Sharan Lokesh, Pal Anubroto, Babu S Sarath, Kumar Ashutosh, Banerjee Sugato
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Kolkata 700054, India.
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, SAS Nagar, Punjab 160062, India.
Life Sci. 2024 Dec 15;359:123203. doi: 10.1016/j.lfs.2024.123203. Epub 2024 Oct 31.
Diabetic neuropathy is associated with mitochondrial dysfunction and neuroinflammation. Chronic hyperglycemia triggers inflammatory responses and oxidative stress, causing peripheral neuropathy, whereas mitochondrial dysfunction caused by increased ROS generation and reduced bioenergetics maintains the inflammatory cycle. The purpose of this study is to evaluate the pharmacological efficacy of Bay 11-7082 (B11) against diabetic neuropathy in rats.
B11 was administered at doses of 1 and 3 mg/kg to STZ-induced diabetic animals (55 mg/kg, i.p). Behavioral and functional assessments were conducted to assess neuropathy. Molecular protein expressions were evaluated for B11's efficacy against STZ-induced diabetic neuropathic rats and in SHSY5Y cells exposed to 175 mM of d-glucose.
Diabetic rats exhibited deficits in nerve functions, altered nociceptive parameters, and increased expression of NLRP3, ASC, Caspase-1, and NF-κB. Additionally, diabetic animals showed reduced levels of PGC1α/Nrf2/HO-1, with an overexpression of PARP1. Compromised mitochondrial function was evident through increased mitochondrial dynamic marker DRP1 and elevated levels of inflammatory cytokines TNF-α, IL-1β, IL-18, and IL-6. However, B11 administration significantly ameliorated these changes, suggesting that B11's NLRP3 inhibition may be attributed to the activation of the mitochondrial biogenesis pathway via PGC1α/Nrf2/HO-1, along with improved mitochondrial health. In high glucose exposed SHSY5Y cells, B11 treatment attenuated neuroinflammation by inhibiting NLRP3 activation and reducing mitochondrial damage.
B11, showed a protective effect against diabetic neuropathy by inhibiting oxidative stress, NLRP3 activation, and improving mitochondrial health in experimental diabetic neuropathy. This study provides new mechanistic insights into the neuroprotective role of Bay 11-7082 against diabetic neuropathy.
糖尿病性神经病变与线粒体功能障碍和神经炎症相关。慢性高血糖引发炎症反应和氧化应激，导致周围神经病变，而活性氧生成增加和生物能量减少所引起的线粒体功能障碍维持了炎症循环。本研究的目的是评估Bay 11 - 7082（B11）对大鼠糖尿病性神经病变的药理疗效。
将B11以1和3mg/kg的剂量给予链脲佐菌素诱导的糖尿病动物（55mg/kg，腹腔注射）。进行行为和功能评估以评估神经病变。评估分子蛋白表达，以确定B11对链脲佐菌素诱导的糖尿病性神经病变大鼠以及暴露于175mM d -葡萄糖的SHSY5Y细胞的疗效。
糖尿病大鼠表现出神经功能缺陷、伤害性感受参数改变，以及NLRP3、ASC、半胱天冬酶 - 1和核因子κB的表达增加。此外，糖尿病动物的PGC1α/Nrf2/HO - 1水平降低，PARP1过表达。线粒体功能受损表现为线粒体动态标志物动力相关蛋白1（DRP1）增加以及炎症细胞因子肿瘤坏死因子 - α、白细胞介素 - 1β、白细胞介素 - 18和白细胞介素 - 6水平升高。然而，给予B11可显著改善这些变化，表明B11对NLRP3的抑制作用可能归因于通过PGC1α/Nrf2/HO - 1激活线粒体生物合成途径以及改善线粒体健康。在高糖暴露的SHSY5Y细胞中，B11处理通过抑制NLRP3激活和减少线粒体损伤减轻了神经炎症。
B11通过抑制氧化应激、NLRP3激活以及改善实验性糖尿病性神经病变中的线粒体健康，对糖尿病性神经病变显示出保护作用。本研究为Bay 11 - 7082对糖尿病性神经病变的神经保护作用提供了新的机制见解。
