preimplantation-factor--synthetic and Multiple-Sclerosis

A typical autoimmune neuro-inflammatory disease (NID), multiple sclerosis (MS), is more prevalent in women than in men. Majority of patients with MS are of child-bearing age; therefore, occurrence in pregnancy is common. Herein, we review proposed disease mechanisms and suggest therapeutic interventions, focusing on the remarkable pregnancy-induced protection against MS - insofar considered as best, albeit temporary therapy for such harsh NID. Current drugs used for MS therapy in pregnancy are described. Role of non-pregnancy-specific agents considered involved in amelioration of disease is also presented. This review highlights pregnancy-derived neuro-protective agents, proposing that unique pregnancy-induced immune-protective environment is because of the conceptus and its direct action. The essential role of pre-implantation factor (PIF) in pregnancy is delineated. Finally, PIF immune-modulatory effects and efficacy in chronic model of neuro-inflammation to reduce inflammation and paralysis coupled with neural regeneration is presented. Overall, we postulate that this embryo-derived-compound holds great promise to improve MS and possibly neuro-inflammation in general.

Topics: alpha-Fetoproteins; Female; Humans; Inflammation; Male; Multiple Sclerosis; Nerve Regeneration; Neuroprotective Agents; Paralysis; Peptides; Pregnancy; Pregnancy Complications; Th1 Cells; Th2 Cells; Vitamin D Deficiency

An autoimmune response against myelin protein is considered one of the key pathogenic processes that initiates multiple sclerosis (MS). The currently available MS disease modifying therapies have demonstrated to reduce the frequency of inflammatory attacks. However, they appear limited in preventing disease progression and neurodegeneration. Hence, novel therapeutic approaches targeting both inflammation and neuroregeneration are urgently needed. A new pregnancy derived synthetic peptide, synthetic PreImplantation Factor (sPIF), crosses the blood-brain barrier and prevents neuro-inflammation. We report that sPIF reduces paralysis and de-myelination of the brain in a clinically-relevant experimental autoimmune encephalomyelitis mice model. These effects, at least in part, are due to post-translational modifications, which involve cyclic AMP dependent protein kinase (PKA), calcium-dependent protein kinase (PKC), and immune regulation. In terms of potential MS treatment, sPIF was successfully tested in neurodegenerative animal models of perinatal brain injury and experimental autoimmune encephalitis. Importantly, sPIF received a FDA Fast Track Approval for first in human trial in autommuninty (completed).

Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Female; Mice; Multiple Sclerosis; Paralysis; Peptides; Protein Processing, Post-Translational

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.. 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.. 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: 12days post-therapy, sPIF reduced circulating IL12 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.. 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.

Topics: Animals; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Inflammation Mediators; Mice; Mice, Inbred Strains; Multiple Sclerosis; Nerve Regeneration; Peptides; Random Allocation