration, Oral; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003929:Diabetic Neuropathies / Q000188:drug therapy*; D005727:Ganglia, Spinal / Q000187:drug effects; D008297:Male; D020932:Nerve Growth Factor / Q000032:analysis / Q000494:pharmacology; D009431:Neural Conduction / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D016716:PC12 Cells; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D020917:Receptor, trkA / Q000378:metabolism; D012794:Sialic Acids / Q000627:therapeutic use*; D012867:Skin / Q000294:innervation; D013311:Streptozocin; D013373:Substance P / Q000032:analysis; D043222:Ubiquitin Thiolesterase / Q000032:analysis
C509574:MCC-257; D018696:Neuroprotective Agents; D012794:Sialic Acids; D013373:Substance P; D013311:Streptozocin; D020932:Nerve Growth Factor; D020917:Receptor, trkA; C489034:UCHL1 protein, rat; D043222:Ubiquitin Thiolesterase