Abstract
Matrix metalloproteinases (MMPs) exert a dual effect in ischemic stroke and thus represent an ideal target for detection and therapy. However, to date, all clinical trials of MMP inhibitors have failed, and alternative drug candidates and therapeutic targets are urgently required. Nonetheless, further investigations are limited by the lack of non-invasive imaging techniques. Here, we report a novel, fast and ultrasensitive MMP activatable optical imaging probe for the dynamic visualization of MMP activity in photothrombotic stroke mice. This probe provides a significant signal enhancement in as little as 15 min, with the highest signal intensity occurring at 1 h post-injection, and shows high sensitivity in measuring MMP activity alterations, which makes it specifically suitable for the real-time visualization of MMP activity and drug discovery in preclinical research. Moreover, using this probe, we successfully demonstrate that the regulation of the p38 mitogen-activated protein kinase (MAPK) signal pathway is capable of modulating MMP activity after stroke, revealing a novel regulatory mechanism of postischemic brain damage and overcoming the limitations of traditional therapeutic strategies associated with MMP inhibitors by using a non-invasive molecular imaging method.
Highlights
Stroke is one of the leading causes of death and disability worldwide, very few therapeutic measures and drugs are available to treat this disease[1,2]
The probe remained in a quenched state until it was degraded by activated Matrix metalloproteinases (MMPs) under pathophysiological conditions and emitted intense fluorescent signals
Phosphorylated-p38 mitogen-activated protein kinase (MAPK) (p-p38) levels were significantly increased from days 2 to 14 after stroke (Fig. 5B), and the ratio of p-p38 to total-p38 (p-p38/total-p38 MAPK (T-p38)) was significantly correlated with increased MMP-9 expression (R2 = 0.6176, P = 0 .002; Fig. 5C) but showed no significant correlation with MMP-2 activity (R2 = 0.3252, P = 0.053; Fig. 5D). These results suggested the involvement of the p38 MAPK pathway in MMP modulation after ischemic stroke, which was mainly achieved through the p38 MAPK-MMP-9 pathway
Summary
Stroke is one of the leading causes of death and disability worldwide, very few therapeutic measures and drugs are available to treat this disease[1,2]. We further test the potential utility of this probe in evaluating the effect of p38 MAPK inhibitor on the non-invasive regulation of MMP activity in the process of ischemic stroke.
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