Amelia Fernandez-Martin

Therapeutic effect of urocortin and adrenomedullin in a murine model of Crohn's disease

Background and aim: Urocortin 1 (UCN) and adrenomedullin (AM) are two recently discovered neuropeptides that, due to their distribution and binding to receptors in immune cells, have emerged as potential endogenous anti-inflammatory factors. Crohn’s disease is a chronic debilitating disease characterised by a Th1 driven severe inflammation of the gastrointestinal tract. This study investigated the therapeutic effect of UCN and AM in a murine model of colitis. Methods and results: Treatment with UCN or AM ameliorated significantly the clinical and histopathological severity of the inflammatory colitis, abrogating body weight loss, diarrhoea, and inflammation, and increased the survival rate of colitic mice. The therapeutic effect was associated with downregulation of both inflammatory and Th1 driven autoimmune responses, including regulation of a wide spectrum of inflammatory mediators. In addition, partial involvement of interleukin 10 secreting regulatory cells in this therapeutic effect was demonstrated. Importantly, UCN or AM treatments were therapeutically effective in established colitis and avoided recurrence of the disease. Conclusions: This work identifies UCN and AM as two potent anti-inflammatory factors with the capacity to deactivate the intestinal inflammatory response and restore mucosal immune tolerance at multiple levels. Consequently, both peptides represent novel multistep therapeutic approaches for the treatment of Crohn’s disease and other Th1 mediated inflammatory diseases.

Vasoactive intestinal peptide induces regulatory T cells during experimental autoimmune encephalomyelitis

CD4+CD25+ regulatory T cells (Treg) control the immune response to a variety of antigens, including self‐antigens. Several models support the idea of the peripheral generation of CD4+CD25+ Treg from CD4+CD25– T cells. Little is known about the endogenous factors and mechanisms controlling the peripheral expansion of CD4+CD25+ Treg. In this study we report on the capacity of the vasoactive intestinal peptide (VIP), an immunosuppressive neuropeptide, to induce functional Treg in vivo during the development of experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis model. The administration of VIP to EAE mice results in the expansion of the CD4+CD25+, Foxp3‐expressing T cells in the periphery and the nervous system, which inhibit encephalitogenic T cell activation. In addition to the increase in the number of CD4+CD25+ Treg, VIP induces more efficient suppressors on a per cell basis. The VIP‐generated CD4+CD25+ Treg transfer suppression and significantly ameliorate the progression of the disease.

VIP prevents experimental multiple sclerosis by downregulating both inflammatory and autoimmune components of the disease.

Abstract:  Multiple sclerosis (MS) is a disabling inflammatory, autoimmune demyelinating disease of the central nervous system (CNS). Despite intensive investigation, the mechanisms of disease pathogenesis remain unclear, and curative therapies are unavailable for MS. The current study describes a new possible strategy for the treatment of MS, based on the administration of the vasoactive intestinal peptide (VIP). Treatment with VIP significantly reduced incidence and severity of experimental autoimmune encephalomyelitis (EAE), an MS‐related rodent model. VIP suppressed EAE neuropathology by reducing CNS inflammation and by selective blocking encephalitogenic T‐cell reactivity, emerging as an attractive candidate for the treatment of human MS.

Vasoactive intestinal peptide family as a therapeutic target for Parkinson’s disease

Parkinson’s disease (PD) is a common neurodegenerative disorder with no effective protective treatment, characterised by a massive degeneration of dopaminergic neurons in the substantia nigra and the subsequent loss of their projecting nerve fibres in the striatum. Because current treatments for PD are not effective, considerable research has been focused recently on a number of regulatory molecules that regulate inflammation characteristic of PD, induce neurotrophic and survival factors and reduce oxidative stress. Vasoactive intestinal peptide (VIP), a neuropeptide with a potent anti-inflammatory, antiapoptotic and neurotrophic effect, has been found to be protective in several inflammatory disorders. This review examines the putative protective effect of VIP and analogues in different models for PD. VIP emerges as a potential valuable neuroprotective agent for the treatment of pathological conditions in the CNS, such as PD, in which inflammation-induced neurodegeneration occurs.