4-(n-(s-glutathionylacetyl)amino)phenylarsenoxide and Disease-Models--Animal

Preclinical studies indicate that minocycline protects against myocardial ischemia/reperfusion injury. In these studies, minocycline was administered before ischemia, which can rarely occur in clinical practice. The current study aimed to evaluate cardioprotection by minocycline treatment upon reperfusion.. Rabbits were subjected to myocardial ischemia/reperfusion injury and received either intravenous minocycline (n = 8) or saline (n = 8) upon reperfusion. Cardiac cell death was assessed by in vivo micro-SPECT/CT after injection of Indium-111-labeled 4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid (. Myocardial damage was visualized by micro-SPECT/CT imaging. Quantitative GSAO uptake (expressed as percent injected dose per gram, %ID/g) in the area at risk was lower in minocycline-treated animals than that in saline-treated control animals (0.32 ± 0.13% vs 0.48 ± 0.15%, P = 0.04). TUNEL staining confirmed the reduction of cell death in minocycline-treated animals.. This study demonstrates cardioprotection by minocycline in a clinically translatable protocol.

Topics: Animals; Arsenicals; Cell Death; Disease Models, Animal; Glutathione; Heart; Indium Radioisotopes; Minocycline; Multimodal Imaging; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Rabbits; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed

Acute insult to the myocardium is associated with substantial loss of cardiomyocytes during the process of myocardial infarction. In this setting, apoptosis (programmed cell death) and necrosis may operate on a continuum. Because the latter is characterized by the loss of sarcolemmal integrity, we propose that an appropriately labeled tracer directed at a ubiquitously present intracellular moiety would allow non-invasive definition of cardiomyocyte necrosis. A trivalent arsenic peptide, GSAO (4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid), is capable of binding to intracellular dithiol molecules such as HSP90 and filamin-A. Since GSAO is membrane impermeable and dithiol molecules abundantly present intracellularly, we propose that myocardial localization would represent sarcolemmal disruption or necrotic cell death. In rabbit and mouse models of myocardial infarction and post-infarct heart failure, we employed In-111-labelled GSAO for noninvasive radionuclide molecular imaging. (111)In-GSAO uptake was observed within the regions of apoptosis seeking agent- (99m)Tc-Annexin A5 uptake, suggesting the colocalization of apoptotic and necrotic cell death processes.

Topics: Animals; Annexin A5; Arsenicals; Disease Models, Animal; Glutathione; Indium; Male; Mice; Microscopy, Fluorescence; Molecular Imaging; Myocardial Infarction; Rabbits; Radionuclide Imaging; Technetium

Traumatic brain injury is a major public health concern and is characterised by both apoptotic and necrotic cell death in the lesion. Anatomical imaging is usually used to assess traumatic brain injuries and there is a need for imaging modalities that provide complementary cellular information. We sought to non-invasively image cell death in a mouse model of traumatic brain injury using a near-infrared fluorescent conjugate of a synthetic heat shock protein-90 alkylator, 4-(N-(S-glutathionylacetyl) amino) phenylarsonous acid (GSAO). GSAO labels both apoptotic and necrotic cells coincident with loss of plasma membrane integrity. The optical GSAO specifically labelled apoptotic and necrotic cells in culture and did not accumulate in healthy organs or tissues in the living mouse body. The conjugate is a very effective imager of cell death in brain lesions. The optical GSAO was detected by fluorescence intensity and GSAO bound to dying/dead cells was detected from prolongation of the fluorescence lifetime. An optimal signal-to-background ratio was achieved as early as 3 h after injection of the probe and the signal intensity positively correlated with both lesion size and probe concentration. This optical GSAO offers a convenient and robust means to non-invasively image apoptotic and necrotic cell death in brain and other lesions.

Topics: Alkylation; Animals; Apoptosis; Arsenicals; Brain Injuries; Cell Line, Tumor; Disease Models, Animal; Fluorescent Dyes; Glutathione; HSP90 Heat-Shock Proteins; Humans; Jurkat Cells; Mice; Spectroscopy, Near-Infrared