Jóźwiak-Bębenista Marta, Wiktorowska-Owczarek Anna, Siatkowska Małgorzata, Komorowski Piotr, Włodarczyk Aneta, Kowalczyk Edward, Sokołowska Paulina
Department of Pharmacology and Toxicology, Medical University of Lodz, Zeligowskiego 7/9, 90-752 Lodz, Poland.
Laboratory of Molecular and Nanostructural Biophysics, Bionanopark, Dubois 114/116, 93-465 Lodz, Poland.
Cells. 2025 Jun 3;14(11):831. doi: 10.3390/cells14110831.
Despite affecting millions worldwide, major depressive disorder (MDD) remains a therapeutic challenge, with approximately one-third of patients failing to respond to standard treatments. The need for innovative, molecularly driven therapies has turned attention to ketamine and its enantiomers. While S-ketamine is clinically approved for treatment-resistant depression (TRD), it has various psychoactive side effects and potential for abuse. Hence, it is necessary to identify alternative compounds, such as R-ketamine, and their metabolites (e.g., 2S,6S-hydroxynorketamine and 2R,6R-hydroxynorketamine, collectively referred to as HNKs). Emerging evidence suggests that the pathophysiology of MDD involves two processes regulated by the unfolded protein response (UPR): endoplasmic reticulum (ER) stress and neuroinflammation. As such, they represent promising therapeutic targets. The study provides the first direct comparison of ketamine enantiomers and their metabolites in modulating ER stress and inflammatory signaling in human microglial cells (HMC3), which play key roles in neuroimmune communication. Both S-ketamine and R-ketamine, along with their metabolites, significantly reduced both the expression and protein levels of CHOP and GRP78-two critical UPR components-under tunicamycin-induced ER stress conditions. Additionally, the compounds significantly decreased IL-6 levels and, to a lesser extent, IL-8 levels in lipopolysaccharide (LPS)-stimulated microglia, indicating anti-inflammatory potential. Taken together, these findings highlight a novel glia-targeted mechanism by which ketamine and its metabolites modulate ER stress and neuroinflammation. CHOP and GRP78 appear to be stress-responsive molecular markers within the UPR pathway. These results justify further in vivo validation and support the development of antidepressants with fewer psychoactive effects.
尽管重度抑郁症（MDD）影响着全球数百万人，但它仍然是一个治疗难题，约有三分之一的患者对标准治疗无反应。对创新的、分子驱动疗法的需求已将注意力转向氯胺酮及其对映体。虽然S-氯胺酮已被临床批准用于治疗抵抗性抑郁症（TRD），但它有各种精神活性副作用和滥用潜力。因此，有必要识别替代化合物，如R-氯胺酮及其代谢物（例如，2S,6S-羟基去甲氯胺酮和2R,6R-羟基去甲氯胺酮，统称为HNKs）。新出现的证据表明，MDD的病理生理学涉及由未折叠蛋白反应（UPR）调节的两个过程：内质网（ER）应激和神经炎症。因此，它们是有前景的治疗靶点。该研究首次直接比较了氯胺酮对映体及其代谢物在调节人小胶质细胞（HMC3）中ER应激和炎症信号传导方面的作用，HMC3在神经免疫通讯中起关键作用。在衣霉素诱导的ER应激条件下，S-氯胺酮和R-氯胺酮及其代谢物均显著降低了CHOP和GRP78（两个关键的UPR成分）的表达和蛋白水平。此外，这些化合物在脂多糖（LPS）刺激的小胶质细胞中显著降低了IL-6水平，并在较小程度上降低了IL-8水平，表明具有抗炎潜力。综上所述，这些发现突出了一种新的针对胶质细胞的机制，通过该机制氯胺酮及其代谢物调节ER应激和神经炎症。CHOP和GRP78似乎是UPR途径中的应激反应分子标志物。这些结果证明了进一步进行体内验证的合理性，并支持开发具有较少精神活性作用的抗抑郁药。
