With the consideration of the multifactorial etiology of diabetic
peripheral neuropathy, an ideal
drug or
drug combination should target at least several key pathogenetic mechanisms. The
flavonoid baicalein (5,6,7-trihydroxyflavone) has been reported to counteract
sorbitol accumulation, activation of 12/
15-lipoxygenase, oxidative-nitrosative stress,
inflammation, and impaired signaling in models of
chronic disease. This study evaluated
baicalein on diabetic
peripheral neuropathy. Control and
streptozotocin-diabetic C57Bl6/J mice were maintained with or without
baicalein treatment (30 mg kg(-1) d(-1), i.p., for 4 weeks after 12 weeks without treatment). Neuropathy was evaluated by sciatic motor and hind-limb digital sensory nerve conduction velocities, thermal algesia (Hargreaves test), tactile response threshold (flexible von Frey filament test), and intraepidermal nerve fiber density (fluorescent immunohistochemistry with confocal microscopy). Sciatic nerve and spinal cord 12/
15-lipoxygenase and total and phosphorylated
p38 mitogen-activated protein kinase expression and nitrated
protein levels were evaluated by Western blot analysis,
12(S)hydroxyeicosatetraenoic acid concentration (a measure of 12/
15-lipoxygenase activity) by ELISA, and
glucose and
sorbitol pathway intermediate concentrations by enzymatic spectrofluorometric assays.
Baicalein did not affect diabetic
hyperglycemia, and alleviated nerve conduction deficit and small sensory nerve fiber dysfunction, but not intraepidermal nerve fiber loss. It counteracted diabetes-associated
p38 mitogen-activated protein kinase phosphorylation, oxidative-nitrosative stress, and 12/
15-lipoxygenase overexpression and activation, but not
glucose or
sorbitol pathway intermediate accumulation. In conclusion,
baicalein targets several mechanisms implicated in diabetic
peripheral neuropathy. The findings provide rationale for studying hydroxyflavones with an improved pharmacological profile as potential treatments for
diabetic neuropathy and other
diabetic complications.