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Imbalanced iron homeostasis plays a crucial role in neurological diseases, yet direct imaging evidence revealing the distribution of active ferrous iron (Fe2+) in the living brain remains scarce. Here, we present a near-infrared excited two-photon fluorescent probe (FeP) for imaging changes of Fe2+ flux in the living epileptic mouse brain. In vivo 3D two-photon brain imaging with FeP directly revealed abnormal elevation of Fe2+ in the epileptic mouse brain. Moreover, we found that dihydroartemisinin (DHA), a lead compound discovered through probe-based high-throughput screening, plays a critical role in modulating iron homeostasis. In addition, we revealed that DHA might exert its antiepileptic effects by modulating iron homeostasis in the brain and finally inhibiting ferroptosis. This work provides a reliable chemical tool for assessing the status of ferrous iron in the living epileptic mouse brain and may aid the rapid discovery of antiepileptic drug candidates. [Display omitted] • FeP, a fluorescent probe, is suitable for brain imaging ferrous iron flux in vivo • 3D two-photon imaging reveals elevation of ferrous iron in the epileptic mouse brain • Dihydroartemisinin (DHA) can modulate iron homeostasis in the epileptic mouse • DHA exhibits a potential antiepileptic effect in the epileptic mouse model Shao et al. develop a near-infrared excited two-photon fluorescent probe for imaging ferrous iron (Fe2+) in brain. Using in vivo 3D two-photon imaging, they observe abnormal elevation of Fe2+ in the epileptic mouse brain and demonstrate that dihydroartemisinin exhibits antiepileptic effects by modulating iron homeostasis in the mouse brain. [ABSTRACT FROM AUTHOR]

Epilepsy is a chronic neurodegenerative disease, and accumulating evidence suggests its pathological progression is closely associated with peroxynitrite (ONOO−). However, understanding the function remains challenging due to a lack of in vivo imaging probes for ONOO− determination in epileptic brains. Here, the first near‐infrared imaging probe (named ONP) is presented for tracking endogenous ONOO− in brains of kainate‐induced epileptic seizures with high sensitivity and selectivity. Using this probe, the dynamic changes of endogenous ONOO− fluxes in epileptic brains are effectively monitored with excellent temporal and spatial resolution. In vivo visualization and in situ imaging of hippocampal regions clearly reveal that a higher concentration of ONOO− in the epileptic brains associates with severe neuronal damage and epileptogenesis; curcumin administration can eliminate excessively increased ONOO−, further effectively protecting neuronal cells. Moreover, by combining high‐content analysis and ONP, a high‐throughput screening method for antiepileptic inhibitors is constructed, which provides a rapid imaging/screening approach for understanding epilepsy pathology and accelerating antiseizure therapeutic discovery. [ABSTRACT FROM AUTHOR]

Hydrogen polysulfide (H 2 S n , n > 1), a member of reactive sulfur species (RSS), is primarily generated during the crosstalk between H 2 S and reactive oxygen species (ROS), which plays important role in physiological and pathological processes. Ferroptosis is a new non-classical mode of cell death, in which ROS-associated lipid peroxidation and iron-dependent accumulation are the main features. However, the biological effects of H 2 S n on ferroptosis and the detailed mechanisms of action remain poorly understood. Thus, there is an urgent need to develop highly selective and sensitive chemical tools for monitoring H 2 S n in living cells. Herein, we develop a two-photon fluorescent probe (PSP) for specifically imaging H 2 S n in live cells and tumor spheroids. This probe exhibited a sensitive and selective response to H 2 S n , which had been used for imaging exogenous and endogenous H 2 S n in living cells by confocal imaging and high content imaging. PSP exhibits excellent photo-stability and two-photon imaging performance when irradiating at 880 nm in 3D HeLa multicellular tumor spheroids. Importantly, our studies revealed that H 2 S n levels were significantly up-regulated during ferroptosis. These excellent properties ensure that PSP is a promising two-photon probe for exploring the biological and pathological effects of H 2 S n during ferroptosis. [Display omitted] • A two-photon fluorescent probe, PSP, was developed for monitoring of H 2 S n. • PSP exhibited high specificity and sensitivity to H 2 S n. • PSP can be used to detect the up-regulation of H 2 S n during ferroptosis in living cells. • PSP can be applied for imaging of endogenous H 2 S n in HeLa MCTSs. [ABSTRACT FROM AUTHOR]