Bay 11-7082 通过抑制 NLRP3 减轻实验性糖尿病神经病变中的氧化应激和线粒体功能障碍。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2024-10-31 DOI:10.1016/j.lfs.2024.123203

Lokesh Sharan , Anubroto Pal , S. Sarath Babu , Ashutosh Kumar , Sugato Banerjee

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引用次数: 0

摘要

目的：糖尿病神经病变与线粒体功能障碍和神经炎症有关：糖尿病神经病变与线粒体功能障碍和神经炎症有关。慢性高血糖会引发炎症反应和氧化应激，导致周围神经病变，而 ROS 生成增加和生物能降低导致的线粒体功能障碍会维持炎症循环。本研究的目的是评估 Bay 11-7082（B11）对大鼠糖尿病神经病变的药理作用：方法：给 STZ 诱导的糖尿病动物（55 毫克/千克，静脉注射）注射 1 毫克/千克和 3 毫克/千克剂量的 B11。进行行为和功能评估以评估神经病变。评估了 B11 对 STZ 诱导的糖尿病神经病变大鼠和暴露于 175 mM d-glucose 的 SHSY5Y 细胞的分子蛋白表达：结果：糖尿病大鼠表现出神经功能缺陷、痛觉参数改变以及 NLRP3、ASC、Caspase-1 和 NF-κB 表达增加。此外，糖尿病动物的 PGC1α/Nrf2/HO-1 水平降低，PARP1 过度表达。线粒体动态标记物 DRP1 的增加以及炎症细胞因子 TNF-α、IL-1β、IL-18 和 IL-6 水平的升高都表明线粒体功能受到了损害。这表明 B11 的 NLRP3 抑制作用可能是由于通过 PGC1α/Nrf2/HO-1 激活了线粒体生物生成途径，并改善了线粒体健康。在暴露于高葡萄糖的 SHSY5Y 细胞中，B11 通过抑制 NLRP3 激活和减少线粒体损伤来减轻神经炎症：结论：在实验性糖尿病神经病变中，B11 通过抑制氧化应激、NLRP3 激活和改善线粒体健康，显示出对糖尿病神经病变的保护作用。本研究为 Bay 11-7082 对糖尿病神经病变的神经保护作用提供了新的机理认识。

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Bay 11-7082 mitigates oxidative stress and mitochondrial dysfunction via NLRP3 inhibition in experimental diabetic neuropathy

Objective

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.

Methods

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.

Results

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.

Conclusion

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.

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.