Tagkalidou Niki, Goyenechea-Cunillera Júlia, Romero-Alfano Irene, Martí Maria Olivella, Bedrossiantz Juliette, Prats Eva, Gomez-Canela Cristian, Raldúa Demetrio
Institute for Environmental Assessment and Water Research (IDAEA-CSIC), Jordi Girona, 18, 08034 Barcelona, Spain.
Department of Analytical and Applied Chemistry, School of Engineering, Institut Químic de Sarrià-Universitat Ramon Llull, Via Augusta 390, 08017 Barcelona, Spain.
Toxics. 2025 Apr 30;13(5):362. doi: 10.3390/toxics13050362.
Acrylamide (ACR) is a potent neurotoxicant that disrupts cellular redox homeostasis by depleting reduced glutathione (GSH) and inducing oxidative stress. Despite its well-characterized mechanism, no effective treatments for ACR-induced neurotoxicity currently exist. This study evaluates the therapeutic efficacy of N-acetylcysteine-amide (AD4), a blood-brain barrier (BBB)-permeable derivative of N-acetylcysteine, in a novel severe acute ACR neurotoxicity model in adult zebrafish. Adult zebrafish received a single intraperitoneal (i.p.) injection of ACR (800 μg/g), followed by AD4 (400 μg/g i.p.) or PBS 24 h later. ACR exposure reduced brain GSH levels by 51% reduction at 48 h, an effect fully reversed by AD4 treatment. Behavioral analyses showed that AD4 rescued ACR-induced deficits in short-term habituation of the acoustic startle response (ASR). Surprisingly, ACR exposure did not alter the neurochemical profile of key neurotransmitters or the expression of genes related to redox homeostasis, synaptic vesicle recycling, regeneration, or myelination. These results demonstrate AD4's neuroprotective effects against acute ACR-induced brain toxicity, highlighting its therapeutic potential and validating adult zebrafish as a translational model for studying neurotoxic mechanisms and neuroprotective interventions.
丙烯酰胺（ACR）是一种强效神经毒素，它通过消耗还原型谷胱甘肽（GSH）和诱导氧化应激来破坏细胞氧化还原稳态。尽管其作用机制已得到充分表征，但目前尚无针对ACR诱导的神经毒性的有效治疗方法。本研究在成年斑马鱼的一种新型严重急性ACR神经毒性模型中评估了N-乙酰半胱氨酸酰胺（AD4）的治疗效果，AD4是一种可透过血脑屏障（BBB）的N-乙酰半胱氨酸衍生物。成年斑马鱼腹腔内（i.p.）单次注射ACR（800μg/g），24小时后注射AD4（400μg/g i.p.）或磷酸盐缓冲液（PBS）。ACR暴露使48小时时脑GSH水平降低了51%，AD4治疗完全逆转了这一效应。行为分析表明，AD4挽救了ACR诱导的听觉惊吓反应（ASR）短期习惯化缺陷。令人惊讶的是，ACR暴露并未改变关键神经递质的神经化学特征或与氧化还原稳态、突触小泡循环、再生或髓鞘形成相关基因的表达。这些结果证明了AD4对急性ACR诱导的脑毒性具有神经保护作用，突出了其治疗潜力，并验证了成年斑马鱼作为研究神经毒性机制和神经保护干预的转化模型的有效性。
