title: HIP/PAP prevents excitotoxic neuronal death and promotes plasticity.
abstract: OBJECTIVE
  Excitotoxicity plays a significant role in the pathogenesis of perinatal brain injuries. Among the consequences of excessive activation of the N-methyl-d-aspartate (NMDA)-type glutamate are oxidative stress caused by free radical release from damaged mitochondria, neuronal death and subsequent loss of connectivity. Drugs that could protect nervous tissue and support regeneration are attractive therapeutic options. The hepatocarcinoma intestine pancreas protein/pancreatitis-associated protein I (HIP/PAP) or Reg3α, which is approved for clinical testing for the protection and regeneration of the liver, is upregulated in the central nervous system following injury or disease. Here, we examined the neuroprotective/neuroregenerative potential of HIP/PAP following excitotoxic brain injury.
  
  
  METHODS
  We studied the expression of HIP/PAP and two of its putative effectors, cAMP-regulated phosphoprotein 19 (ARPP19) and growth-associated protein 43 (GAP-43), in the neonatal brain, and the protective/regenerative properties of HIP/PAP in three paradigms of perinatal excitotoxicity: intracerebral injection of the NMDA agonist ibotenate in newborn pups, a pediatric model of traumatic brain injury, and cultured primary cortical neurons.
  
  
  RESULTS
  HIP/PAP, ARPP19, and GAP-43 were expressed in the neonatal mouse brain. HIP/PAP prevented the formation of cortical and white matter lesions and reduced neuronal death and glial activation following excitotoxic insults in vivo. In vitro, HIP/PAP promoted neuronal survival, preserved neurite complexity and fasciculation, and protected cell contents from reactive oxygen species (ROS)-induced damage.
  
  
  CONCLUSIONS
  HIP/PAP has strong neuroprotective/neuroregenerative potential following excitotoxic injury to the developing brain, and could represent an interesting therapeutic strategy in perinatal brain injury.
authors.affiliation: National Brain Research Centre Manesar, India ; Centre for Neuroscience, IISC Bangalore, India.
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authors.affiliation: Inserm U1141 Paris, France ; Univ Paris Diderot, Sorbonne Paris Cité UMRS 1141, Paris, France ; PremUP Paris, France.
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authors.lastname: Dupuis
authors.affiliation: Inserm U1141 Paris, France ; Univ Paris Diderot, Sorbonne Paris Cité UMRS 1141, Paris, France ; PremUP Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Degos
authors.affiliation: Inserm U785, Centre Hépatobiliaire Villejuif, France ; Faculté de Médecine, Université Paris-Sud Villejuif, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Moniaux
authors.affiliation: Inserm U1141 Paris, France ; Univ Paris Diderot, Sorbonne Paris Cité UMRS 1141, Paris, France ; PremUP Paris, France ; Division of Imaging Sciences and Biomedical Engineering, Centre for the Developing Brain, King's College London, King's Health Partners, St. Thomas' Hospital London, United Kingdom.
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authors.affiliation: Inserm U1141 Paris, France ; Univ Paris Diderot, Sorbonne Paris Cité UMRS 1141, Paris, France ; PremUP Paris, France.
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authors.initials: S
authors.lastname: Rasika
authors.affiliation: Inserm U1141 Paris, France ; Univ Paris Diderot, Sorbonne Paris Cité UMRS 1141, Paris, France ; PremUP Paris, France.
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authors.lastname: Schwendimann
authors.affiliation: Inserm U1141 Paris, France ; Univ Paris Diderot, Sorbonne Paris Cité UMRS 1141, Paris, France ; PremUP Paris, France.
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authors.initials: T
authors.lastname: le Charpentier
authors.affiliation: Inserm U1141 Paris, France ; Univ Paris Diderot, Sorbonne Paris Cité UMRS 1141, Paris, France ; PremUP Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Rougier
authors.affiliation: Alfact Innovation Paris, France.
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authors.lastname: Amouyal
authors.affiliation: Alfact Innovation Paris, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Amouyal
authors.affiliation: Inserm U1141 Paris, France ; Univ Paris Diderot, Sorbonne Paris Cité UMRS 1141, Paris, France ; PremUP Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Dournaud
authors.affiliation: Inserm U785, Centre Hépatobiliaire Villejuif, France ; Faculté de Médecine, Université Paris-Sud Villejuif, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Bréchot
authors.affiliation: Inserm U1141 Paris, France ; Univ Paris Diderot, Sorbonne Paris Cité UMRS 1141, Paris, France ; PremUP Paris, France.
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authors.initials: V
authors.lastname: El Ghouzzi
authors.affiliation: Inserm U785, Centre Hépatobiliaire Villejuif, France ; Faculté de Médecine, Université Paris-Sud Villejuif, France.
authors.forename: Jamila
authors.initials: J
authors.lastname: Faivre
authors.affiliation: Inserm U1141 Paris, France ; Univ Paris Diderot, Sorbonne Paris Cité UMRS 1141, Paris, France ; PremUP Paris, France ; Division of Imaging Sciences and Biomedical Engineering, Centre for the Developing Brain, King's College London, King's Health Partners, St. Thomas' Hospital London, United Kingdom.
authors.forename: Bobbi
authors.initials: B
authors.lastname: Fleiss
authors.affiliation: National Brain Research Centre Manesar, India ; Centre for Neuroscience, IISC Bangalore, India.
authors.forename: Shyamala
authors.initials: S
authors.lastname: Mani
authors.affiliation: Inserm U1141 Paris, France ; Univ Paris Diderot, Sorbonne Paris Cité UMRS 1141, Paris, France ; PremUP Paris, France ; Division of Imaging Sciences and Biomedical Engineering, Centre for the Developing Brain, King's College London, King's Health Partners, St. Thomas' Hospital London, United Kingdom.
authors.forename: Pierre
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authors.lastname: Gressens