Kim Seon-Hyeok, Hong Seong-Min, Ko Eun-Ji, Park Min-Jeong, Kim Ji-Youn, Kim Sun-Yeou
College of Pharmacy and Institute of Pharmaceutical Science, Gachon University, Incheon 21936, Republic of Korea.
Department of Exercise Rehabilitation, Gachon University, Incheon 21936, Republic of Korea.
Nutrients. 2025 Apr 30;17(9):1548. doi: 10.3390/nu17091548.
Methylglyoxal (MGO), a reactive dicarbonyl compound, has been implicated in the formation of advanced glycation end-products (AGEs) and neuronal dysfunction. This study investigated the neuroprotective effects of the combination of trans-resveratrol and hesperidin (tRES-HESP) against MGO-induced neurotoxicity, focusing on memory dysfunction and depression-like behavior.
Neuroblastoma 2a (N2a) cells were treated with MGO to induce neurotoxicity. The effects of tRES-HESP on cell viability, reactive oxygen species (ROS) production, apoptotic markers (BAX/Bcl 2 ratio, caspase 3 activity, and poly [ADP ribose] polymerase cleavage), and components of the glyoxalase system (glyoxalase-1, glyoxalase- 2, and receptors for AGEs) were assessed. The activation of the Kelch-like ECH-associated protein 1/Nuclear factor erythroid-2-related factor 2/Heme oxygenase-1 (Keap1/Nrf2/HO-1) pathway was also evaluated. In vivo, mice with MGO-induced depressive amnesia were treated with tRES-HESP (200 mg/kg) for eight weeks, and behavioral, biochemical, and histological assessments were performed.
tRES-HESP significantly reduced MGO-induced cytotoxicity, ROS production, and apoptosis in N2a cells. In addition, it restored the glyoxalase system and activated the Keap1/Nrf2/HO-1 pathway. In an in vivo model, tRES-HESP improved memory and depression-like behaviors, reduced cortisol and interleukin (IL)-6 levels, increased IL-10 levels, and lowered the expression of amyloid precursor protein and amyloid beta. Furthermore, tRES-HESP protected CA2/3 hippocampal subregions from MGO-induced damage. tRES-HESP exhibited neuroprotective effects through antioxidant, anti-apoptotic, and anti-inflammatory mechanisms.
Our results suggest that tRES-HESP is a potential dietary supplement for preventing cognitive decline and depression, particularly in neurodegenerative conditions such as Alzheimer's disease. Further studies are required to assess its clinical relevance and efficacy in the human population.
甲基乙二醛（MGO）是一种活性二羰基化合物，与晚期糖基化终产物（AGEs）的形成及神经元功能障碍有关。本研究调查了反式白藜芦醇和橙皮苷组合（tRES-HESP）对MGO诱导的神经毒性的神经保护作用，重点关注记忆功能障碍和抑郁样行为。
用MGO处理神经母细胞瘤2a（N2a）细胞以诱导神经毒性。评估tRES-HESP对细胞活力、活性氧（ROS）生成、凋亡标志物（BAX/Bcl 2比值、半胱天冬酶3活性和聚[ADP核糖]聚合酶裂解）以及乙二醛酶系统成分（乙二醛酶-1、乙二醛酶-2和AGEs受体）的影响。还评估了 Kelch样ECH相关蛋白1/核因子红细胞2相关因子2/血红素加氧酶-1（Keap1/Nrf2/HO-1）途径的激活情况。在体内，用tRES-HESP（200 mg/kg）对MGO诱导的抑郁性失忆小鼠进行八周治疗，并进行行为、生化和组织学评估。
tRES-HESP显著降低了MGO诱导的N2a细胞毒性、ROS生成和凋亡。此外，它恢复了乙二醛酶系统并激活了Keap1/Nrf2/HO-1途径。在体内模型中，tRES-HESP改善了记忆和抑郁样行为，降低了皮质醇和白细胞介素（IL）-6水平，提高了IL-10水平，并降低了淀粉样前体蛋白和淀粉样β的表达。此外，tRES-HESP保护CA2/3海马亚区免受MGO诱导的损伤。tRES-HESP通过抗氧化、抗凋亡和抗炎机制发挥神经保护作用。
我们的结果表明，tRES-HESP是一种潜在的膳食补充剂，可预防认知能力下降和抑郁症，尤其是在阿尔茨海默病等神经退行性疾病中。需要进一步研究以评估其在人群中的临床相关性和疗效。
