Nrf2 and NF-κB Modulation by Sulforaphane Counteracts Multiple Manifestations of Diabetic Neuropathy in Rats and High Glucose-Induced Changes
Nrf2 and NF-κB Modulation by Sulforaphane Counteracts Multiple Manifestations of Diabetic Neuropathy in Rats and High Glucose-Induced Changes
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DOI：
10.2174/156720211798120972
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发表时间：
2011-11-01
影响因子：
2.1
通讯作者：
Sharma, Shyam S.
中科院分区：
文献类型：
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作者：
Negi, Geeta;Kumar, Ashutosh;Sharma, Shyam S.
高糖驱动的活性氧中间产物的产生和炎症损伤是公认的糖尿病神经病变中神经功能障碍和随后的损害的贡献者。萝卜硫素是一种已知的化疗药物，由于其具有双重抗氧化和抗炎活性，因此有望用于治疗糖尿病神经病变。本研究观察萝卜硫素对链脲佐菌素(STZ)诱导的大鼠糖尿病神经病变的影响。在体外实验中，神经2a细胞在正常(5.5 mM)和高糖(30 MM)条件下与萝卜硫素孵育。对于体内研究，萝卜硫素(0.5和1 mg/kg)在糖尿病诱导后6周给予，连续2周。萝卜硫素能改善运动神经传导速度(MNCV)、神经血流量(NBF)和疼痛行为，降低丙二醛(MDA)水平。萝卜硫素的抗氧化作用源于核红系2相关因子2(Nrf2)的激活，表现为Nrf2及其下游靶标HO-1和NAD(P)H：QO-1在糖尿病动物神经2a细胞和坐骨神经中的表达增加。萝卜硫素的抗炎活性可能与核因子-kappaB的抑制有关，因为其核因子-kappa B的表达和I kappa B激酶(IKK)的磷酸化减少，诱导型一氧化氮合酶(INOS)和环氧合酶-2(COX-2)的表达以及肿瘤坏死因子-α(TNF-α)和白细胞介素6(IL-6)的水平降低。在这项研究中，我们提供了萝卜硫素在逆转实验性糖尿病神经病变的各种缺陷方面有效的证据。本研究支持Nrf2在氧化应激条件下对神经元的防御作用，并提示核因子-kappaB通路是糖尿病神经病变中炎性损伤的重要调节因子。
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-kappa B) inhibition seemed to be responsible for anti-inflammatory activity of sulforaphane as there was reduction in NF-kappa B expression and I kappa B kinase (IKK) phosphorylation along with abrogation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression and tumor necrosis factor-alpha (TNF-alpha) 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-kappa B pathway is an important modulator of inflammatory damage in diabetic neuropathy.