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Targeting CB2 receptor with a novel antagonist reverses cognitive decline, neurodegeneration and pyroptosis in a TAU-dependent frontotemporal dementia mouse model

Article

作者: López, Manuela G ; Páez, Juan Antonio ; Campillo, Nuria ; Lastres-Becker, Isabel ; Sastre, Eric Del ; Silva-Llanes, Ignacio ; González-Naranjo, Pedro ; Rodríguez-López, Silvia

Frontotemporal dementia (FTD) comprises a group of disorders characterized by a progressive decline in behavior or language linked to the degeneration of the frontal and anterior temporal lobes followed by hippocampal atrophy. There are no effective treatments for FTD and for this reason, novel pharmacological targets, such as the endocannabinoid system (ECS), are being explored. Previous results from our laboratory showed a TAU^P301L-dependent increase in CB₂ receptor expression in hippocampal neurons of a FTD mouse model, alongside the neuroprotective impact of CB₂ ablation. In this study, we evaluated the therapeutic potential of a new CB₂ antagonist (PGN36) in our TAU-dependent FTD mouse model. Six-month-old mice received stereotaxic injections of an adeno-associated virus expressing human TAU^P301L protein (AAV-TAU^P301L) into the right hippocampus and were treated daily with PGN36 (5 mg/kg, i.p.) or vehicle for three weeks. By integrating behavioral tests, RNA-seq, qPCR expression analysis, and immunofluorescence in the AAV expressing TAU mouse model, we found that PGN36 treatment reverses key features of the neurodegenerative process triggered by TAU^P301L overexpression. PGN36 treatment effectively countered TAU^P301L-induced cognitive decline by reducing TAU protein expression levels and restoring markers of synaptic plasticity. Notably, we observed neuroprotection in the dentate gyrus granular layer, which we attribute to the modulation of pyroptosis. This programmed cell death pathway, is triggered by TAU^P301L overexpression. PGN36 appears to modulate the pyroptotic cascade, thereby preventing the pyroptosis-induced neuronal loss. These findings collectively underscore the neuroprotective potential of this novel CB₂ antagonist treatment against TAU-associated FTD.

2025-05-01·European Journal of Medicinal Chemistry

Exploring the broad-spectrum activity of carbohydrate-based Iberin analogues: From anticancer effect to antioxidant properties

Article

作者: Valdivia, V ; Nogueira, J J ; Prieto, L A ; León, R ; Calderón-Montaño, J M ; Recio, R ; López-Lázaro, M ; Fernández, I ; Khiar-Fernández, N ; Lucía-Tamudo, J ; Moreno, N

Iberin is a lower homologue of sulforaphane (SFN) which has shown effectiveness in addressing various pathologies, including its anti-inflammatory properties, antitumor activity against various cancers, and antimicrobial effects. Building on this activity, a series of carbohydrate-based analogues of the natural isothiocyanate (ITC) iberin were synthesized, and their anticancer and antioxidant activities were evaluated. Cytotoxicity studies on three cancer cell lines using Resazurin assay demonstrated significant cytotoxic activity, particularly against bladder cancer. The sulfonyl derivatives exhibited the most potent effects, with IC₅₀ values comparable to those of reference natural isothiocyanates (from 10 to 20 μM). Computational simulations support the hypothesis that carbohydrate-based ITCs can interact with STAT3's SH2 domain in a manner similar to SFN, laying the groundwork for their potential development as STAT3-targeted anticancer agents. The antioxidant potential of these compounds was assessed by their ability to activate the Nrf2 factor, yielding CD values (concentration required to double luciferase activity compared to basal conditions) between 1.55 and 10.36 μM, without cytotoxicity at these concentrations. Notably, the phenylsulfone derivative 22β displayed slightly higher or comparable antioxidant activity to that of natural isothiocyanates. Based on these findings, this phenylsulfone analogue was selected as the optimal compound due to its dual anticancer and antioxidant activities. An additional advantage of this carbohydrate-based ITC is that it is a solid compound, making it easier to handle than natural isothiocyanates, which are typically liquids.

2025-04-01·Redox Biology

Health position paper and redox perspectives – Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases

Review

作者: Rojo, Ana I ; Kensler, Thomas W ; Manda, Gina ; Dinkova-Kostova, Albena T ; López, Manuela G ; Yamamoto, Masayuki ; Fernández-Ginés, Raquel ; Motohashi, Hozumi ; León, Rafael ; Valverde, Ángela M ; Bach, Anders ; Moerland, Jessica A ; Liby, Karen T ; Sykiotis, Gerasimos P ; Levonen, Anna-Liisa ; Cazalla, Eduardo ; Taguchi, Keiko ; Grochot-Przeczek, Anna ; Bathish, Boushra ; Hakomäki, Henriikka ; DeNicola, Gina M ; Hayes, John D ; Cuadrado, Antonio ; Naidu, Sharadha Dayalan ; Shivakumar, Akshatha Kalavathi

Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-activated transcription factor regulating cellular defense against oxidative stress, thereby playing a pivotal role in maintaining cellular homeostasis. Its dysregulation is implicated in the progression of a wide array of human diseases, making NRF2 a compelling target for therapeutic interventions. However, challenges persist in drug discovery and safe targeting of NRF2, as unresolved questions remain especially regarding its context-specific role in diseases and off-target effects. This comprehensive review discusses the dualistic role of NRF2 in disease pathophysiology, covering its protective and/or destructive roles in autoimmune, respiratory, cardiovascular, and metabolic diseases, as well as diseases of the digestive system and cancer. Additionally, we also review the development of drugs that either activate or inhibit NRF2, discuss main barriers in translating NRF2-based therapies from bench to bedside, and consider the ways to monitor NRF2 activation in vivo.

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