Ahmed Zainab, Tokhi Ahmed, Arif Mehreen, Rehman Naeem Ur, Sheibani Vahid, Rauf Khalid, Sewell Robert D E
Department of Pharmacy, COMSATS University Islamabad, Abbottabad campus, Abbottabad, Pakistan.
Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of MedicalSciences, Kerman, Iran.
Front Pharmacol. 2023 Mar 23;14:1135497. doi: 10.3389/fphar.2023.1135497. eCollection 2023.
Chronic unpredictable stress (CUS) induces long-term neuronal and synaptic plasticity with a neurohormonal disbalance leading to the development of co-existing anxiety, depression, and cognitive decline. The side effects and delayed onset of current clinically used antidepressants has prompted a quest for antidepressants with minimum drawbacks. Fraxetin is a natural coumarin derivative with documented antioxidant and neuroprotective activity though its effects on stress are unknown. This study therefore aimed to investigate any possible acute effect of fraxetin in behavioral tests including a CUS paradigm in correlation with brain regional neurochemical changes. Mice were subjected to a series of mild stressors for 14 days to induce CUS. Furthermore, behavioral performance in the open field test, forced swim test (FST), Y-maze and elevated plus-maze were evaluated. frontal cortical, hippocampal and striatal tissues were analyzed high-performance liquid chromatography (HPLC) for neurochemical changes. Acute administration of fraxetin (20-60 mg/kg, orally) decreased depression-like behavior in the FST and behavioral anxiety in both the open field test and elevated plus-maze. Memory deficits induced during the CUS paradigm were markedly improved as reflected by enhanced Y maze performance. Concurrent biochemical and neurochemical analyses revealed that only the two higher fraxetin doses decreased elevated serum corticosterone levels while diminished serotonin levels in the frontal cortex, striatum and hippocampus were reversed, though noradrenaline was only raised in the striatum. Concomitantly, dopamine levels were restored by fraxetin at the highest dose exclusively in the frontal cortex. Acute treatment with fraxetin attenuated CUS-induced behavioral deficits, ameliorated the increased corticosterone level and restored altered regional neurotransmitter levels and this may indicate a potential application of fraxetin in the management of anxiety and depression modeled by CUS. However, further studies are warranted regarding the chronic effects of fraxetin behaviorally and neurochemically.
慢性不可预测应激（CUS）会引发长期的神经元和突触可塑性，并伴有神经激素失衡，进而导致焦虑、抑郁和认知能力下降等症状同时出现。目前临床使用的抗抑郁药存在副作用且起效延迟，这促使人们寻找缺点最少的抗抑郁药。紫铆亭是一种天然香豆素衍生物，具有抗氧化和神经保护活性，但其对压力的影响尚不清楚。因此，本研究旨在探讨紫铆亭在行为测试中的任何可能的急性作用，包括与脑区神经化学变化相关的CUS范式。将小鼠置于一系列轻度应激源下14天以诱导CUS。此外，还评估了旷场试验、强迫游泳试验（FST）、Y迷宫和高架十字迷宫中的行为表现。采用高效液相色谱法（HPLC）分析额叶皮质、海马和纹状体组织的神经化学变化。急性给予紫铆亭（20 - 60毫克/千克，口服）可减少FST中的抑郁样行为以及旷场试验和高架十字迷宫中的行为焦虑。CUS范式期间诱导的记忆缺陷得到显著改善，Y迷宫表现增强即反映了这一点。同时进行的生化和神经化学分析表明，只有两个较高剂量的紫铆亭降低了血清皮质酮水平的升高，而额叶皮质、纹状体和海马中血清素水平的降低得到逆转，不过去甲肾上腺素仅在纹状体中升高。同时，紫铆亭仅在额叶皮质以最高剂量恢复了多巴胺水平。紫铆亭的急性治疗减轻了CUS诱导的行为缺陷，改善了皮质酮水平的升高，并恢复了改变的区域神经递质水平，这可能表明紫铆亭在管理由CUS模拟的焦虑和抑郁方面具有潜在应用。然而，关于紫铆亭在行为和神经化学方面的慢性影响，仍需要进一步研究。
