PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling

Müller, Martin; Schoeberlein, Andreina; Zhou, J; Jörger Messerli, Marianne; Oppliger, Byron; Reinhart, Ursula; Bordey, A; Surbek, Daniel; Barnea, E R; Huang, Y; Paidas, M (2015). PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling. Cell death and differentiation, 22(12), pp. 2078-2086. Nature Publishing Group 10.1038/cdd.2015.55

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Gynaecology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Pränatale Medizin

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Müller, Martin; Schoeberlein, Andreina; Jörger Messerli, Marianne; Oppliger, Byron; Reinhart, Ursula and Surbek, Daniel

Subjects:

600 Technology > 610 Medicine & health
500 Science
500 Science > 570 Life sciences; biology

ISSN:

1350-9047

Publisher:

Nature Publishing Group

Funders:

[UNSPECIFIED] Eagle Foundation, Crans-près-Céligny,Switzerland
[UNSPECIFIED] Cryo-Save Switzerland
[UNSPECIFIED] Forschungs-Grant, University Hospital Bern, Switzerland
[UNSPECIFIED] BioIncept LLC, NJ, USA

Language:

English

Submitter:

Andreina Schoeberlein

Date Deposited:

09 Feb 2016 09:43

Last Modified:

27 Mar 2019 12:42

Publisher DOI:

10.1038/cdd.2015.55

PubMed ID:

25976303

BORIS DOI:

10.7892/boris.75194

URI:

https://boris.unibe.ch/id/eprint/75194

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