2. Academic Validation
  3. Vitamin K-Trolox synergism realized in hybrid neuroprotectant with potent anti-ferroptosi/oxytosis activity, reduced toxicity, and in vivo efficacy in Alzheimer's disease mouse model

Vitamin K-Trolox synergism realized in hybrid neuroprotectant with potent anti-ferroptosi/oxytosis activity, reduced toxicity, and in vivo efficacy in Alzheimer's disease mouse model

  • Eur J Med Chem. 2025 Dec 5:299:118068. doi: 10.1016/j.ejmech.2025.118068.
Feng He 1,  Julian Hofmann 2,  Eleonora Poeta 3,  Barbara Monti 4,  Lucie Crouzier 5,  Tangui Maurice 5,  Michael Decker 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; Julius-Maximilians-Universität Würzburg (JMU), Institut für Pharmazie und Lebensmittelchemie, Pharmazeutische und Medizinische Chemie, Am Hubland, 97074, Würzburg, Germany.
  • 2 Julius-Maximilians-Universität Würzburg (JMU), Institut für Pharmazie und Lebensmittelchemie, Pharmazeutische und Medizinische Chemie, Am Hubland, 97074, Würzburg, Germany.
  • 3 Department of Pharmacy and Biotechnology, University of Bologna, Via Selmi 3, 40126, Bologna, Italy.
  • 4 Department of Pharmacy and Biotechnology, University of Bologna, Via Selmi 3, 40126, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, 40139 Bologna, Italy.
  • 5 MMDN, Univ Montpellier, EPHE, INSERM, Montpellier, France.
  • 6 Julius-Maximilians-Universität Würzburg (JMU), Institut für Pharmazie und Lebensmittelchemie, Pharmazeutische und Medizinische Chemie, Am Hubland, 97074, Würzburg, Germany. Electronic address: michael.decker@uni-wuerzburg.de.
PMID: 40839917 DOI: 10.1016/j.ejmech.2025.118068
Abstract

In pursuit of developing advanced neuroprotective agents for neurodegenerative disorders, we rationally designed a series of novel hybrid molecules through structural integration of a vitamin K derivative with well-known Antioxidants (ferulic acid, melatonin, α-lipoic acid, and Trolox, respectively). Systematic pharmacological evaluation revealed that most hybrids exhibited superior antioxidant activity in both DPPH radical scavenging and ORAC assays. Among these, a Trolox-vitamin K conjugate (compound 16e) emerged as a promising compound, demonstrating exceptional neuroprotective efficacy across multiple neuronal injury models, including oxytosis, Ferroptosis, and ATP depletion in HT22 hippocampal neurons. Mechanistic studies confirmed that this compound preserved synergistic cytoprotective effects of its parent pharmacophores against Ferroptosis while concurrently exhibiting immunomodulatory activity in microglial cells. Notably, it significantly ameliorated Aβ25-35-induced cognitive deficits in a murine Alzheimer's disease model at a very low dose (0.1 mg/kg, i.p.), outperforming conventional neuroprotectants in therapeutic potency. These findings position this Trolox/vitamin K hybrid molecule as a neuroprotective candidate with translational potential for treating neurodegenerative pathologies.

Keywords

Alzheimer's disease; Ferroptosis; Oxytosis; Trolox; Vitamin K.

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