title: PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling.
abstract: A synthetic peptide (sPIF) analogous to the mammalian embryo-derived PreImplantation Factor (PIF) enables neuroprotection in rodent models of experimental autoimmune encephalomyelitis and perinatal brain injury. The protective effects have been attributed, in part, to sPIF's ability to inhibit the biogenesis of microRNA let-7, which is released from injured cells during central nervous system (CNS) damage and induces neuronal death. Here, we uncover another novel mechanism of sPIF-mediated neuroprotection. Using a clinically relevant rat newborn brain injury model, we demonstrate that sPIF, when subcutaneously administrated, is able to reduce cell death, reverse neuronal loss and restore proper cortical architecture. We show, both in vivo and in vitro, that sPIF activates cyclic AMP dependent protein kinase (PKA) and calcium-dependent protein kinase (PKC) signaling, leading to increased phosphorylation of major neuroprotective substrates GAP-43, BAD and CREB. Phosphorylated CREB in turn facilitates expression of Gap43, Bdnf and Bcl2 known to have important roles in regulating neuronal growth, survival and remodeling. As is the case in sPIF-mediated let-7 repression, we provide evidence that sPIF-mediated PKA/PKC activation is dependent on TLR4 expression. Thus, we propose that sPIF imparts neuroprotection via multiple mechanisms at multiple levels downstream of TLR4. Given the recent FDA fast-track approval of sPIF for clinical trials, its potential clinical application for treating other CNS diseases can be envisioned.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.|Department of Obstetrics and Gynecology, University Hospital Bern, Bern, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Mueller
authors.affiliation: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: A
authors.identifier: http://orcid.org/0000-0002-6716-9551
authors.initials: A
authors.lastname: Schoeberlein
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.|Department of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, PR China.
authors.forename: J
authors.identifier: http://orcid.org/0000-0002-0727-4034
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Joerger-Messerli
authors.affiliation: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Oppliger
authors.affiliation: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: U
authors.initials: U
authors.lastname: Reinhart
authors.affiliation: Department of Neurosurgery, Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bordey
authors.affiliation: Department of Obstetrics and Gynecology, University Hospital Bern, Bern, Switzerland.|Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Surbek
authors.affiliation: Society for the Investigation of Early Pregnancy, Cherry Hill, NJ, USA.|BioIncept LLC, Cherry Hill, NJ, USA.
authors.forename: E R
authors.initials: ER
authors.lastname: Barnea
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.|Women and Children's Center for Blood Disorders, Yale School of Medicine, New Haven, CT, USA.
authors.forename: M
authors.initials: M
authors.lastname: Paidas
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004195:Disease Models, Animal; D019922:GAP-43 Protein / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D019922:GAP-43 Protein; C548145:MIRNLET7 microRNA, rat; D035683:MicroRNAs; D018696:Neuroprotective Agents; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D051025:bcl-Associated Death Protein; C569738:preimplantation factor, synthetic; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C