title: The sigma-1 receptor agonist 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) protects against newborn excitotoxic brain injury by stabilizing the mitochondrial membrane potential in vitro and inhibiting microglial activation in vivo.
abstract: Premature birth represents a clinical situation of risk for brain injury. The diversity of pathophysiological processes complicates efforts to find effective therapeutic strategies. Excitotoxicity is one important factor in the pathogenesis of preterm brain injury. The observation that sigma-1 receptor agonists possess neuroprotective potential, at least partly mediated by a variety of anti-excitotoxic mechanisms, has generated great interest in targeting those receptors to counteract brain injury. The objective of this study was to evaluate the effect of the highly specific sigma-1 receptor agonist, 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) to protect against excitotoxic developmental brain injury in vivo and in vitro. Primary hippocampal neurons were pre-treated with PPBP before glutamate was applied and subsequently analyzed for cell death (PI/calcein AM), mitochondrial activity (TMRM) and morphology of the neuronal network (WGA) using confocal microscopy. Using an established neonatal mouse model we also determined whether systemic injection of PPBP significantly attenuates excitotoxic brain injury. PPBP significantly reduced neuronal cell death in primary hippocampal neurons exposed to glutamate. Neurons treated with PPBP showed a less pronounced loss of mitochondrial membrane potential and fewer morphological changes after glutamate exposure. A single intraperitoneal injection of PPBP given one hour after the excitotoxic insult significantly reduced microglial cell activation and lesion size in cortical gray and white matter. The present study provides strong support for the consideration of sigma-1 receptor agonists as a candidate therapy for the reduction of neonatal excitotoxic brain lesions and might offer a novel target to counteract developmental brain injury.
authors.affiliation: Department of Pediatrics II (Neonatology), Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: Karina
authors.initials: K
authors.lastname: Wegleiter
authors.affiliation: Department of Anaesthesiology and Critical Care Medicine, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Hermann
authors.affiliation: Department of Pediatrics II (Neonatology), Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: Anna
authors.initials: A
authors.lastname: Posod
authors.affiliation: Department of Pediatrics II (Neonatology), Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: Karina
authors.initials: K
authors.lastname: Wechselberger
authors.affiliation: Department of Physiology and Medical Physics, Innsbruck Medical University, Fritz-Pregl-Strasse 3, 6020 Innsbruck, Austria.
authors.forename: Ruslan I
authors.initials: RI
authors.lastname: Stanika
authors.affiliation: Department of Physiology and Medical Physics, Innsbruck Medical University, Fritz-Pregl-Strasse 3, 6020 Innsbruck, Austria.
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Obermair
authors.affiliation: Department of Pediatrics II (Neonatology), Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: Ursula
authors.initials: U
authors.lastname: Kiechl-Kohlendorfer
authors.affiliation: Department of Pediatrics II (Neonatology), Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Urbanek
authors.affiliation: Department of Pediatrics II (Neonatology), Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria. Electronic address: Elke.Griesmaier@i-med.ac.at.
authors.forename: Elke
authors.initials: E
authors.lastname: Griesmaier
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001930:Brain Injuries / Q000139:chemically induced / Q000517:prevention & control*; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018698:Glutamic Acid / Q000494:pharmacology; D006023:Glycoproteins / Q000378:metabolism; D006220:Haloperidol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006624:Hippocampus / Q000166:cytology; D007051:Ibotenic Acid / Q000633:toxicity; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D051379:Mice; D017628:Microglia / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D017480:Receptors, sigma / Q000819:agonists*; D018709:Statistics, Nonparametric; D000097605:Sigma-1 Receptor
chemical_list: D051033:Apoptosis Inducing Factor; D053148:Caspase 3; D018690:Excitatory Amino Acid Agonists; D018698:Glutamic Acid; D006023:Glycoproteins; D006220:Haloperidol; D007051:Ibotenic Acid; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C473590:isolectin B4-binding glycoprotein, mouse; C094850:4-phenyl-1-(4-phenylbutyl)piperidine
keywords: Brain damage; Excitotoxicity; Microglia cell activation; Mitochondrial membrane potential; Preterm infant; Sigma receptor agonist