Aim

Neurodegeneration is one of the serious adverse effects of stimulant agents such as nicotine. Minocycline possess established neuroprotective properties. The role of CREB-BDNF signaling pathway in mediating the neuroprotective effects of minocycline against nicotine-induced neurodegeneration in rats was evaluated in current study.

Methods

Seventy adult male rats were divided randomly into seven groups. Group 1 and 2, received 0.7 ml/rat of normal saline (i.p) and nicotine (10 mg/kg, s.c) respectively. Groups 3, 4, 5 and 6, treated concurrently with nicotine (10 mg/kg) and minocycline (10, 20, 30 and 40 mg/kg, i.p, respectively) for 21 days. Group 7 received minocycline alone (40 mg/kg, i.p) for 21 days. From 17th to 21 st days of experiment, Morris water maze (MWM) was used to evaluate learning and spatial memory in rats treated in different groups. According to the critical role of hippocampus in cognitive behavior, hippocampal neurodegenerative parameters (oxidative stress and inflammatory biomarkers) and also cyclic AMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) levels were evaluated in isolated hippocampus in day 22 of experiment and after drug treatment. Also hippocampal cell density and tissue changes were evaluated by hematoxylin and eosin staining.

Result

Nicotine administration impaired the learning and spatial memory in rats and simultaneous treatment with various doses of minocycline attenuated the nicotine-induced cognition disturbances. In addition, nicotine treatment increased lipid peroxidation and the levels of oxidized form of glutathione (GSSG), interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and Bax protein, while decreasing reduced form of glutathione (GSH), Bcl-2 protein, P-CREB and BDNF levels in the hippocampus of experimental animals. Nicotine also reduced the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) in the hippocampus. Minocycline attenuated nicotine-induced neurodegeneration and elevating CREB (both forms) and BDNF levels. Also minocycline treatment alone increases the cognitive activity and increased CREB (both forms) and BDNF levels and decreased oxidative stress, inflammation and apoptotic biomarkers. Minocycline at high doses cause inhibition of nicotine induced cell density and changes in both area of dentate gyrus (DG) and CA1 in hippocampus.

Conclusion

It can be concluded that minocycline, probably through activation of P-CREB/BDNF signaling pathway, confers neuroprotection against nicotine-induced neurodegeneration in rat hippocampus.

中文翻译：

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米诺环素对尼古丁诱导的神经变性和认知障碍的神经保护作用的分子、组织学和行为证据：CREB-BDNF 信号通路的可能作用

目的

神经变性是尼古丁等兴奋剂的严重不良反应之一。米诺环素具有既定的神经保护特性。本研究评估了 CREB-BDNF 信号通路在介导米诺环素对大鼠尼古丁诱导的神经变性的神经保护作用中的作用。

方法

七十只成年雄性大鼠随机分为七组。第 1 组和第 2 组分别接受 0.7 ml/大鼠的生理盐水 (ip) 和尼古丁 (10 mg/kg，sc)。第 3、4、5 和 6 组同时用尼古丁（10 毫克/千克）和米诺环素（分别为 10、20、30 和 40 毫克/千克，ip）治疗 21 天。第 7 组仅接受米诺环素 (40 mg/kg, ip) 21 天。从实验的第17天到第21天，使用Morris水迷宫（MWM）评估不同组治疗大鼠的学习和空间记忆。根据海马体在认知行为中的关键作用，在实验的第 22 天和药物治疗后，在离体海马中评估了海马神经退行性参数（氧化应激和炎症生物标志物）以及环 AMP 反应元件结合蛋白 (CREB) 和脑源性神经营养因子 (BDNF) 水平。还通过苏木精和伊红染色评估海马细胞密度和组织变化。

结果

尼古丁给药会损害大鼠的学习和空间记忆，同时用不同剂量的米诺环素治疗可减轻尼古丁引起的认知障碍。此外，尼古丁治疗会增加脂质过氧化和氧化型谷胱甘肽 (GSSG)、白细胞介素 1 β (IL-1β)、肿瘤坏死因子 α (TNF-α) 和 Bax 蛋白的水平，同时降低谷胱甘肽的还原形式。 GSH)、Bcl-2 蛋白、P-CREB ​​和 BDNF 在实验动物海马中的水平。尼古丁还降低了海马中超氧化物歧化酶 (SOD)、谷胱甘肽过氧化物酶 (GPx) 和谷胱甘肽还原酶 (GR) 的活性。米诺环素减轻尼古丁诱导的神经变性并提高 CREB（两种形式）和 BDNF 水平。此外，单独的米诺环素治疗会增加认知活动并增加 CREB（两种形式）和 BDNF 水平，并减少氧化应激、炎症和凋亡生物标志物。高剂量的米诺环素会抑制尼古丁诱导的细胞密度以及海马齿状回 (DG) 和 CA1 区域的变化。

结论

可以得出结论，米诺环素可能通过激活 P-CREB/BDNF 信号通路，对大鼠海马中尼古丁诱导的神经变性具有神经保护作用。