Inyang Happiness O, Ezemagu Uchenna K, Okori Stephen O, Ijomone Olayemi K, Ijomone Omamuyovwi M
Laboratory for Experimental and Translational Neurobiology, University of Medical Sciences, Ondo, Nigeria.
Department of Anatomy, Faculty of Basic Medical Sciences, University of Cross River, Okuku, Cross River, Nigeria.
Neurochem Res. 2025 Jun 30;50(4):223. doi: 10.1007/s11064-025-04466-z.
Manganese (Mn), though an essential trace element, can become neurotoxic after excessive exposure. Established mechanisms of Mn neurotoxicity include oxidative stress, apoptotic signalling, and inflammatory responses. D-ribose-L-cysteine (RibCys), a cysteine derivative, is reported to mitigate oxidative damage. In this study, we investigated its effects on B-cell lymphoma 2-associated X protein (Bax)/B-cell lymphoma 2 (Bcl-2) apoptotic signaling, tumor necrosis factor-alpha (TNF-α) inflammatory response, and extracellular signal-regulated kinase (ERK) pathway across various brain regions. Adult male Wistar rats were treated with saline (control), Mn (25 mg/kg intraperitoneally for 2 weeks, 8 doses at 48-hour intervals), RibCys (200 mg/kg orally for 2 weeks), or both Mn and RibCys. Biochemical assays for oxidative stress and antioxidant activity, Golgi staining for dendritic morphology, and immunohistochemistry for key protein markers were performed. Results showed that RibCys reduced Mn-induced distortions in brain neurochemistry and dendritic morphology. Mn increased lipid peroxidation, myeloperoxidase, and nitric oxide levels while decreasing glutathione peroxidase and sulfhydryl content, and these effects were attenuated by RibCys. Mn also disrupted dendritic arborization, which improved with RibCys treatment. Furthermore, Mn exposure elevated Bax/Bcl-2, TNF-α, and ERK1/2 expression in selected brain regions. RibCys co-administration mitigated these molecular alterations. Our findings suggest that RibCys is a promising therapeutic agent against Mn-induced neurotoxicity with potential for broader application. A notable limitation of this study was the absence of direct measurements of reduced and oxidized glutathione, and cysteine. Future studies should include these key antioxidant markers, assess long-term outcomes of RibCys treatment, and incorporate female animal models to evaluate potential sex-specific responses to Mn toxicity and intervention.
锰（Mn）虽是一种必需的微量元素，但过度接触后会产生神经毒性。已确定的锰神经毒性机制包括氧化应激、凋亡信号传导和炎症反应。据报道，半胱氨酸衍生物D - 核糖 - 半胱氨酸（RibCys）可减轻氧化损伤。在本研究中，我们研究了其对不同脑区中B细胞淋巴瘤2相关X蛋白（Bax）/B细胞淋巴瘤2（Bcl - 2）凋亡信号传导、肿瘤坏死因子 - α（TNF - α）炎症反应以及细胞外信号调节激酶（ERK）途径的影响。成年雄性Wistar大鼠分别接受生理盐水（对照）、锰（25 mg/kg腹腔注射，共2周，每48小时注射1次，共8剂）、RibCys（200 mg/kg口服，共2周）或锰与RibCys联合处理。进行了氧化应激和抗氧化活性的生化测定、树突形态的高尔基染色以及关键蛋白标志物的免疫组织化学检测。结果表明，RibCys减少了锰诱导的脑神经化学和树突形态畸变。锰增加了脂质过氧化、髓过氧化物酶和一氧化氮水平，同时降低了谷胱甘肽过氧化物酶和巯基含量，而RibCys减轻了这些影响。锰还破坏了树突分支，而RibCys处理可改善这一情况。此外，锰暴露使选定脑区的Bax/Bcl - 2、TNF - α和ERK1/2表达升高。联合使用RibCys可减轻这些分子改变。我们的研究结果表明，RibCys是一种有前景的抗锰诱导神经毒性的治疗剂，具有更广泛应用的潜力。本研究的一个显著局限性是未直接测量还原型和氧化型谷胱甘肽以及半胱氨酸。未来的研究应纳入这些关键的抗氧化标志物，并评估RibCys治疗的长期效果，同时纳入雌性动物模型以评估对锰毒性和干预的潜在性别特异性反应。
