Baicalein alleviates diabetic peripheral neuropathy through inhibition of oxidative–nitrosative stress and p38 MAPK activation

Abstract

With consideration of 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 mgkg−1d−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 improved pharmacological profile as potential treatments for diabetic neuropathy and other diabetic complications.

Animal Models of Peripheral Neuropathies

“…Use of intraepidermal nerve fiber density as a true morphological correlate of the degree of sensory axonal loss is likely to improve the usefulness of rodent models of DPN, both in mechanistic studies and in preclinical efficacy studies of potential therapeutic drugs. Recent examples of drugs demonstrating efficacy in reversing loss of epidermal innervation in diabetic rats and mice include drugs aimed at different molecular mechanisms of DPN [35][36][37][38][39][40]. It remains to be seen whether these drugs fare better in clinical trials compared to previous drugs that relied on changes in nerve conduction velocity as the primary outcome measures in preclinical studies.…”

Diabetic Peripheral Neuropathy: Should a Chaperone Accompany Our Therapeutic Approach?

“…Enhanced PARP activity depletes NAD ϩ , leading to energy failure, increased oxidative stress, and an inhibition of glyceraldehyde 3-phosphate dehydrogenase (Obrosova et al, 2005;Pacher and Szabo, 2008;Negi et al, 2010a,b). PARP has been implicated in nerve conduction velocity deficits, neurovascular dysfunction, thermal and mechanical hyper-and hypoalgesia, mechanical allodynia, and myelinated fiber loss (Obrosova et al, 2005(Obrosova et al, , 2009aPacher and Szabo, 2008;Homs et al, 2011;Stavniichuk et al, 2011;Dieckmann et al, 2012). Moreover, an increase in poly(ADP-ribosylated) proteins has been reported after 4 weeks of diabetes in rat sciatic nerve and in cultured human Schwann cells (Obrosova et al, 2005).…”

Long-circulating nanoliposomes (LCNs) sustained delivery of baicalein (BAI) with desired oral bioavailabilityin vivo

“…Baicalein (BAI,5,6, is obtained from Traditional Chinese Medicine -Scutellaria baicalensis with diverse interesting bioactivities such as anti-inflammation (Lee et al, 2011), attenuating oxidative stress (Choi et al, 2010;Stavniichuk et al, 2011) and anticancer (Wang et al, 2010;Takahashi et al, 2011). In China, combined with other herbs, BAI has been widely used in the treatment of inflammation, fever, cough, dysentery, jaundice, hepatitis and hypertension for many years (Zhang et al, 2001).…”