Motaghinejad Majid, Motevalian Manijeh, Fatima Sulai
Razi Drug Research Center, Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
Razi Drug Research Center, Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran..
Life Sci. 2017 Jun 15;179:37-53. doi: 10.1016/j.lfs.2017.01.002. Epub 2017 Jan 10.
Prolonged abuse of methylphenidate (MPH) often causes neuronal damage. Topiramate (TPM) has neuroprotective properties, but its mechanism of action remains unclear. The current study evaluates in vivo role of various doses of TPM (10, 30, 50, 70 and 100mg/kg) and its possible mechanisms against MPH-induced hippocampal oxidative stress, inflammation and apoptosis, in absence and presence of different receptor agonists and antagonists. Domoic acid (DOM) as AMPA/kainate receptor agonist, bicuculline (BIC) as GABA receptor antagonist, ketamine (KET) as NMDA receptor antagonist, yohimbine (YOH) as ɑ adrenergic receptor antagonist and haloperidole (HAL) as D dopamine receptor antagonist was used. Open Field Test (OFT) was used to investigate the disturbances in motor activity. Hippocampal oxidative, anti-oxidant and inflammatory parameters and apoptotic factors were studied. Expressions of BDNF at gene and protein levels were also evaluated. Crystal violet staining was performed to determine neuronal cell density. TPM (70 and 100mg/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 BDNF gene and protein expressions, Bcl-2 expression, the level of reduced form of glutathione (GSH) and activities of enzymes superoxide dismutase, glutathione peroxidase and glutathione reductase.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 BDNF expressions. Thus, TPM by interacting with AMPA/kainate, GABA, NMDA and ɑ-adrenergic receptors improves BDNF expression and acts as a neuroprotective agent against MPH-induced neurodegeneration.
长期滥用哌醋甲酯（MPH）常导致神经元损伤。托吡酯（TPM）具有神经保护特性，但其作用机制尚不清楚。本研究评估了不同剂量的TPM（10、30、50、70和100mg/kg）在体内的作用及其在有无不同受体激动剂和拮抗剂存在的情况下，对抗MPH诱导的海马氧化应激、炎症和细胞凋亡的可能机制。使用了作为AMPA/海人酸受体激动剂的软骨藻酸（DOM）、作为GABA受体拮抗剂的荷包牡丹碱（BIC）、作为NMDA受体拮抗剂的氯胺酮（KET）、作为α肾上腺素能受体拮抗剂的育亨宾（YOH）以及作为多巴胺D受体拮抗剂的氟哌啶醇（HAL）。采用旷场试验（OFT）研究运动活动的紊乱情况。研究了海马的氧化、抗氧化和炎症参数以及凋亡因子。还评估了脑源性神经营养因子（BDNF）在基因和蛋白水平的表达。进行结晶紫染色以确定神经元细胞密度。TPM（70和100mg/kg）降低了MPH诱导的脂质过氧化、谷胱甘肽氧化形式（GSSG）、白细胞介素-1β和肿瘤坏死因子-α水平、Bax表达以及运动活动紊乱。此外，TPM治疗增加了BDNF基因和蛋白表达、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活性。TPM还抑制了MPH诱导的海马变性。用DOM、BIC、KET和YOH对动物进行预处理可抑制TPM诱导的神经保护作用，并增加氧化应激、神经炎症、神经细胞凋亡和神经变性，同时降低BDNF表达。因此，TPM通过与AMPA/海人酸、GABA、NMDA和α-肾上腺素能受体相互作用，改善BDNF表达，并作为一种神经保护剂对抗MPH诱导的神经变性。
