Nrf2 and NF-κB Modulation by Sulforaphane Counteracts Multiple Manifestations of Diabetic Neuropathy in Rats and High Glucose-Induced Changes

Abstract

High glucose driven reactive oxygen intermediates production and inflammatory damage are recognized contributors of nerve dysfunction and subsequent damage in diabetic neuropathy. Sulforaphane, a known chemotherapeutic agent holds a promise for diabetic neuropathy because of its dual antioxidant and anti-inflammatory activities. The present study investigated the effect of sulforaphane in streptozotocin (STZ) induced diabetic neuropathy in rats. For in vitro experiments neuro2a cells were incubated with sulforaphane in the presence of normal (5.5 mM) and high glucose (30 mM). For in vivo studies, sulforaphane (0.5 and 1 mg/kg) was administered six weeks post diabetes induction for two weeks. Motor nerve conduction velocity (MNCV), nerve blood flow (NBF) and pain behavior were improved and malondialdehyde (MDA) level was reduced by sulforaphane. Antioxidant effect of sulforaphane is derived from nuclear erythroid 2-related factor 2 (Nrf2) activation as demonstrated by increased expression of Nrf2 and downstream targets hemeoxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO-1) in neuro2a cells and sciatic nerve of diabetic animals. Nuclear factor-kappa B (NF-κB) inhibition seemed to be responsible for antiinflammatory activity of sulforaphane as there was reduction in NF-κB expression and IκB kinase (IKK) phosphorylation along with abrogation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression and tumor necrosis factor-α (TNF-α) and interleukine-6 (IL-6) levels. Here in this study we provide an evidence that sulforaphane is effective in reversing the various deficits in experimental diabetic neuropathy. This study supports the defensive role of Nrf2 in neurons under conditions of oxidative stress and also suggests that the NF-κB pathway is an important modulator of inflammatory damage in diabetic neuropathy.

Potential role for Nrf2 activation in the therapeutic effect of MG132 on diabetic nephropathy in OVE26 diabetic mice

“…THERAPEUTIC EFFECT OF MG132 ON DIABETIC NEPHROPATHY tissue damage (22), and by resveratrol prevented diabetesinduced renal damage (23). There was also an in vitro study showing the preventative effect of Nrf2 induced by MG132 on H 2 O 2 -induced cardiac cell damage (10), and an in vivo study showing the preventative effect on diabetes-induced renal damage (19).…”

Sulforaphane Ameliorates 3-Nitropropionic Acid-Induced Striatal Toxicity by Activating the Keap1-Nrf2-ARE Pathway and Inhibiting the MAPKs and NF-κB Pathways

“…Furthermore, the Keap1-Nrf2-ARE signaling pathway was involved in the suppression of NF-κB and its inflammatory effects [16]. SFN exerts antipromotion or anti-progression effects by modulating NF-κB [16,38]. Thus, we examined whether SFN modulates the 3-NP-induced expression of NF-κB in striatum.…”

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

“…inflammatory damage in experimental diabetic neuropathy and nephropathy (Negi et al, 2011;Zheng et al, 2011a). On the other hand, although the mechanisms are not well known, garlic has been successfully used to reduce HFD-induced obesity in rodents .…”