Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Recife, Pernambuco, Brazil; Postgraduate Program in Biological Sciences (PPGCB), Federal University of Pernambuco Recife, Pernambuco, Brazil.
Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Recife, Pernambuco, Brazil.
Toxicol Appl Pharmacol. 2019 Sep 15;379:114673. doi: 10.1016/j.taap.2019.114673. Epub 2019 Jul 16.
Tadalafil displays important neuroprotective effects in experimental models of neurodegenerative diseases, however its mechanisms of action remain poorly understood. The aim of the present study was to investigate the action of Tadalafil on learning and memory, neuroinflammation, glial cell activation and neuroprotection in the experimental model of hepatic encephalopathy (HE) induced by Thioacetamide (TAA) in mice.
Mice received intraperitoneal injections of TAA, for 3 consecutive days, reaching the final dose of 600 mg/kg. Tadalafil 15 mg/kg body weight was administered by gavage during 15 days after TAA induction. Mice underwent a Barnes maze for learning and memory evaluation.
Animals with hepatic encephalopathy showed reduced learning and spatial memory in the Barnes Maze, presented astrocyte and microglia activation and increased neuroinflammatory markers such as TNF-α, IL-1β, IL-6, p-p38, p-ERK and p-NF-kB. In addition, the signaling pathway PKA/PKG/CREB/BDNF/NeuN/synaptophysin and glutamate receptors were deregulated by TAA. Tadalafil treatment regulated the inflammation signaling pathways restoring learning and spatial memory.
Tadalafil significantly reduced neuroinflammation, promoted neuroprotection and plasticity, regulated the expression of hippocampal glutamate receptor and restored spatial learning ability and memory.
他达拉非在神经退行性疾病的实验模型中显示出重要的神经保护作用，但作用机制仍知之甚少。本研究旨在探讨他达拉非在硫代乙酰胺（TAA）诱导的肝性脑病（HE）小鼠模型中对学习和记忆、神经炎症、神经胶质细胞激活和神经保护的作用。
小鼠连续 3 天腹腔注射 TAA，达到终剂量 600mg/kg。TAA 诱导后 15 天，通过灌胃给予他达拉非 15mg/kg 体重。小鼠进行 Barnes 迷宫以评估学习和记忆。
肝性脑病动物在 Barnes 迷宫中表现出学习和空间记忆能力下降，星形胶质细胞和小胶质细胞激活，以及 TNF-α、IL-1β、IL-6、p-p38、p-ERK 和 p-NF-kB 等神经炎症标志物增加。此外，TAA 还使 PKA/PKG/CREB/BDNF/NeuN/synaptophysin 等信号通路和谷氨酸受体失调。他达拉非治疗调节炎症信号通路，恢复学习和空间记忆。
他达拉非可显著减轻神经炎症，促进神经保护和可塑性，调节海马谷氨酸受体表达，恢复空间学习能力和记忆。
