Silva Adriana L, Oliveira Joana L, do Nascimento Ravena P, Santos Letícia O, de Araújo Fillipe M, Dos Santos Balbino L, Santana Rejane C, Moreira Eduardo Luiz T, Batatinha Maria José M, Alves Iura M, Velozo Eudes S, Victor Mauricio M, Assis Adriano M, Almeida Roberto F, de Souza Diogo O G, Silva Victor Diógenes A, Costa Silvia L
Laboratory of Neurochemistry and Cellular Biology, Institute of Health Sciences, Federal University of Bahia, Brazil.
Laboratory of Neurochemistry and Cellular Biology, Institute of Health Sciences, Federal University of Bahia, Brazil; Federal University of Vale do São Francisco, Brazil.
Neurotoxicology. 2023 Jan;94:59-70. doi: 10.1016/j.neuro.2022.10.017. Epub 2022 Nov 3.
Pyrrolizidine alkaloids (PAs) are secondary plant metabolites playing an important role as phytotoxins in the plant defense mechanisms and can be present as contaminant in the food of humans and animals. The PA monocrotaline (MCT), one of the major plant derived toxin that affect humans and animals, is present in a high concentration in Crotalaria spp. (Leguminosae) seeds and can induce toxicity after consumption, characterized mainly by hepatotoxicity and pneumotoxicity. However, the effects of the ingestion of MCT in the central nervous system (CNS) are still poorly elucidated. Here we investigated the effects of MCT oral acute administration on the behavior and CNS toxicity in rats. Male adult Wistar were treated with MCT (109 mg/Kg, oral gavage) and three days later the Elevated Pluz Maze test demonstrated that MCT induced an anxiolytic-like effect, without changes in novelty habituation and in operational and spatial memory profiles. Histopathology revealed that the brain of MCT-intoxicated animals presented hyperemic vascular structures in the hippocampus, parahippocampal cortex and neocortex, mild perivascular edema in the neocortex, hemorrhagic focal area in the brain stem, hemorrhage and edema in the thalamus. MCT also induced neurotoxicity in the cortex and hippocampus, as revealed by Fluoro Jade-B and Cresyl Violet staining, as well astrocyte reactivity, revealed by immunocytochemistry for glial fibrillary acidic protein. Additionally, it was demonstrated by RT-qPCR that MCT induced up-regulation on mRNA expression of neuroinflammatory mediator, especially IL1β and CCL2 in the hippocampus and cortex, and down-regulation on mRNA expression of neurotrophins HGDF and BDNF in the cortex. Together, these results demonstrate that the ingestion of MCT induces cerebrovascular lesions and toxicity to neurons that are associated to astroglial cell response and neuroinflammation in the cortex and hippocampus of rats, highlighting CNS damages after acute intoxication, also putting in perspective it uses as a model for cerebrovascular damage.
吡咯里西啶生物碱（PAs）是植物的次生代谢产物，在植物防御机制中作为植物毒素发挥重要作用，并且可能作为污染物存在于人类和动物的食物中。PA野百合碱（MCT）是影响人类和动物的主要植物源性毒素之一，在猪屎豆属（豆科）种子中含量很高，食用后可诱发毒性，主要表现为肝毒性和肺毒性。然而，摄入MCT对中枢神经系统（CNS）的影响仍未得到充分阐明。在此，我们研究了MCT口服急性给药对大鼠行为和CNS毒性的影响。成年雄性Wistar大鼠接受MCT（109 mg/Kg，灌胃）治疗，三天后高架十字迷宫试验表明，MCT诱导了抗焦虑样效应，在新奇习惯化、操作和空间记忆方面没有变化。组织病理学显示，MCT中毒动物的大脑在海马体、海马旁皮质和新皮质出现血管充血结构，新皮质出现轻度血管周围水肿，脑干出现出血灶，丘脑出现出血和水肿。氟玉髓-B和甲酚紫染色显示，MCT还诱导了皮质和海马体的神经毒性，免疫细胞化学检测胶质纤维酸性蛋白显示星形胶质细胞反应性增强。此外，RT-qPCR表明，MCT诱导神经炎症介质mRNA表达上调，尤其是海马体和皮质中的IL1β和CCL2，同时诱导皮质中神经营养因子HGDF和BDNF的mRNA表达下调。总之，这些结果表明，摄入MCT会诱导脑血管病变和对神经元的毒性，这与大鼠皮质和海马体中的星形胶质细胞反应和神经炎症有关，突出了急性中毒后对中枢神经系统的损害，也为其作为脑血管损伤模型的应用提供了参考。
