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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]