一氧化氮对铅神经毒性大鼠模型中氧相关过程的依赖性调节:缺氧抵抗因子的影响。

IF 2.5 Q3 CELL BIOLOGY Cellular Physiology and Biochemistry Pub Date : 2024-10-20 DOI:10.33594/000000734
Natalia Kurhaluk, Piotr Kamiński, Oleksandr Lukash, Halina Tkaczenko
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引用次数: 0

摘要

背景/目的:众所周知,铅暴露会诱发氧化应激和神经毒性。一氧化氮(NO)在调节氧化应激中起着重要作用,L-精氨酸是 NO 的前体,而 Nω-硝基-L-精氨酸(L-NNA)是 NO 合酶的抑制剂,NO 合酶是催化 L-精氨酸产生一氧化氮(NO)的酶:本研究调查了 L-精氨酸和 L-NNA 对不同耐缺氧程度的大鼠脑组织氧化应激标记物和生化变化的不同影响。低耐受性或高耐受性大鼠暴露于硝酸铅(每天口服 3.6 毫克硝酸铅/千克体重,持续 30 天),并在暴露于硝酸铅前后 30 分钟接受 L-精氨酸(600 毫克/千克体重,静注)或 L-NNA(35 毫克/千克体重,静注,在暴露于硝酸铅前后 30 分钟)治疗。对脑组织样本进行了脂质过氧化、蛋白质氧化修饰、抗氧化酶(包括超氧化物歧化酶、过氧化氢酶、谷胱甘肽还原酶和过氧化物酶)活性和总抗氧化状态(TAS)分析。我们还检测了涉及丙氨酸和天冬氨酸氨基转移酶、琥珀酸脱氢酶(SDH)和α-酮戊二酸脱氢酶(KGDH)活性的生化途径生物标志物。此外,对脑组织中乙酰胆碱水平和乙酰胆碱酯酶活性(ACh-AChE 系统)的评估也支持所观察到的趋势:结果:在耐缺氧能力低的大鼠中,L-精氨酸处理能显著降低脂质过氧化和氧化蛋白质修饰,但能提高抗氧化酶的活性,这表明它对铅诱导的氧化应激具有保护作用。相反,在耐缺氧能力较强的大鼠中,L-NNA 具有保护作用,可减少铅诱导的氧化损伤并降低脂质过氧化,而 L-精氨酸则会加剧氧化应激并损害抗氧化防御能力。这些发现得到了乙酰胆碱-乙酰胆碱酯酶系统相应变化的支持,反映了观察到的铅诱导氧化应激和神经毒性模式。研究表明,L-精氨酸通过改善 TAS,减少铅诱导的氧化损伤,从而发挥保护作用。我们的研究表明,接触硝酸铅会显著增加脑组织中的丙氨酸氨基转移酶和天冬氨酸氨基转移酶活性,L-精氨酸会加剧这种效应,而 L-NNA 则会逆转这种效应。硝酸铅暴露还影响了 SDH 和 KGDH 的活性,而这两种物质对细胞能量生产和耐缺氧非常重要,L-精氨酸会根据耐缺氧程度改变 SDH 的活性,而 L-NNA 则会增强 SDH 和 KGDH 的活性。ACh-AChE 系统的改变进一步验证了这些趋势,凸显了 NO 依赖性机制在根据缺氧抵抗性调节铅诱导的神经毒性中的不同作用:这些发现提出了基于氧化应激特征的潜在靶向治疗策略,并强调了一氧化氮系统调节剂在抗衡铅诱导的生化改变和 ACh-AChE 系统动态方面的潜力,这取决于生物体的个体生理反应性。
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Nitric Oxide-Dependent Regulation of Oxygen-Related Processes in a Rat Model of Lead Neurotoxicity: Influence of the Hypoxia Resistance Factor.

Background/aims: Lead exposure is known to induce oxidative stress and neurotoxicity. Nitric oxide (NO) plays an important role in modulating oxidative stress, with L-arginine as a precursor of NO and Nω-nitro-L-arginine (L-NNA) as an inhibitor of NO synthase, an enzyme that catalyses the production of nitric oxide (NO) from L-arginine.

Methods: This study investigated the differential effects of L-arginine and L-NNA on markers of oxidative stress and biochemical changes in brain tissue from rats with different levels of resistance to hypoxia exposed to lead nitrate. Rats with either low or high resistance to hypoxia were exposed to lead nitrate (oral 3.6 mg lead nitrate/kg b.w. per day for 30 days) and treated with L-arginine (600 mg/kg b.w., i.p., 30 min before and after exposure to lead nitrate) or L-NNA (35 mg/kg b.w., i.p., 30 min before and after exposure to lead nitrate). Brain tissue samples were analysed for lipid peroxidation, oxidative modification of proteins, and activity of antioxidant enzymes, including superoxide dismutase, catalase, glutathione reductase, and peroxidase, and total antioxidant status (TAS). We also examined the biomarkers of biochemical pathways involving the activity of alanine and aspartate aminotransferases, succinate dehydrogenase (SDH), and α-ketoglutarate dehydrogenase (KGDH). In addition, the trend observed was supported by assessments of the acetylcholine levels and acetylcholinesterase activity (ACh-AChE system) in brain tissue.

Results: In rats with low resistance to hypoxia, the L-arginine treatment significantly reduced lipid peroxidation and oxidative protein modification but increased antioxidant enzyme activity, suggesting a protective effect against lead-induced oxidative stress. Conversely, in rats with high resistance to hypoxia, L-NNA had a protective effect, reducing lead-induced oxidative damage and decreasing lipid peroxidation, whereas L-arginine exacerbated oxidative stress and impaired antioxidant defences. These findings were supported by corresponding changes in the acetylcholine-acetylcholinesterase system, reflecting the observed patterns of lead-induced oxidative stress and neurotoxicity. The study shows that L-arginine exerts a protective effect by reducing lead-induced oxidative damage via an improvement in TAS. Our study shows that lead nitrate exposure significantly increases ala-nine and aspartate aminotransferase activity in brain tissue, with L-arginine exacerbating and L-NNA reversing this effect. The lead nitrate exposure also affected the activities of SDH and KGDH, which are important for cellular energy production and hypoxia resistance, with L-arginine altering SDH activity depending on the level of resistance and L-NNA enhancing both SDH and KGDH activities. These trends were further validated by alterations in the ACh-AChE system, highlighting the differential role of NO-dependent mechanisms in modulating lead-induced neurotoxicity based on hypoxia resistance.

Conclusion: These findings suggest potential targeted therapeutic strategies based on the oxidative stress profile and highlight the potential of nitric oxide system modulators in counteracting lead-induced biochemical alterations and the dynamics of the ACh-AChE system depending on the individual physiological reactivity of organisms.

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来源期刊
CiteScore
5.80
自引率
0.00%
发文量
86
审稿时长
1 months
期刊介绍: Cellular Physiology and Biochemistry is a multidisciplinary scientific forum dedicated to advancing the frontiers of basic cellular research. It addresses scientists from both the physiological and biochemical disciplines as well as related fields such as genetics, molecular biology, pathophysiology, pathobiochemistry and cellular toxicology & pharmacology. Original papers and reviews on the mechanisms of intracellular transmission, cellular metabolism, cell growth, differentiation and death, ion channels and carriers, and the maintenance, regulation and disturbances of cell volume are presented. Appearing monthly under peer review, Cellular Physiology and Biochemistry takes an active role in the concerted international effort to unravel the mechanisms of cellular function.
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