橙皮苷通过5- ht2a相关的神经化学、氧化和炎症通路调节减轻慢性应激性抑郁症:实验和计算机证据。

IF 3.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Mimansa Kandhwal, Amarjot Kaur Grewal, Varinder Singh, Ojashvi Sharma, Heena Khan, Manjinder Singh, Amit Kumar, Thakur Gurjeet Singh, Tanveer Singh, Sheikh F. Ahmad, Haneen A. Al-Mazroua, Gamaleldin I. Harisa
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引用次数: 0

摘要

抑郁症与单胺能失调、氧化应激和神经炎症有关,其中5-羟色胺2a (5-HT2A)受体起着关键作用。本研究调查了橙皮苷(HSP)的抗抑郁样潜力,橙皮苷是一种柑橘衍生的类黄酮,长期给药(100或200 mg/kg,每天口服一次,持续21天)给暴露于慢性不可预测的轻度应激(CUMS)的小鼠。进一步探讨了5- ht2a相关的神经化学和分子机制,强调了其在应激相关神经保护中的作用。暴露于CUMS会产生抑郁样行为,并伴有皮质酮升高、氧化应激、炎症以及5-羟色胺和多巴胺的消耗。HSP治疗通过恢复蔗糖偏好、减少强迫游泳测试中的静止时间和使开阔场地测试中的运动活动正常化,有效地逆转了这些变化。在神经化学水平上,HSP治疗恢复了5-HT和多巴胺水平,降低了皮质酮,减弱了氧化(MDA、GSH、SOD、过氧化氢酶)和炎症(NF-κB、IL-1β、IL-6、TNF-α)标志物。此外,热休克蛋白改善神经元结构,强调其神经保护潜力。同时给予5- ht2a受体激动剂(±)-2,5-二甲氧基-4-碘安非他明盐酸(DOI, 5 mg/kg,皮下注射,每天1次,在21天的治疗方案中)可消除HSP的作用,暗示其机制中有5- ht2a拮抗作用。计算机实验证实了HSP与5-HT2A受体的强而稳定的结合(- 72.99 kcal/mol),关键的相互作用涉及Trp151、Asp155、Ser159和Phe340。分子动力学模拟(100 ns)支持络合物的稳定性。这些结果表明,HSP通过调节5-HT2A受体,恢复HPA轴平衡,减少氧化应激和神经炎症,并使单胺能功能正常化,具有抗抑郁样作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Hesperidin Attenuates Chronic Stress-Induced Depression via 5-HT2A-Linked Modulation of Neurochemical, Oxidative, and Inflammatory Pathways: Experimental and In Silico Evidence

Hesperidin Attenuates Chronic Stress-Induced Depression via 5-HT2A-Linked Modulation of Neurochemical, Oxidative, and Inflammatory Pathways: Experimental and In Silico Evidence

Depression is associated with monoaminergic dysregulation, oxidative stress, and neuroinflammation, with the 5-hydroxytryptamine 2 A (5-HT2A) receptor playing a key role. The present study investigated the antidepressant-like potential of hesperidin (HSP), a citrus-derived flavonoid, administered chronically (100 or 200 mg/kg, orally once daily for 21 days) in mice exposed to chronic unpredictable mild stress (CUMS). These effects were further explored through 5-HT2A-associated neurochemical and molecular mechanisms, highlighting its role in stress-related neuroprotection. Exposure to CUMS produced depressive-like behavior, accompanied by increased corticosterone, oxidative stress, inflammation, and depletion of 5-HT and dopamine. Treatment with HSP effectively reversed these alterations by restoring sucrose preference, reducing immobility time in the forced swim test, and normalizing locomotor activity in the open field test. At the neurochemical level, HSP treatment reinstated 5-HT and dopamine levels, reduced corticosterone, and attenuated oxidative (MDA, GSH, SOD, catalase) and inflammatory (NF-κB, IL-1β, IL-6, TNF-α) markers. Moreover, HSP improved neuronal architecture, underscoring its neuroprotective potential. Co-administration of the 5-HT2A receptor agonist, (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI, 5 mg/kg, subcutaneously, once daily during the 21-day protocol) abolished HSP’s effects, implicating 5-HT2A antagonism in its mechanism. In silico studies confirmed strong and stable binding of HSP to 5-HT2A receptors (− 72.99 kcal/mol), with key interactions involving Trp151, Asp155, Ser159, and Phe340. Molecular dynamics simulations (100 ns) supported complex stability. These results suggest that HSP exerts antidepressant-like effects by modulating 5-HT2A receptors, restoring HPA axis balance, reducing oxidative stress and neuroinflammation, and normalizing monoaminergic function.

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来源期刊
Neurochemical Research
Neurochemical Research 医学-神经科学
CiteScore
7.70
自引率
2.30%
发文量
320
审稿时长
6 months
期刊介绍: Neurochemical Research is devoted to the rapid publication of studies that use neurochemical methodology in research on nervous system structure and function. The journal publishes original reports of experimental and clinical research results, perceptive reviews of significant problem areas in the neurosciences, brief comments of a methodological or interpretive nature, and research summaries conducted by leading scientists whose works are not readily available in English.
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