Illuminating the Function of the Hydroxyl Radical in the Brains of Mice with Depression Phenotypes by Two‐Photon Fluorescence Imaging

Abstract

Depression is intimately linked with oxidative stress. As one of the most reactive and oxidative reactive oxygen species that is overproduced during oxidative stress,t he hydroxyl radical (COH) can cause macromolecular damage and subsequent neurological diseases.However,due to the high reactivity and lowconcentration of COH, precise exploration of COH in brains remains ac hallenge.T he two-photon fluorescence probe MD-B was developed for in situ COH imaging in living systems.T his probe achieves exceptional selectivity towards COH through the one-electron oxidation of 3-methylpyrazolone as an ew specific recognition site.M D-B can be used to map COH in mouse brain, therebyr evealing that increased COH is positively correlated with the severity of depression phenotypes.F urthermore, COH has been shown to inactivate deacetylase SIRT1,therebyleading to the occurrence and development of depression phenotypes.T his work provides anew strategy for the future treatment of depression.Depression as one of the most common and disabling mental disorders,w ith aw orldwide prevalence of approximately 17 %. [1] However,u nderstanding of the pathophysiology of depression is still rudimentary due to its complex aetiology. [2] Previous findings suggest that oxidative stress contributes to the pathogenesis of depression. [3][4][5] Theh ydroxyl radical (COH) is one of the most reactive and oxidative reactive oxygen species (ROS) that is overproduced during oxidative stress. [6] Excess COH leads to irreparable damage to neural cells and potentially even to neurological disease. [7] Therefore,t here is an urgent need to develop an effective means for tracing COH in living brain to define the relationship between depression and COH levels.Recently,f luorescence imaging has become ar obust approach for real-time monitoring of molecular events in living cells and in vivo because of its non-destructive nature and spatiotemporal resolution. [8][9][10] Fluorescent probes have been developed to reveal the biological functions of COH in living cells,i nz ebrafish, and in the abdomens of mice. [11][12][13][14][15][16][17][18][19] Given the very high reactivity and low concentration of COH and the particularly complicated construction of the brain, two-photon (TP) fluorescence imaging is the most appropriate for brain imaging because it provides ah igher signal-tobackground ratio,d eeper tissue imaging, higher spatialtemporal resolution, and less specimen photodamage than one-photon (OP) fluorescence imaging. [20][21][22][23] Molecular fluorescent probes have some appealing performance characteristics in terms of stability,ease of crossing of the blood-brain barrier (BBB), and easy excretion, which is preferable for the TP in situ imaging of COH in the brains of living mice with depression-like behaviours.However,suitable TP fluorescent probes for brain imaging of COH with specificity,h igh sensitivity,and instantaneous response are still scarce.Inspired by the specific one-electron oxidation reaction between COH and 3-methyl-pyrazolone in the...

Fluorescent small organic probes for biosensing

“…One such class of analytes are reactive oxygen species (ROS), which are associated with oxidative stress and as a result received much attention in the world of fluorescent probes for biological applications. 58,59 In 2019, a TP fluorescent probe for the detection of the ROS hydroxyl radical ( • OH) was developed by Tang et al 60 It is known that • OH can cause oxidative damage, which has been suggested to contribute to the pathogenesis of depression. The authors proposed that live monitoring of • OH in the brain is key to understanding this relationship, and of all the bioimaging tools two photon microscopy (TPM) would be the most advantageous.…”

Two-photon small-molecule fluorescence-based agents for sensing, imaging, and therapy within biological systems

“…The TP turn-on probe 61 based on coumarin (Cou151) bearing a trifluoromethyl group as the TP reporter was developed to image in situ brain OH (Scheme 25). 34 With probe 61, 3-methyl-pyrazolone was chosen as the specific reaction site for OH. The one-electron oxidation reaction between OH and 3-methyl-pyrazolone, cleaved the electronwithdrawing ring and restored the push-pull electron effect of the coumarin ring.…”

Generation of hydroxyl radical-activatable ratiometric near-infrared bimodal probes for early monitoring of tumor response to therapy

“…In the past few decades, several analytical methods, including electron spin resonance (ESR) spectroscopy 22 , 23 , ultraviolet–visible (UV–vis) chromatography 24 , and fluorescence (FL) imaging 25 – 29 , have been devoted for the detection of •OH. Among them, FL imaging of •OH has attracted tremendous attention due to the advantage of high sensitivity, easy operation, rapid acquirement, and minimum invasiveness 30 – 32 .…”