Bergenin Reduces Experimental Painful Diabetic Neuropathy by Restoring Redox and Immune Homeostasis in the Nervous System

Abstract

<jats:p>Diabetic neuropathy is a frequent complication of diabetes. Symptoms include neuropathic pain and sensory alterations—no effective treatments are currently available. This work characterized the therapeutic effect of bergenin in a mouse (C57/BL6) model of streptozotocin-induced painful diabetic neuropathy. Nociceptive thresholds were assessed by the von Frey test. Cytokines, antioxidant genes, and oxidative stress markers were measured in nervous tissues by ELISA, RT-qPCR, and biochemical analyses. Single (3.125–25 mg/kg) or multiple (25 mg/kg; twice a day for 14 days) treatments with bergenin reduced the behavioral signs of diabetic neuropathy in mice. Bergenin reduced both nitric oxide (NO) production in vitro and malondialdehyde (MDA)/nitrite amounts in vivo. These antioxidant properties can be attributed to the modulation of gene expression by the downregulation of inducible nitric oxide synthase (iNOS) and upregulation of glutathione peroxidase and Nrf2 in the nervous system. Bergenin also modulated the pro- and anti-inflammatory cytokines production in neuropathic mice. The long-lasting antinociceptive effect induced by bergenin in neuropathic mice, was associated with a shift of the cytokine balance toward anti-inflammatory predominance and upregulation of antioxidant pathways, favoring the reestablishment of redox and immune homeostasis in the nervous system. These results point to the therapeutic potential of bergenin in the treatment of painful diabetic neuropathy.</jats:p>

Bergenin attenuates TNF-α-induced oxidative stress and inflammation in HaCaT cells by activating Nrf2 pathway and inhibiting NF-κB pathway

“…The activation of immune cells then promoted the secretion of proinflammatory factors and contributed to angiogenesis and keratinocyte over-proliferation [5]. Bergenin reduced the levels of MDA, iNOS, Gpx and nitrite in streptozotocin-induced mice, and exerted anti-oxidant effect against diabetic neuropathy [15]. This study showed that bergenin enhanced the level of SOD, and reduced the levels of MDA and iNOS in TNF-αtreated HaCaT, thereby contributing to the antioxidant effect against psoriasis.…”

Bergenin protects pancreatic beta cells against cytokine-induced apoptosis in INS-1E cells

“…Using Griess reagent, we assessed cellular nitrite production, a surrogate marker for NO. Bergenin has been reported to downregulate the expression of inducible nitric oxide synthase (iNOS), thereby reducing NO production [ 44 , 45 ]. Similarly, in our current study, the cytokine cocktail we used highly elevated NO production in INS-1E cells; however, addition of beregnin significantly reduced NO levels in beta cells with an IC 50 value of 6.82 μM ( Table 1 ).…”

The Effects of Nuclear Factor Erythroid 2 (NFE2)-Related Factor 2 (Nrf2) Activation in Preclinical Models of Peripheral Neuropathic Pain

“…In addition, paeoniflorin, the main active ingredient of peony, also decreased SC apoptosis via the PERK/Nrf2 pathway [ 61 ]. A large variety of natural products can suppress the expression of NF-κB and other proinflammatory and apoptotic markers, including bergenin [ 62 ], diosgenin [ 63 ], deguelin [ 64 ], fisetin [ 65 ], anomalin [ 66 ], resveratrol [ 67 ], rutin [ 68 ], taurine [ 69 ], diphenyl diselenide [ 70 ], tanshinone IIA (one of the most active components of the traditional Chinese herbal medicine Danshen ) [ 71 ], as well as Nrf2 inducers bardoxolone methyl [ 72 ] and oltipraz [ 73 ]. These natural products can also enhance the expression of Nrf2, as well as other antioxidative enzymes (HO-1, GLUT1,3), by activating Nrf2 signaling pathways in diabetic animals.…”