Razi Drug Research Center and Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
J Neural Transm (Vienna). 2017 Nov;124(11):1369-1387. doi: 10.1007/s00702-017-1771-2. Epub 2017 Aug 9.
Chronic abuse of methylphenidate (MPH) often causes neuronal cell death. Topiramate (TPM) carries neuroprotective effects, but its exact mechanism of action remains unclear. In the present study, the role of various doses of TPM and its possible mechanisms, receptors and signaling pathways involved against MPH-induced hippocampal neurodegeneration were evaluated in vivo. Thus, domoic acid (DOM) was used as AMPA/kainate receptor agonist, bicuculline (BIC) as GABA receptor antagonist, ketamine (KET) as NMDA receptor antagonist, yohimbine (YOH) as α adrenergic receptor antagonist and haloperidol (HAL) was used as dopamine D receptor antagonist. Open field test (OFT) was used to investigate the disturbances in motor activity. Hippocampal neurodegenerative parameters were evaluated. Protein expressions of CREB/BDNF and Akt/GSK3 signaling pathways were also evaluated. Cresyl violet staining was performed to show and confirm the changes in the shape of the cells. TPM (70 and 100 mg/kg) reduced MPH-induced rise in lipid peroxidation, oxidized form of glutathione (GSSG), IL-1β and TNF-α levels, Bax expression and motor activity disturbances. In addition, TPM treatment increased Bcl-2 expression, the level of reduced form of glutathione (GSH) and the levels and activities of superoxide dismutase, glutathione peroxidase and glutathione reductase enzymes. TPM also inhibited MPH-induced hippocampal degeneration. Pretreatment of animals with DOM, BIC, KET and YOH inhibited TPM-induced neuroprotection and increased oxidative stress, neuroinflammation, neuroapoptosis and neurodegeneration while reducing CREB, BDNF and Akt protein expressions. Also pretreatment with DOM, BIC, KET and YOH inhibited TPM-induced decreases in GSK3. It can be concluded that the mentioned receptors by modulation of CREB/BDNF and Akt/GSK3 pathways, are involved in neuroprotection of TPM against MPH-induced neurodegeneration.
慢性滥用哌醋甲酯（MPH）常导致神经元细胞死亡。托吡酯（TPM）具有神经保护作用，但确切的作用机制尚不清楚。在本研究中，评估了不同剂量的 TPM 及其可能的机制、涉及的受体和信号通路在对抗 MPH 诱导的海马神经退行性变中的作用。因此，使用海人藻酸（DOM）作为 AMPA/KA 受体激动剂，印防己毒素（BIC）作为 GABA 受体拮抗剂，氯胺酮（KET）作为 NMDA 受体拮抗剂，育亨宾（YOH）作为α肾上腺素受体拮抗剂，氟哌啶醇（HAL）作为多巴胺 D 受体拮抗剂。旷场试验（OFT）用于研究运动活动的干扰。评估海马神经退行性变参数。还评估了 CREB/BDNF 和 Akt/GSK3 信号通路的蛋白表达。使用 Cresyl 紫染色显示和确认细胞形状的变化。TPM（70 和 100mg/kg）降低了 MPH 诱导的脂质过氧化、氧化型谷胱甘肽（GSSG）、IL-1β 和 TNF-α 水平、Bax 表达和运动活动干扰的升高。此外，TPM 治疗增加了 Bcl-2 表达、还原型谷胱甘肽（GSH）水平以及超氧化物歧化酶、谷胱甘肽过氧化物酶和谷胱甘肽还原酶的水平和活性。TPM 还抑制了 MPH 诱导的海马变性。用 DOM、BIC、KET 和 YOH 预处理动物抑制了 TPM 诱导的神经保护作用，并增加了氧化应激、神经炎症、神经细胞凋亡和神经退行性变，同时降低了 CREB、BDNF 和 Akt 蛋白表达。此外，用 DOM、BIC、KET 和 YOH 预处理也抑制了 TPM 诱导的 GSK3 降低。可以得出结论，通过调节 CREB/BDNF 和 Akt/GSK3 通路的所述受体参与了 TPM 对抗 MPH 诱导的神经退行性变的神经保护作用。
