title: Baicalein alleviates diabetic peripheral neuropathy through inhibition of oxidative-nitrosative stress and p38 MAPK activation.
abstract: 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.
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Stavniichuk
authors.forename: Viktor R
authors.initials: VR
authors.lastname: Drel
authors.forename: Hanna
authors.initials: H
authors.lastname: Shevalye
authors.forename: Yury
authors.initials: Y
authors.lastname: Maksimchyk
authors.forename: Tamara M
authors.initials: TM
authors.lastname: Kuchmerovska
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Nadler
authors.forename: Irina G
authors.initials: IG
authors.lastname: Obrosova
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D004195:Disease Models, Animal; D044950:Flavanones / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009431:Neural Conduction / Q000187:drug effects; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects*; D011930:Reaction Time / Q000187:drug effects; D018055:Receptors, Eicosanoid / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D018709:Statistics, Nonparametric; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C475064:12-15-lipoxygenase; C066652:12-hydroxyeicosatetraenoic acid receptor; D000975:Antioxidants; D001786:Blood Glucose; D044950:Flavanones; D016376:Oligonucleotides, Antisense; D018055:Receptors, Eicosanoid; C002744:3-nitrotyrosine; D014443:Tyrosine; C006680:baicalein; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D048051:p38 Mitogen-Activated Protein Kinases