Abstract: The present invention provides methods of making and using 5-(2-(indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one derivatives having HIV-1 or JSP-1 inhibitory activity.

Abstract: Parkinson's disease is caused by the preferential loss of substantia nigra dopamine neurons. A Parkin Interacting Substrate, PARIS (ZNF746) is identified. The levels of PARIS are regulated by the ubiquitin proteasome system via binding to and ubiquitination by the E3 ubiquitin ligase, parkin. PARIS is a KRAB and zinc finger protein that accumulates in models of parkin inactivation and in human brain Parkinson's disease patients. PARIS represses the expression of the transcriptional co-activator, PGC-1? and the PGC-1? target gene, NRF-1 by binding to insulin response sequences in the PGC-1? promoter. Conditional knockout of parkin in adult animals leads to progressive loss of dopamine (DA) neurons that is PARIS dependent. Overexpression of PARIS causes selective loss of DA neurons in the substantia nigra, which is reversed by either parkin or PGC-1? co-expression. The identification of PARIS provides a molecular mechanism for neurodegeneration due to parkin inactivation.

Abstract: Research into neuroprotective mechanisms has at its heart the goal of developing new therapeutic strategies to treat patients. For example, the compositions and induction strategies disclosed herein have use for acute injuries such as stroke or trauma, and would be extremely useful in treating patients undergoing cardiac bypass surgery, neurosurgery or other surgical cohorts where ischemia is a risk. Further, patients with subarachnoid hemorrhage, transient ischemic attacks, soldiers at risk for blast injury or patients suffering from chronic neurodegenerative diseases would also benefit from enhanced neuronal survival based upon the techniques and compositions disclosed herein. In addition, protecting against cell death by, for example, interfering with PAR polymer signaling via the compositions and processes disclosed herein, offers new therapeutic strategies for the treatment of neurologic disorders.

Abstract: Apoptosis inducing factor (“AIF”) contains a PAR-binding motif (“PBM”) that binds to Poly(ADP-ribose) (“PAR”). Binding of PAR to AIF via the PBM is required for AIF release from the mitochondria to occur, and that this PAR-related release is a key step in the programmed cell death process known as parthanatos, both in vitro and in vivo. Preventing or disrupting this release can inhibit parthanatos and thus be the basis for treatments for patients suffering from diseases or medical conditions during which parthanatos commonly occurs, including Parkinson's disease or diabetes, or patients who have had and are recovering from heart attack, stroke and other ischemia reperfusion-related injuries. Alternatively, agents could be identified that enhance the release of AIF, thereby promoting parthanatos and serving as potential anti-tumor chemotherapeutic agents.

Abstract: Immunophilin-binding agents inhibit the phosphatase calcineurin, leading to the increased phosphorylation of certain brain proteins, including nitric oxide synthase. The increased levels of phosphorylation of nitric oxide synthase inhibits the enzymatic production of nitric oxide. Thus the neurotoxic effects of glutamate, which are ordinarily the result of vascular strokes and other neurodegenerative diseases, are minimized, because the neurotoxic effects are at least partially mediated by nitric oxide. Thus immunophilin-binding drugs can be used therapeutically in the treatment of vascular stroke and neurodegenerative disorders such as Alzheimer's disease and Huntington's disease.

Abstract: Neutral tissue damage resulting for ischemia and reperfusion injury or neurodegenerative diseases can be prevented by administering therapeutically effective amounts of certain selective inhibitors of poly(ADP-ribose)polymerase. The inhibitors can be administered intravenously, intraperitoneally, intramuscularly, intraventricularly, or orally. They can be administered as a capsule or tablet containing single or divided dose. Alternatively, the inhibitors can be administered as a sterile solution, suspension or emulsion.

Abstract: Immunophilin ligands act by binding to receptor proteins, immunophilins, which in turn can bind to and regulate the Ca.sup.2+ dependent phosphatase, calcineurin, and the Ca.sup.2+ release channel, the ryanodine receptor. Immunophilin ligands have been discovered to enhance neurite outgrowth in neuronal cell systems by increasing sensitivity to neurotrophic factors. The effects of the immunophilin ligands are detected at subnanomolar concentrations indicating therapeutic application in diseases involving neural degeneration.

Abstract: Immunophilin ligands act by binding to receptor proteins, immunophilins, which in turn can bind to and regulate the Ca.sup.2+ dependent phosphatase, calcineurin, and the Ca.sup.2+ release channel, the ryanodine receptor. Immunophilin ligands have been discovered to enhance neurite outgrowth in neuronal cell systems by increasing sensitivity to neurotrophic factors. The effects of the immunophilin ligands are detected at subnanomolar concentrations indicating therapeutic application in diseases involving neural degeneration.

Abstract: Inhibitors of poly(ADP-ribose) synthetase can be used to prevent neurotoxicity mediated through N-methyl-D-aspartate (NMDA) receptors. Poly(ADP-ribose) synthetase inhibitors can be used therapeutically in the treatment of vascular stroke and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease.

Abstract: Inhibitors of nitric acid synthase can be used to prevent neurotoxicity mediated through glutamate receptors. Nitric oxide synthase inhibitors can be used therapeutically in the treatment of vascular stroke and neurodegenerative disorders such as Alzheimer's disease and Huntington's disease.

Abstract: Inhibitors of poly(ADP-ribose) synthetase can be used to prevent neurotoxicity mediated through N-methyl-D-aspartate (NMDA) receptors. Poly(ADP-ribose) synthetase inhibitors can be used therapeutically in the treatment of vascular stroke and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease.