title: Expression of pancreatitis-associated protein after traumatic brain injury: a mechanism potentially contributing to neuroprotection in human brain.
abstract: Neuronal cell death after severe traumatic brain injury (TBI) is caused by a complex interplay of pathological mechanisms including excitotoxicity, oxidative stress, mitochondrial dysfunction, extensive neuroinflammation, and ischemia-reperfusion injury. Pancreatitis-associated protein I (PAP I/reg2) was reported to be a survival factor for peripheral neurons, particularly sensory and motor neurons. In rat brains, by experimental TBI as well as by kainic acid induced brain seizure, PAP I and PAP III were found to be up-regulated in central neurons. In this study, we performed immunohistochemical staining in postmortem human brain from patients who died after severe TBI to demonstrate PAP expression on protein level in cerebellar Purkinje cells, pyramidal and granular neurons in cerebral cortex, and cortical neurons in the fore- and mid-brain. In primary cultures of rat brain cortical, hippocampal, and cerebellar neurons, we found neuroprotective effects for PAP I on H(2)O(2)-induced oxidative stress. Moreover, serum K(+)-deprivation induces apoptotic cell death in 55% of cerebellar granule neurons (CGN), whereas upon treatment with PAP I only 32% of CGN are apoptotic. Using Western blot analyses, we compared protein phosphorylation in neuronal signaling pathways activated by PAP I versus Interleukin-6 (IL-6). We found a rapid activation of Akt-kinase phosphorylation by PAP I with a peak at 15 min, whereas IL-6 induces Akt-phosphorylation lasting longer than 30 min. Phosphorylation of MAP-42/44 kinases is stimulated in a comparable fashion. Both, IL-6 and PAP I increase phosphorylation of NFκB for activation of gene transcription, whereas only IL-6 recruits STAT3 phosphorylation, indicating that STAT3 is not a target of PAP I transcription activation in brain neurons. Application of the Akt-inhibitor Wortmanin reveals only a partial inhibition of PAP I-dependent protection of CGN from H(2)O(2)-induced oxidative stress. Based on our findings, we suggest that PAP I is a long lasting neurotrophic signal for central neurons. The neuroprotective effects parallel those that have been described for effects of PAP I in ciliary neurotrophic factor (CNTF)-mediated survival of sensory and motor neurons. PAP I may act in autocrine and/or paracrine fashion and thus may contribute to endogenous protective mechanisms relevant under harmful conditions like oxidative stress, brain injury, or neurodegeneration.
authors.affiliation: Translational Research, Hoffmann-LaRoche Ltd, Grenzacherstrasse, 4070 Basel, Switzerland.
authors.forename: Pia
authors.initials: P
authors.lastname: März-Weiss
authors.forename: Dieter
authors.initials: D
authors.lastname: Kunz
authors.forename: Daniel
authors.initials: D
authors.lastname: Bimmler
authors.forename: Caroline
authors.initials: C
authors.lastname: Berkemeier
authors.forename: Suat
authors.initials: S
authors.lastname: Özbek
authors.forename: Beatrice
authors.initials: B
authors.lastname: Dimitriades-Schmutz
authors.forename: Johannes
authors.initials: J
authors.lastname: Haybaeck
authors.forename: Uwe
authors.initials: U
authors.lastname: Otten
authors.forename: Rolf
authors.initials: R
authors.lastname: Graf
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D000073718:Pancreatitis-Associated Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D015850:Interleukin-6; D037181:Lectins, C-Type; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D016877:Oxidants; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D011993:Recombinant Fusion Proteins; C000612142:Reg2 protein, rat; C000612144:Reg3b protein, rat; D006861:Hydrogen Peroxide; D051057:Proto-Oncogene Proteins c-akt