In this fiscal year we studied to reveal the therapeutic regimen and mechanism of action underlying hypothermia treatment in combination with stem cell transplantation for ameliorating neonatal hypoxic-ischemic-like injury. Primary rat neurons were exposed to oxygen-glucose deprivation (OGD), which produced hypoxic-ischemic-like injury in vitro, then incubated at 25C (severe hypothermia), 34C (moderate hypothermia), and 37C (normothermia) with or without subsequent co-culture with mesenchymal stromal cells (MSCs). Combination treatment of moderate hypothermia and MSCs significantly improved cell survival and mitochondrial activity after OGD exposure. The exposure of delta opioid human embryonic kidney cells (HEK293) to moderate hypothermia attenuated OGD-mediated cell alterations, which were much more pronounced in HEK293 cells overexpressing the delta opioid receptor. Further, the addition of delta opioid peptide to 34C hypothermia and stem cell treatment in primary rat neurons showed synergistic neuroprotective effects against OGD which were significantly more robust than the dual combination of moderate hypothermia and MSCs, and were significantly reduced, but not completely abolished, by the opioid receptor antagonist naltrexone altogether implicating a ligand-receptor mechanism of neuroprotection. Further investigations into non-opioid therapeutic signaling pathways revealed growth factor mediation and anti-apoptotic function accompanying the observed therapeutic benefits. These results support combination therapy of hypothermia and stem cells for hypoxic-ischemic-like injury in vitro, which may have a direct impact on current clinical trials using stand-alone hypothermia or stem cells for treating neonatal encephalopathy.

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National Institute on Drug Abuse
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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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