Intrinsic mechanisms that guide damaged axons to regenerate following spinal cord injury remain poorly understood. Manipulation of posttranslational modifications of key proteins in mature neurons could re-invigorate growth machinery after injury. One such modification is acetylation, a reversible process controlled by two enzyme families acting in opposition, the Histone Deacetylases (HDACs) and the Histone Acetyl Transferases (HATs). While acetylated histones in the nucleus is associated with upregulation of growth promoting genes, de-acetylated tubulin in the axoplasm is associated with more labile microtubules, conducive to axon growth. In this study we investigated the effects of HAT inhibitors and HDAC inhibitors on cultured adult dorsal root ganglia (DRG) neurons. We found that inhibition of HATs, using Anacardic Acid or CPTH2, improved axon outgrowth, while inhibition of HDACs using TSA or Tubacin, inhibited axon growth. Furthermore, Anacardic Acid increased the number of axons able to cross an inhibitory chondroitin sulfate proteoglycan (CSPG) border. Histone acetylation, but not tubulin acetylation levels, was affected by HAT inhibitors, whereas tubulin acetylation levels were increased in the presence of HDAC inhibitor Tubacin. Although microtubule stabilizing drug taxol did not have an effect on the lengths of DRG axons, nocodazole decreased axon lengths. While the mechanistic basis will require future studies, our data show that inhibitors of HAT can augment axon growth in adult DRG neurons, with the potential of aiding axon growth over inhibitory substrates produced by the glial scar.
A new onset acute heart failure (HF) with a sudden drop in the left ventricular ejection fraction (LVEF) post orthotopic liver transplant (LT) is a rare but a potentially fatal complication. Because in most of the cases there is no evidence of coronary thrombosis, it can be classified as nonischemic cardiomyopathy. More specifically, clinical presentation of this syndrome shares many features with stress-induced or takotsubo cardiomyopathy. The known factors that predispose these patients to acute HF during or shortly after LT include cirrhotic cardiomyopathy, rapid hemodynamic changes during LT surgery, and the large concentrations of catecholamines, either administered or released endogenously during surgery. The hemodynamic changes during surgery, such as the drop in preload during the anhepatic phase (occasionally requiring massive transfusions and vasopressors) and subsequent increase in preload with acidic and hyperkalemic plasma in the reperfusion phase, lead to rapid electrolyte and hemodynamic shifts. In several cases, intraoperative onset of HF, with or without ventricular arrythmia, could be timed to the reperfusion phase (and occasionally in the anhepatic and pre-anhepatic phases). In other cases, the HF syndrome started hours to days post-surgery. Recovery of cardiac function occurred in the majority of patients during the same admission; however, these patients generally need significantly longer hospitalizations and aggressive supportive care (occasionally requiring mechanical ionotropic and ventilatory support). If recover, the patients have a similar 1-year mortality as those LT patients that did not have this complication. Because no reliable risk stratification currently exists, intraoperative transesophageal echocardiography might be the most dependable way of detecting and addressing this syndrome promptly. Given the mechanism of takotsubo cardiomyopathy, beta-blockade and a preferential use of non-catecholaminergic vasopressors may be a reasonable way to manage this syndrome.
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