Abstract

Metal dyshomeostasis in the brain is a key feature of many neuropathologies, including hypoxic and traumatic injury and chronic conditions such as Alzheimer’s and Parkinson’s disease. Ferroptosis is a form of cell death driven by the intracellular accumulation of iron. This is primarily characterised by a loss in endogenous antioxidant capacity and uncontrolled lipid peroxidation. Ferroptosis has been reported to underlie the pathology associated with several neurological and neurodegenerative conditions and has, therefore, become an attractive target for therapeutic intervention. Salicylaldehyde benzoylhydrazone (SBH) is a specialised hydrazone agent, known for its antibacterial and anticancer properties. It has robust metal-chelating capacity, with a particular affinity for complexing with iron and copper. The current study sought to investigate the potential of SBH to act as an anti-ferroptotic agent and to alleviate the neurotoxic and dysfunctional consequences of iron overload. We demonstrate that SBH can alleviate the death of HT22 hippocampal neurons, induced by exposure to the iron donor, ferric ammonium citrate (FAC). This was accompanied by a reduction in intracellular iron and lipid peroxidation, and alleviation of hallmark changes in gene expression indicative of ferroptosis. Using FAC-incubated zebrafish larvae as an in vivo model of iron overload, we reveal that SBH can reduce the mortality and toxicity associated with FAC exposure. Moreover, we report a FAC-mediated dysfunction in intrinsic sensorimotor reflex behaviour, which is restored by SBH. Taken together, our findings highlight SBH as an anti-ferroptotic agent and support its further investigation as a potential neurotherapeutic for conditions associated with iron dysregulation.

Keywords

Ferric ammonium citrate, HT22 cells, Iron overload, Lipid peroxidation, Schiff base, Zebrafish larvae

Publication Date

2025-01-01

Publication Title

Journal of Molecular Neuroscience

Volume

75

Issue

2

ISSN

0895-8696

Deposit Date

2026-05-06

Funding

Open Access funding provided by the IReL Consortium. This work was supported by Taighde Éireann grant agreement GOIPG/2024/3286. A portion of the work was supported by the European Union’s Horizon 2020 Marie Skłodowska-Curie Actions research and innovation programme under grant agreement ID 101007931. This publication has emanated from research supported (in part) by the UCD STEM Challenge Fund. Data is contained within the article and supplementary information

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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