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.

Synthetic PreImplantation Factor (PIF) prevents fetal loss by modulating LPS induced inflammatory response

“…Notably, IL-18 contributes to preterm birth in part by modulating TLR4 signaling [36] and TLR4 activation is necessary for PIF effects [27, 28]. We focused on NALP-3 and ASC proteins expression in the placenta as these are the key components of inflammasome signaling [4, 5].…”

PreImplantation Factor (PIF*) endogenously prevents preeclampsia: Promotes trophoblast invasion and reduces oxidative stress

“…These are in line with observations made in non-pregnant in vivo models. Specifically, in several models of immunity and transplant, PIF led to protection against oxidative stress (Weiss et al, 2011(Weiss et al, , 2012Azar et al, 2013;Shainer et al, 2013;Almogi-Hazan et al, 2014;Mueller et al, 2014Mueller et al, , 2015. In addition, as recently shown, PIF also protects against ionized radiation-induced damage (Shainer et al, 2014).…”

Preimplantation factor is an anti-apoptotic effector in human trophoblasts involving p53 signaling pathway

“…37 Our results agree with those observed in brain and pancreas, where sPIF has an important role in preventing cell death. 16, 38, 39 In particular, it has recently been reported that the PIF-associated inhibition of the death of mouse neuroblastoma cells is associated with an increase in BCL2 expression and a decrease in microRNA let-7 levels. 38, 39 Hence, the sPIF's neuroprotective effect may be due (at least in part) to its ability to inhibit the release of a microRNA that is specifically produced after central nervous system damage.…”