Bardoxolone methyl (Bard), a nuclear factor erythroid 2-related factor 2 (Nrf2) activator regulates multiple oxidative and inflammatory diseases. However, the role of Bard in painful diabetic neuropathy (DN) remains unknown. Bard administration at two dose levels (15 & 30 mg/kg/day) to STZ (55 mg/kg, i.p) induced diabetic rats for last two weeks of eight week study significantly improved motor nerve conduction velocity (61.84 ± 1.9 vs. 38.57 ± 1.08 m/s), sensory nerve conduction velocity (66.86 ± 5.1 vs. 39.43 ± 3.3 m/s), nerve blood flow (86.28 ± 6.4 vs. 56.56 ± 1.62 PU), and intraepidermal nerve fiber density. Additionally, Bard treatment attenuated thermal and mechanical hyperalgesia in diabetic rats. Further molecular investigation on dorsal root ganglions (DRG) tissue isolated from L4-L6 regions of diabetic rats and High glucose (HG) exposed PC12 cells displayed decreased expression and transcriptional activity of Nrf2 which might have resulted in depleted antioxidant enzymes and mitochondrial chaperones. Bard treatment significantly reversed these effects in diabetic rats and also in HG exposed PC12 cells. Moreover, mitochondrial complex activities were diminished in DRG mitochondrial fractions of diabetic rats and mitochondrial isolates of HG exposed PC12 cells and Bard treatment significantly reversed these effects. Furthermore, Bard treatment significantly impeded the impact of hyperglycemic insults on mitochondrial membrane potential, ROS production and mitochondrial oxygen consumption rate (OCR) (Basal respiration, Maximal respiration, ATP production and spare respiratory capacity) in PC12 cells. Collectively our data suggests that Bard treatment to STZ induced diabetic rats robustly reduces DN which may be due to its effect on Keap1-Nrf2-ARE pathway and have contributed to improvement in mitochondrial function.

Bardoxolonemethyl (Bard) 是一种核因子红细胞 2 相关因子 2 (Nrf2) 激活剂，可调节多种氧化和炎症疾病。然而，巴德在疼痛性糖尿病神经病变 (DN) 中的作用仍然未知。在为期八周的研究的最后两周，以两种剂量水平（15 和 30 毫克/公斤/天）对 STZ（55 毫克/公斤，腹腔注射）诱导的糖尿病大鼠进行巴德给药显着改善了运动神经传导速度（61.84 ± 1.9 对 38.57 ± 1.08 m/s）、感觉神经传导速度（66.86 ± 5.1 vs. 39.43 ± 3.3 m/s）、神经血流量（86.28 ± 6.4 vs. 56.56 ± 1.62 PU）和表皮内神经纤维密度。此外，Bard 治疗可减轻糖尿病大鼠的热痛和机械痛觉过敏。对从糖尿病大鼠 L4-L6 区域分离的背根神经节 (DRG) 组织和高糖 (HG) 暴露的 PC12 细胞进行的进一步分子研究显示 Nrf2 的表达和转录活性降低，这可能导致抗氧化酶和线粒体伴侣的耗尽。Bard 治疗显着逆转了糖尿病大鼠以及暴露于 HG 的 PC12 细胞中的这些影响。此外，糖尿病大鼠的 DRG 线粒体部分和 HG 暴露的 PC12 细胞的线粒体分离物的线粒体复合物活性降低，Bard 治疗显着逆转了这些影响。此外，Bard 治疗显着阻碍了高血糖损伤对线粒体膜电位、ROS 产生和线粒体耗氧率 (OCR) 的影响（基础呼吸、最大呼吸、ATP 产生和备用呼吸能力）在 PC12 细胞中。总的来说，我们的数据表明 Bard 对 STZ 诱导的糖尿病大鼠的治疗可显着降低 DN，这可能是由于其对 Keap1-Nrf2-ARE 通路的影响，并有助于改善线粒体功能。