Preimplantation Factor (PIF*) reverses neuroinflammation while promoting neural repair in EAE model

Introduction: Embryo-derived PIF modulates systemic maternal immunity without suppression. Synthetic analog (sPIF) prevents juvenile diabetes, preserves islet function, reducing oxidative stress/protein misfolding. We investigate sPIF effectiveness in controlling neuroinflammation/MS. Methods: Examine sPIF-induced protection against harsh, clinical-relevant murine EAE-PLP acute and chronic models. Evaluate clinical indices: circulating cytokines, spinal cord histology, genome, canonical global proteome, cultured PLP-activated splenocytes cytokines, and immunophenotype. Results: Short-term, low-dose sPIF prevented paralysis development and lowered mortality (P<0.05). Episodic sPIF reversed chronic paralysis (P<0.0001) completely in >50%, by day 82. Prevention model: 12 days post-therapy, sPIF reduced circulating 112 ten-fold and inflammatory cells access to spinal cord. Regression model: sPIF blocked PLP-induced IL17 and IL6 secretions. Long-term chronic model: sPIF reduced spinal cord pro-inflammatory cytokines/chemokines, (ALCAM, CF1, CCL8), apoptosis-promoters, inflammatory cells access (JAM3, OPA1), solute channels (ATPases), aberrant coagulation factors (Serpins), and pro-antigenic MOG. Canonical proteomic analysis demonstrated reduced oxidative phosphorylation, vesicle traffic, cytoskeleton remodeling involved in neuro-cytoskeleton breakdown (tubulins), associated with axon re-assembly by (MTAPs)/improved synaptic transmission. Conclusion: sPIF - through coordinated central and systemic multi-targeted action - reverses neuroinflammation/MS and imparts significant neuroprotective effects up to total paralysis resolution. Clinical testing is warranted and planned. (C) 2011 Elsevier B.V. All rights reserved.