Bellver-Sanchis Aina, Ribalta-Vilella Marta, Lillo Jaume, Ortuño-Sahagún Daniel, Franco Rafael, Pallàs Mercè, Navarro Gemma, Griñán-Ferré Christian
Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain.
Facultat de Farmàcia i Ciències de l'Alimentació or Facultat de Biologia (Depending on the Faculty You Are Registered with), Universitat de Barcelona, Avda. Diagonal 643, 08028 Barcelona, Spain.
Neurotherapeutics. 2025 Sep;22(5):e00616. doi: 10.1016/j.neurot.2025.e00616. Epub 2025 May 31.
Epigenetic alterations are key contributors to Alzheimer's disease (AD), driving age-related cognitive decline. This study explores the combined neuroprotective effects of G9a histone methyltransferase inhibition (via UNC0642) and cannabinoid receptor activation (CB1R: ACEA; CB2R: JWH133) in AD models. We used HEK-293T cells and hippocampal neurons to demonstrate that G9a inhibition selectively enhances CB1R-mediated ERK/cAMP signaling. In SAMP8 mice (sporadic AD model), we evaluated the effects of pharmacological inhibition of G9a (UNC0642), combined with CBR agonism (ACEA) and/or CBR agonism (JWH133), on cognitive recovery, neuronal morphology, and neuroinflammation. Our results demonstrated that SAMP8 mice treated with UNC0642 and ACEA exhibited significant recovery in short-term memory, as assessed by the Novel Object Recognition Test (NORT), and complete recovery of spatial memory in the Object Location Test (OLT). These improvements were accompanied by enhanced neuronal morphology (increased dendritic length and density) and reduced neuroinflammation markers, suggesting a synergistic effect of G9a inhibition and CBR activation. Importantly, JWH133 treatment, both alone and in combination with UNC0642, resulted in a pronounced reduction of neuroinflammatory markers (Trem2, Cd33, iNOS) and a significant restoration of dendritic spine density and branching length, with the dual treatment showing the most robust effects. JWH133 alone produced moderate cognitive improvement, but its combination with G9a inhibition led to outcomes comparable to those of control animals. Thus, the results underscore G9a inhibition's potential to amplify cannabinoid receptor-mediated neuroprotection while mitigating psychoactive risks, offering a promising multi-target approach for neurodegenerative diseases.
表观遗传改变是阿尔茨海默病（AD）的关键促成因素，推动与年龄相关的认知衰退。本研究探讨了在AD模型中，G9a组蛋白甲基转移酶抑制（通过UNC0642）和大麻素受体激活（CB1R：ACEA；CB2R：JWH133）的联合神经保护作用。我们使用HEK - 293T细胞和海马神经元来证明G9a抑制选择性增强CB1R介导的ERK/cAMP信号传导。在SAMP8小鼠（散发性AD模型）中，我们评估了G9a的药理学抑制（UNC0642）与CBR激动剂（ACEA）和/或CBR激动剂（JWH133）联合对认知恢复、神经元形态和神经炎症的影响。我们的结果表明，用UNC0642和ACEA处理的SAMP8小鼠在通过新物体识别测试（NORT）评估的短期记忆中表现出显著恢复，并且在物体位置测试（OLT）中空间记忆完全恢复。这些改善伴随着神经元形态的增强（树突长度和密度增加）和神经炎症标志物的减少，表明G9a抑制和CBR激活具有协同作用。重要的是，单独使用JWH133治疗以及与UNC0642联合使用，均导致神经炎症标志物（Trem2、Cd33、iNOS）显著降低，树突棘密度和分支长度显著恢复，联合治疗显示出最强的效果。单独使用JWH133产生了适度的认知改善，但其与G9a抑制的联合导致的结果与对照动物相当。因此，结果强调了G9a抑制在放大大麻素受体介导的神经保护作用同时减轻精神活性风险方面的潜力，为神经退行性疾病提供了一种有前景的多靶点方法。
