Quincozes-Santos André, Bobermin Larissa Daniele, Tramontina Ana Carolina, Wartchow Krista Minéia, Da Silva Vanessa-Fernanda, Gayger-Dias Vitor, Thomaz Natalie K, de Moraes Aline Daniel Moreira, Schauren Daniele, Nardin Patrícia, Gottfried Carmem, Souza Diogo Onofre, Gonçalves Carlos-Alberto
Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Neurotox Res. 2025 Jan 27;43(1):7. doi: 10.1007/s12640-025-00730-w.
Resveratrol, a natural polyphenol, has shown promising neuroprotective effects in several in vivo and in vitro experimental models. However, the mechanisms by which resveratrol mediates these effects are not fully understood. Glutamate is the major excitatory neurotransmitter in the brain; however, excessive extracellular glutamate levels can affect neural activity in several neurological diseases. Astrocytes are the glial cells that maintain brain homeostasis and can attenuate excitotoxicity by actively participating in glutamate neurotransmission. This study aimed to investigate the glioprotective effects of resveratrol against glutamate-induced cellular dysfunction in hippocampal slices and primary astrocyte cultures, with a focus on the role of heme-oxygenase 1 (HO-1). Glutamate impaired glutamate uptake activity through a glutamate receptor-dependent mechanism, in addition to altering other important astroglial parameters, including glutamine synthetase activity, glutathione levels and cystine uptake, which were normalized by resveratrol. Resveratrol also prevented glutamate-induced disruption in antioxidant defenses, as well as in trophic and inflammatory functions, including the nuclear factor κB (NFκB) transcriptional activity. Most of the effects of resveratrol, mainly in astrocytes, were dependent on the HO-1 signaling pathway, as they were abrogated when HO-1 was pharmacologically inhibited. Resveratrol also increased HO-1 mRNA expression and its transcriptional regulator, nuclear factor erythroid-derived 2-like 2 (Nrf2). Finally, resveratrol prevented glutamate-induced p21 senescence marker, indicating an anti-aging effect. Therefore, we demonstrated that the activation of the Nrf2/HO-1 system in astrocytes by resveratrol represents an astrocyte-targeted neuroprotective mechanism in neurodegeneration, with glutamate excitotoxicity, oxidative stress, and neuroinflammation as common neurochemical alterations.
白藜芦醇是一种天然多酚，在多种体内和体外实验模型中均显示出有前景的神经保护作用。然而，白藜芦醇介导这些作用的机制尚未完全明确。谷氨酸是大脑中的主要兴奋性神经递质；然而，细胞外谷氨酸水平过高会在多种神经系统疾病中影响神经活动。星形胶质细胞是维持大脑内环境稳态的神经胶质细胞，可通过积极参与谷氨酸神经传递来减轻兴奋性毒性。本研究旨在探讨白藜芦醇对海马脑片和原代星形胶质细胞培养物中谷氨酸诱导的细胞功能障碍的神经胶质保护作用，重点关注血红素加氧酶1（HO-1）的作用。谷氨酸通过依赖谷氨酸受体的机制损害谷氨酸摄取活性，此外还改变了其他重要的星形胶质细胞参数，包括谷氨酰胺合成酶活性、谷胱甘肽水平和胱氨酸摄取，而白藜芦醇可使其恢复正常。白藜芦醇还可预防谷氨酸诱导的抗氧化防御以及营养和炎症功能的破坏，包括核因子κB（NFκB）转录活性。白藜芦醇的大多数作用，主要在星形胶质细胞中，依赖于HO-1信号通路，因为当HO-1受到药理抑制时这些作用会被消除。白藜芦醇还增加了HO-1 mRNA表达及其转录调节因子核因子红细胞2相关因子2（Nrf2）。最后，白藜芦醇可预防谷氨酸诱导的p21衰老标志物，表明其具有抗衰老作用。因此，我们证明白藜芦醇在星形胶质细胞中激活Nrf2/HO-1系统代表了神经退行性变中一种以星形胶质细胞为靶点的神经保护机制，谷氨酸兴奋性毒性、氧化应激和神经炎症是常见的神经化学改变。
