Ebrahim Neven A, Elnagar Mohamed R, El-Gamal Randa, Habotta Ola Ali, Albadawi Emad A, Albadrani Muayad, Bahashwan Abdulrahman S, Hassan Hend M
Department of Basic Medical Sciences, College of Medicine, Taibah University, Madinah, Saudi Arabia.
Department of Human Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Heliyon. 2024 Sep 18;10(19):e38081. doi: 10.1016/j.heliyon.2024.e38081. eCollection 2024 Oct 15.
Cancer is a critical health problem, and chemotherapy administration is mandatory for its eradication. However, chemotherapy like doxorubicin (Dox) has serious side-effects including cognitive impairment or chemo brain. Melatonin is a neuroprotective agent that has antioxidant, and anti-inflammatory effects. We aimed to explore melatonin's effect on Dox-induced chemo brain to discover new mechanisms associated with Dox-induced neurotoxicity and try to prevent its occurrence. Thirty-two male albino rats had been equally divided into four groups; control, melatonin-administrated, Dox-induced chemo brain, and melatonin + Dox treated. On the 9th day, brain had been excised after scarification and had been assessed for reactive oxygen species measurement, histopathological analysis, immunohistochemical, gene and protein expressions for the nuclear factor erythroid 2-related factor 2 (Nrf2), p53 and Silent information regulator 2 homolog 1 (SIRT1). Our results show that melatonin coadministration diminished Dox induced hippocampal and prefrontal cortex (PFC) cellular degeneration. It alleviated Nitric Oxide (NO) level and reversed the decline of antioxidant enzyme activities. It also upregulated Nrf2, SIRT1 and downregulated p53 gene expression in rats receiving Dox. Moreover, melatonin elevated the protein expression level of Nrf2, SIRT1 and reduced p53 corresponding to immunohistochemical results. The data suggested that melatonin can mitigate Dox-induced neurotoxicity by aggravating the endogenous antioxidants and inducing neurogenesis through activation of Nrf2/p53-SIRT1signaling pathway in adult rats' PFC. These effects were associated with Nrf2, SIRT1 activation and p53 inhibition. This could be guidance to add melatonin as an adjuvant supplement to Dox regimens to limit its adverse effect on the brain function.
癌症是一个严重的健康问题，化疗是根除癌症的必要手段。然而，像阿霉素（Dox）这样的化疗药物有严重的副作用，包括认知障碍或化疗脑。褪黑素是一种具有抗氧化和抗炎作用的神经保护剂。我们旨在探索褪黑素对阿霉素诱导的化疗脑的影响，以发现与阿霉素诱导的神经毒性相关的新机制，并试图预防其发生。32只雄性白化大鼠被平均分为四组：对照组、褪黑素给药组、阿霉素诱导的化疗脑组和褪黑素+阿霉素治疗组。在第9天，处死大鼠后取出大脑，评估活性氧测量、组织病理学分析、免疫组织化学、核因子红细胞2相关因子2（Nrf2）、p53和沉默信息调节因子2同源物1（SIRT1）的基因和蛋白表达。我们的结果表明，联合使用褪黑素可减少阿霉素诱导的海马体和前额叶皮质（PFC）细胞变性。它降低了一氧化氮（NO）水平，逆转了抗氧化酶活性的下降。在接受阿霉素的大鼠中，它还上调了Nrf2、SIRT1并下调了p53基因表达。此外，褪黑素提高了Nrf2、SIRT1的蛋白表达水平，并降低了与免疫组织化学结果相对应的p53水平。数据表明，褪黑素可以通过增强内源性抗氧化剂和通过激活成年大鼠PFC中的Nrf2/p53-SIRT1信号通路诱导神经发生来减轻阿霉素诱导的神经毒性。这些作用与Nrf2、SIRT1激活和p53抑制有关。这可以为在阿霉素治疗方案中添加褪黑素作为辅助补充剂以限制其对脑功能的不良影响提供指导。
