Laboratory of Physiology and Pharmacology, National School of Veterinary Medicine, University of Manouba, Sidi Thabet, Tunisia.
Neurophysiology Laboratory and Functional Pathology, Department of Biological Sciences, Faculty of Sciences of Tunis, University Campus of Al-Manar, Tunis, Tunisia.
Inflammopharmacology. 2020 Apr;28(2):487-497. doi: 10.1007/s10787-019-00655-9. Epub 2019 Oct 30.
Excessive reactive oxygen species (ROS) production can induce tissue injury involved in a variety of neurodegenerative disorders such as neurodegeneration observed in pilocarpine-induced temporal lobe epilepsy. Ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist has beneficial effects in pilocarpine-induced temporal lobe epilepsy, when administered within minutes of seizure to avoid the harmful neurological lesions induced by pilocarpine. However, the enzymes involved in ROS productions and the effect of ketamine on this process remain less documented. Here we show that during pilocarpine-induced epilepsy in mice, the expression of the phagocyte NADPH oxidase NOX2 subunits (NOX2/gp91, p22, and p47) and the expression of myeloperoxidase (MPO) were dramatically increased in mice brain treated with pilocarpine. Interestingly, treatment of mice with ketamine before or after pilocarpine administration decreased this process, mainly when injected before pilocarpine. Finally, our results showed that pilocarpine induced p47 phosphorylation and HO production in mice brain and ketamine was able to inhibit these processes. Our results show that pilocarpine induced NOX2 activation to produce ROS in mice brain and that administration of ketamine before or after the induction of temporal lobe epilepsy by pilocarpine inhibited this activation in mice brain. These results suggest a key role of the phagocyte NADPH oxidase NOX2 and MPO in epilepsy and identify a novel effect of ketamine.
过量的活性氧（ROS）产生可诱导组织损伤，涉及多种神经退行性疾病，如匹鲁卡品诱导的颞叶癫痫中观察到的神经退行性变。氯胺酮是一种非竞争性 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，在癫痫发作后几分钟内给药可预防匹鲁卡品引起的有害神经病变，从而在匹鲁卡品诱导的颞叶癫痫中具有有益作用。然而，ROS 产生中涉及的酶以及氯胺酮对该过程的影响仍记录较少。在这里，我们显示在小鼠匹鲁卡品诱导的癫痫发作期间，用匹鲁卡品处理的小鼠大脑中吞噬细胞 NADPH 氧化酶 NOX2 亚基（NOX2/gp91、p22 和 p47）的表达和髓过氧化物酶（MPO）的表达显着增加。有趣的是，在匹鲁卡品给药之前或之后用氯胺酮治疗可降低该过程，主要是在匹鲁卡品之前注射时。最后，我们的结果表明，匹鲁卡品诱导了小鼠大脑中 p47 的磷酸化和 HO 的产生，并且氯胺酮能够抑制这些过程。我们的结果表明，匹鲁卡品诱导的 NOX2 激活在小鼠大脑中产生 ROS，并且在匹鲁卡品诱导颞叶癫痫之前或之后给予氯胺酮可抑制小鼠大脑中的这种激活。这些结果表明吞噬细胞 NADPH 氧化酶 NOX2 和 MPO 在癫痫中的关键作用，并确定了氯胺酮的新作用。
