Rajendran Peramaiyan, Althumairy Duaa, Bani-Ismail Mohammad, Bekhet Gamal M, Ahmed Emad A
Department of Biological Sciences, College of Science, King Faisal University, Al-Ahsa, Saudi Arabia.
Centre of Molecular Medicine and Diagnostics, Department of Bio-Chemistry, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India.
Front Pharmacol. 2023 Apr 18;14:1103940. doi: 10.3389/fphar.2023.1103940. eCollection 2023.
Although aluminum (Al) is not biologically crucial to the human body, classical studies have demonstrated that excessive human exposure to Al can induce oxidative damage, neuroinflammatory conditions and neurotoxic manifestations implicated in Alzheimer's disease (AD). Exposure to Al was reported to be associated with oxidative damage, neuroinflammation, and to enhance progressive multiregional neurodegeneration in animal models. Several plant-derived natural biomolecules have been recently used to reduce the toxic effects of Al through decreasing the oxidative stress and the associated diseases. A good candidate still to be tested is an active natural furanocoumarin, the isoimperatorin (IMP) that can be extracted from Lemon and lime oils and other plants. Here, we examined the neuroprotective effects of IMP on aluminum chloride (AlCl3)-induced neurotoxicity in albino mice. Twenty-four male albino mice were used in this study. Mice were randomly devided into 5 groups. The first group was given distilled water as a control, the second group was given AlCl3 orally (10 mg/wt/day) starting from the 2nd week to the end of the 6th week, the third group received AlCl3 orally and IMP interperitoneally, i. p. (30 mg/wt/day) starting from week 2 till week 6 where IMP was supplement 1st and then 4 h later AlCl3 was given to mice. The fourth group received the control (IMP 30 mg/wt, i. p.) from the 2nd week till the end of the experiment. Rodent models of central nervous system (CNS) disorders were assessed using object location memory and Y-maze tests in 6th week began. Essential anti-inflammatory and oxidative stress indicators were evaluated, including interleukin-1 β (IL-1β), tumor necrosis factor α (TNF-α), malondialdehyde (MDA), total antioxidant capacity (TAC), and catalase activity (CAT). In addition, serum levels of brain neurotransmitters such as corticosterone, acetylcholine (ACh), dopamine and serotonin in brain homogenates were measured calorimetrically. The study results revealed that the daily treatment of AlCl3 upregulated the TNF-α and IL-1β levels, increased MDA accumulation, and decreased TAC and CAT activity. In addition, aluminum induced a reduction in concentrations of ACh, serotonin and dopamine in the brain. However, IMP significantly ameliorates the effect of AlCl3 through modulating the antioxidant and regulating the inflammatory response through targeting Nrf2 (NF-E2-related factor 2) and mitogen-activated protein kinase (MAPK). Thus, IMP might be a promising treatment option for neurotoxicity and neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, which are associated with neuro-inflammation and oxidative stress.
虽然铝（Al）对人体并非生物学上的关键元素，但经典研究表明，人体过量接触铝可引发氧化损伤、神经炎症以及与阿尔茨海默病（AD）相关的神经毒性表现。据报道，接触铝与氧化损伤、神经炎症有关，并会加剧动物模型中的进行性多区域神经退行性变。最近，几种植物源天然生物分子已被用于通过降低氧化应激及相关疾病来减轻铝的毒性作用。一种仍有待测试的良好候选物是活性天然呋喃香豆素异欧前胡素（IMP），它可从柠檬和酸橙油以及其他植物中提取。在此，我们研究了IMP对氯化铝（AlCl3）诱导的白化小鼠神经毒性的神经保护作用。本研究使用了24只雄性白化小鼠。小鼠被随机分为5组。第一组给予蒸馏水作为对照，第二组从第2周开始至第6周结束口服AlCl3（10毫克/体重/天），第三组从第2周开始至第6周口服AlCl3并腹腔注射IMP（30毫克/体重/天），其中IMP先给药，4小时后再给小鼠注射AlCl3。第四组从第2周开始至实验结束接受对照（腹腔注射30毫克/体重的IMP）。在第6周开始时，使用物体位置记忆和Y迷宫测试评估中枢神经系统（CNS）疾病的啮齿动物模型。评估了重要的抗炎和氧化应激指标，包括白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）、丙二醛（MDA）、总抗氧化能力（TAC）和过氧化氢酶活性（CAT）。此外，采用比色法测量了脑匀浆中血清脑内神经递质如皮质酮、乙酰胆碱（ACh）、多巴胺和血清素的水平。研究结果显示，每日给予AlCl3会使TNF-α和IL-1β水平上调，增加MDA积累，并降低TAC和CAT活性。此外，铝会导致大脑中ACh、血清素和多巴胺浓度降低。然而，IMP通过靶向核因子E2相关因子2（Nrf2）和丝裂原活化蛋白激酶（MAPK）调节抗氧化作用并调节炎症反应，从而显著改善AlCl3的影响。因此，IMP可能是治疗与神经炎症和氧化应激相关的神经毒性和神经退行性疾病（如阿尔茨海默病和帕金森病）的一种有前景的治疗选择。
