Harnessing hypoxic adaptation to prevent, treat, and repair stroke

The brain demands oxygen and glucose to fulfill its roles as the master regulator of body functions as diverse as bladder control and creative thinking. Chemical and electrical transmission in the nervous system is rapidly disrupted in stroke as a result of hypoxia and hypoglycemia. Despite being highly evolved in its architecture, the human brain appears to utilize phylogenetically conserved homeostatic strategies to combat hypoxia and ischemia. Specifically, several converging lines of inquiry have demonstrated that the transcription factor hypoxia-inducible factor-1 (HIF1-1) mediates the activation of a large cassette of genes involved in adaptation to hypoxia in surviving neurons after stroke. Accordingly, pharmacological or molecular approaches that engage hypoxic adaptation at the point of one of its sensors (e.g., inhibition of HIF prolyl 4 hydroxylases) leads to profound sparing of brain tissue and enhanced recovery of function. In this review, we discuss the potential mechanisms that could subserve protective and restorative effects of augmenting hypoxic adaptation in the brain. The strategy appears to involve HIF-dependent and HIF-independent pathways and more than 70 genes and proteins activated transcriptionally and post-transcriptionally that can act at cellular, local, and system levels to compensate for oxygen insufficiency. The breadth and depth of this homeostatic program offers a hopeful alternative to the current pessimism towards stroke therapeutics

Comparing PMMA and calcium sulfate as carriers for the local delivery of antibiotics to infected surgical sites

Antibiotic-loaded bone cement is a primary option for treatment of orthopedic infections. Poly(methyl methacrylate) (PMMA) is a widely used cement that, when loaded with antibiotics in spacer or bead form, has been shown to reduce infection rates. However, PMMA is not resorbable and requires a second surgery for removal, while also acting as a potential foreign body for bacterial colonization. Alternatively, resorbable bone cements, such as calcium sulfate, have been proposed and present the advantage of being completely reabsorbed. It is unknown whether the antibiotic elution characteristics of absorbable bone cements are similar to PMMA. This study (1) characterized antibiotic elution from synthetic, highly purified calcium sulfate cement beads of varying sizes against pathogenic bacteria both in liquid culture and seeded on agar plates, (2) tested calcium sulfate beads against PMMA beads loaded with the same antibiotics, and (3) analyzed the structural differences between how PMMA and calcium sulfate bind to antibiotics. In every assay, the calcium sulfate beads performed as well as, or better than, the PMMA beads in inhibition of bacterial growth and elution of vancomycin in vitro with complete elution observed from calcium sulfate within three days. These data suggest that calcium sulfate, functions, as well as PMMA in the patient setting for infection control

Biofilms in periprosthetic orthopedic infections

As the number of total joint arthroplasty and internal fixation procedures continues to rise, the threat of infection following surgery has significant clinical implications. These infections may have highly morbid consequences to patients, who often endure additional surgeries and lengthy exposures to systemic antibiotics, neither of which are guaranteed to resolve the infection. Of particular concern is the threat of bacterial biofilm development, since biofilm-mediated infections are difficult to diagnose and effective treatments are lacking. Developing therapeutic strategies have targeted mechanisms of biofilm formation and the means by which these bacteria communicate with each other to take on specialized roles such as persister cells within the biofilm. In addition, prevention of infection through novel coatings for prostheses and the local delivery of high concentrations of antibiotics by absorbable carriers has shown promise in laboratory and animal studies. Biofilm development, especially in an arthoplasty environment, and future diagnostic and treatment options are discussed

HIF Prolyl Hydroxylase Inhibitors Prevent Neuronal Death Induced by Mitochondrial Toxins: Therapeutic Implications for Huntington's Disease and Alzheimer's Disease

Mitochondrial dysfunction is a central feature of a number of acute and chronic neurodegenerative conditions, but clinically approved therapeutic interventions are only just emerging. Here we demonstrate the potential clinical utility of low molecular weight inhibitors of the hypoxia inducible factor prolyl-4-hydroxylases (HIF PHDs) in preventing mitochondrial toxin-induced cell death in mouse striatal neurons that express a “knock-in” mutant Huntingtin allele. Protection from 3-nitropropionic acid (3-NP, a complex II inhibitor)-induced toxicity by HIF PHD inhibition occurs without rescue of succinate dehydrogenase activity. Although HIF-1α mRNA is dramatically induced by mutant huntingtin, HIF-1α depletion by short interfering RNAs (siRNA) does not affect steady-state viability or protection from 3-NP-induced death by HIF PHD inhibitors in these cells. Moreover, 3-NP-induced complex II inhibition in control or mutant striatal neurons does not lead to activation of HIF-dependent transcription. HIF PHD inhibition also protects cortical neurons from 3-NP-induced cytotoxicity. Protection of cortical neurons by HIF PHD inhibition correlates with enhanced VEGF but not PGC-1α gene expression. Together, these findings suggest that HIF PHD inhibitors are promising candidates for preventing cell death in conditions such as Huntington's disease and Alzheimer's disease that are associated with metabolic stress in the central nervous system. Antioxid. Redox Signal. 12, 435–443

Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease

Caused by a polyglutamine expansion in the huntingtin protein, Huntington's disease leads to stnatal degeneration via the transcriptional dysregulation of a number of genes, including those involved in mitochondnal biogenesis. Here we show that transglutaminase 2, which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes; transglutaminase 2 interacts directly with histone H3 in the nucleus. In a cellular model of HD, transglutaminase inhibition de-repressed two established regulators of mitochondrial function, PGC-l alpha and cytochrome c and reversed susceptibility of human HD cells to the mitochondrial toxin, 3-nitroproprionic acid; however, protection mediated by transglutaminase inhibition was not associated with improved mitochondnal bioenergetics. A gene microarray analysis indicated that transglutaminase inhibition normalized expression of not only mitochondrial genes but also 40% of genes that are dysregulated in HD striatal neurons, including chaperone and histone genes. Moreover, transglutaminase inhibition attenuated degeneration in a Drosophila model of HD and protected mouse HD stnatal neurons from excitotoxicity. Altogether these findings demonstrate that selective TG inhibition broadly corrects transcriptional dysregulation in HD and defines a novel HDAC-independent epigenetic strategy for treating neurodegeneration

Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease

Caused by a polyglutamine expansion in the huntingtin protein, Huntington's disease leads to stnatal degeneration via the transcriptional dysregulation of a number of genes, including those involved in mitochondnal biogenesis. Here we show that transglutaminase 2, which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes; transglutaminase 2 interacts directly with histone H3 in the nucleus. In a cellular model of HD, transglutaminase inhibition de-repressed two established regulators of mitochondrial function, PGC-l alpha and cytochrome c and reversed susceptibility of human HD cells to the mitochondrial toxin, 3-nitroproprionic acid; however, protection mediated by transglutaminase inhibition was not associated with improved mitochondnal bioenergetics. A gene microarray analysis indicated that transglutaminase inhibition normalized expression of not only mitochondrial genes but also 40% of genes that are dysregulated in HD striatal neurons, including chaperone and histone genes. Moreover, transglutaminase inhibition attenuated degeneration in a Drosophila model of HD and protected mouse HD stnatal neurons from excitotoxicity. Altogether these findings demonstrate that selective TG inhibition broadly corrects transcriptional dysregulation in HD and defines a novel HDAC-independent epigenetic strategy for treating neurodegeneration