Two studies were performed this year. In the first study, we used a protease-resistant pentapeptide called DADLE that has been shown by us in the past to induce a hypo-metabolic state in animals and examined if the drug might help attenuate brain damages caused by stroke in rats. Histological examination using triphenyltetrazolium chloride revealed that brains from ischemic animals treated with DADLE exhibited almost completely intact striata. In contrast, brains from ischemic animals that received saline showed significant infarction in the lateral striatum. Analyses of apoptotic cell death revealed a significant increase in the p-53 mRNA expression in the striatum of ischemic animals that received saline, while those that received DADLE exhibited near normal striatal p-53 expression. This protective effect was accompanied by significant increments in protein levels of glial cell line-derived neurotrophic factor in the striatum of DADLE-treated ischemic animals. These results indicate that DADLE protected against necrotic and apoptotic cell death processes associated with ischemia-reperfusion injury. In the second study, DADLE was used to examine if it can increase the survival of CNS neuronal progenitor cell line. DADLE (1 pM, 0.1 nM, or 10 nM) caused a significant growth inhibition on AF5 cells. DADLE did not cause apoptosis as evidenced by negative TUNEL staining. The cell-cycle progression analysis indicated that DADLE (0.1 nM) caused an arrest of AF5 cell cycle progression at the G1 checkpoint. Neuronal marker indicated that DADLE-treated AF5 cells tend to differentiate more when compared to controls. Results demonstrate that DADLE causes cell cycle arrest and differentiation in a CNS neural progenitor cell line and suggest some potential utilization of DADLE in stem cell research.

Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2012
Total Cost
$178,490
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
Zip Code
Ciesielski, Jenna; Su, Tsung-Ping; Tsai, Shang-Yi (2016) Myristic acid hitchhiking on sigma-1 receptor to fend off neurodegeneration. Receptors Clin Investig 3:
Williams, Abasha; Hayashi, Teruo; Wolozny, Daniel et al. (2016) The non-apoptotic action of Bcl-xL: regulating Ca(2+) signaling and bioenergetics at the ER-mitochondrion interface. J Bioenerg Biomembr 48:211-25
Su, Tzu-Chieh; Lin, Shu-Hui; Lee, Pin-Tse et al. (2016) The sigma-1 receptor-zinc finger protein 179 pathway protects against hydrogen peroxide-induced cell injury. Neuropharmacology 105:1-9
Tsai, Shang-Yi A; Pokrass, Michael J; Klauer, Neal R et al. (2015) Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid. Proc Natl Acad Sci U S A 112:6742-7
Lewis, Abasha; Hayashi, Teruo; Su, Tsung-Ping et al. (2014) Bcl-2 family in inter-organelle modulation of calcium signaling; roles in bioenergetics and cell survival. J Bioenerg Biomembr 46:1-15
Mori, Tomohisa; Hayashi, Teruo; Su, Tsung-Ping (2012) Compromising ýý-1 receptors at the endoplasmic reticulum render cytotoxicity to physiologically relevant concentrations of dopamine in a nuclear factor-ýýB/Bcl-2-dependent mechanism: potential relevance to Parkinson's disease. J Pharmacol Exp Ther 341:663-71
Fujimoto, Michiko; Hayashi, Teruo; Urfer, Roman et al. (2012) Sigma-1 receptor chaperones regulate the secretion of brain-derived neurotrophic factor. Synapse 66:630-9
Tsai, Shang-Yi; Rothman, Richard Kyle; Su, Tsung-Ping (2012) Insights into the Sigma-1 receptor chaperone's cellular functions: a microarray report. Synapse 66:42-51
Kaneko, Yuji; Tajiri, Naoki; Su, Tsung-Ping et al. (2012) Combination treatment of hypothermia and mesenchymal stromal cells amplifies neuroprotection in primary rat neurons exposed to hypoxic-ischemic-like injury in vitro: role of the opioid system. PLoS One 7:e47583
Fujimoto, Michiko; Hayashi, Teruo; Su, Tsung-Ping (2012) The role of cholesterol in the association of endoplasmic reticulum membranes with mitochondria. Biochem Biophys Res Commun 417:635-9

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