Programa de Pós-graduação em Neurociências, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Campus Trindade, Florianópolis, SC, 88040-900, Brazil.
Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Campus Trindade, Florianópolis, SC, 88040-900, Brazil.
Neurotox Res. 2018 Oct;34(3):452-462. doi: 10.1007/s12640-018-9903-5. Epub 2018 Apr 20.
N-methyl D-aspartate (NMDA) preconditioning is evoked by the administration of a subtoxic dose of NMDA and is protective against neuronal excitotoxicity. This effect may involve a diversity of targets and cell signaling cascades associated to neuroprotection. Phosphatidylinositol-3 kinase/protein kinase B (PI3K/Akt) and mitogen-activated protein kinases (MAPKs) such as extracellular regulated protein kinase 1/2 (ERK1/2) and p38 pathways play a major role in neuroprotective mechanisms. However, their involvement in NMDA preconditioning was not yet fully investigated. The present study aimed to evaluate the effect of NMDA preconditioning on PI3K/Akt, ERK1/2, and p38 pathways in the hippocampus of mice and characterize the involvement of PI3K on NMDA preconditioning-evoked prevention of seizures and hippocampal cell damage induced by quinolinic acid (QA). Thus, mice received wortmannin (a PI3K inhibitor) and 15 min later a subconvulsant dose of NMDA (preconditioning) or saline. After 24 h of this treatment, an intracerebroventricular QA infusion was administered. Phosphorylation levels and total content of Akt, glycogen synthase protein kinase-3β (GSK-3β), ERK1/2, and p38 were not altered after 24 h of NMDA preconditioning with or without wortmmanin pretreatment. Moreover, after QA administration, behavioral seizures, hippocampal neuronal degeneration, and Akt activation were evaluated. Inhibition of PI3K pathway was effective in abolishing the protective effect of NMDA preconditioning against QA-induced seizures, but did not modify neuronal protection promoted by preconditioning as evaluated by Fluoro-Jade B staining. The study confirms that PI3K participates in the mechanism of protection induced by NMDA preconditioning against QA-induced seizures. Conversely, NMDA preconditioning-evoked protection against neuronal degeneration is not altered by PI3K signaling pathway inhibition. These results point to differential mechanisms regarding protection against a behavioral and cellular manifestation of neural damage.
N-甲基-D-天冬氨酸（NMDA）预处理是通过给予亚毒性剂量的 NMDA 而引发的，可防止神经元兴奋性毒性。这种效应可能涉及多种与神经保护相关的靶标和细胞信号转导级联。磷脂酰肌醇-3 激酶/蛋白激酶 B（PI3K/Akt）和丝裂原活化蛋白激酶（MAPKs），如细胞外调节蛋白激酶 1/2（ERK1/2）和 p38 途径，在神经保护机制中发挥重要作用。然而，它们在 NMDA 预处理中的作用尚未完全研究清楚。本研究旨在评估 NMDA 预处理对小鼠海马中 PI3K/Akt、ERK1/2 和 p38 途径的影响，并探讨 PI3K 在 NMDA 预处理诱发的喹啉酸（QA）诱导的癫痫发作和海马细胞损伤中的作用。因此，小鼠接受了渥曼青霉素（一种 PI3K 抑制剂），15 分钟后给予亚惊厥剂量的 NMDA（预处理）或生理盐水。在这种治疗 24 小时后，给予脑室注射 QA。在 NMDA 预处理 24 小时后，无论是否用渥曼青霉素预处理，Akt、糖原合酶蛋白激酶-3β（GSK-3β）、ERK1/2 和 p38 的磷酸化水平和总含量均未改变。此外，在给予 QA 后，评估了行为性癫痫发作、海马神经元变性和 Akt 激活。PI3K 通路的抑制有效消除了 NMDA 预处理对 QA 诱导的癫痫发作的保护作用，但如 Fluoro-Jade B 染色所示，并未改变预处理所促进的神经元保护作用。该研究证实，PI3K 参与了 NMDA 预处理诱导的针对 QA 诱导的癫痫发作的保护机制。相反，PI3K 信号通路的抑制并未改变 NMDA 预处理诱发的对神经元变性的保护作用。这些结果表明，针对神经损伤的行为和细胞表现，存在不同的保护机制。
