Excitatory amino acids are an integral part of ischemic brain injury mechanisms. Because sigma-receptor ligands modulate neuronal responses to pharmacologic N-methyl D-aspartate (NMDA) receptor stimulation in vitro via a specific sigma ligand recognition site, they are of potential therapeutic value in stroke and may not be associate with the same spectrum of undesired side-effects which limit the clinical utility of NMDA receptor antagonists 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) is a prototypic sigma- receptor ligand which provides neuroprotection but the exact mechanism of protection has not been previously elicited in vivo. Conclusions from in vitro experiments have suggested that sigma-receptor ligands may interfere with excitatory amino acid-induced neurotoxicity by interacting with the NMDA receptor complex. Further, sigma-receptor ligands may advantageously decrease excitotoxic neurotransmitter and catecholamine release during ischemia, specifically glutamate and dopamine. The overall goal of this project is to define the in vivo signaling process that accounts for the marked neuroprotective properties of sigma-receptor ligands in transient focal ischemia. The general hypothesis is that these ligands protect the brain by a unique sigma-receptor pathway which inhibits excitotoxin release and NMDA activation, and, therefore, prevents consequent neuronal nitric oxide synthase (nNOS) activation and cell death.
The specific aims will: define the most efficacious treatment paradigm sigma-receptor ligand, PPBP, in transient focal ischemia; determine if sigma-receptor activation inhibits excitotoxic mechanisms of focal ischemic brain injury; characterize basal and post-ischemic sigma-receptor signaling mechanisms in vivo; determine if sigma receptor mediated mechanisms of neuroprotection are specific to the constitutive neuronal isoform of NOS. The methodology will include use of an intravascular thread occlusion model of transient focal ischemia in rodents (both rats and mice), microdialysis measurement of spontaneous and NMDA-stimulated NOS activity, microdialysis measurement of excitatory amino acids and dopamine with its metabolites, immunochemistry for detection of G-protein and autoradiography for measurement of sigma-receptor distribution. These techniques are combined to test the hypothesis that sigma-receptor ligands improve neurologic outcome (histology and neurologic function) by interfering with excitatory amino acid mechanisms during ischemia and reperfusion through a G-protein second messenger, all which ultimately result in decreased production of NO and decreased brain injury.

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Fonken, Laura K; Gaudet, Andrew D; Gaier, Kristopher R et al. (2016) MicroRNA-155 deletion reduces anxiety- and depressive-like behaviors in mice. Psychoneuroendocrinology 63:362-9
Ni, Xinli; Yang, Zeng-Jin; Wang, Bing et al. (2012) Early antioxidant treatment and delayed hypothermia after hypoxia-ischemia have no additive neuroprotection in newborn pigs. Anesth Analg 115:627-37
Ni, Xinli; Yang, Zeng-Jin; Carter, Erin L et al. (2011) Striatal neuroprotection from neonatal hypoxia-ischemia in piglets by antioxidant treatment with EUK-134 or edaravone. Dev Neurosci 33:299-311
Woodworth, K Nina; Palmateer, Julie; Swide, Joseph et al. (2011) Short- and long-term behavioral effects of exposure to 21%, 40% and 100% oxygen after perinatal hypoxia-ischemia in the rat. Int J Dev Neurosci 29:629-38
Yang, Sufang; Abrahams, Matthew S; Hurn, Patricia D et al. (2011) Local anesthetic Schwann cell toxicity is time and concentration dependent. Reg Anesth Pain Med 36:444-51
Nakano, Takaaki; Hurn, Patricia D; Herson, Paco S et al. (2010) Testosterone exacerbates neuronal damage following cardiac arrest and cardiopulmonary resuscitation in mouse. Brain Res 1357:124-30
Yang, Zeng-Jin; Carter, Erin L; Torbey, Michel T et al. (2010) Sigma receptor ligand 4-phenyl-1-(4-phenylbutyl)-piperidine modulates neuronal nitric oxide synthase/postsynaptic density-95 coupling mechanisms and protects against neonatal ischemic degeneration of striatal neurons. Exp Neurol 221:166-74
Ohata, Hiroto; Gebremedhin, Debebe; Narayanan, Jayashree et al. (2010) Onset of pulmonary ventilation in fetal sheep produces pial arteriolar constriction dependent on cytochrome p450 omega-hydroxylase activity. J Appl Physiol 109:412-7
Zhu, W; Wang, L; Zhang, L et al. (2010) Isoflurane preconditioning neuroprotection in experimental focal stroke is androgen-dependent in male mice. Neuroscience 169:758-69
Neigh, Gretchen N; Karelina, Kate; Glasper, Erica R et al. (2009) Anxiety after cardiac arrest/cardiopulmonary resuscitation: exacerbated by stress and prevented by minocycline. Stroke 40:3601-7

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