Influence of chronic L-DOPA treatment on immune response following allogeneic and xenogeneic graft in a rat model of Parkinson's disease

Although intrastriatal transplantation of fetal cells for the treatment of Parkinson’s disease had shown encouraging results in initial open-label clinical trials, subsequent double-blind studies reported more debatable outcomes. These studies highlighted the need for greater preclinical analysis of the parameters that may influence the success of cell therapy. While much of this has focused on the cells and location of the transplants, few have attempted to replicate potentially critical patient centered factors. Of particular relevance is that patients will be under continued L-DOPA treatment prior to and following transplantation, and that typically the grafts will not be immunologically compatible with the host. The aim of this study was therefore to determine the effect of chronic L-DOPA administered during different phases of the transplantation process on the survival and function of grafts with differing degrees of immunological compatibility. To that end, unilaterally 6-OHDA lesioned rats received sham surgery, allogeneic or xenogeneic transplants, while being treated with L-DOPA before and/or after transplantation. Irrespective of the L-DOPA treatment, dopaminergic grafts improved function and reduced the onset of L-DOPA induced dyskinesia. Importantly, although L-DOPA administered post transplantation was found to have no detrimental effect on graft survival, it did significantly promote the immune response around xenogeneic transplants, despite the administration of immunosuppressive treatment (cyclosporine). This study is the first to systematically examine the effect of L-DOPA on graft tolerance, which is dependent on the donor-host compatibility. These findings emphasize the importance of using animal models that adequately represent the patient paradigm

Platelet Serotonin Aggravates Myocardial Ischemia/Reperfusion Injury via Neutrophil Degranulation

Background: Platelets store large amounts of serotonin that they release during thrombus formation or acute inflammation. This facilitates hemostasis and modulates the inflammatory response. Methods: Infarct size, heart function, and inflammatory cell composition were analyzed in mouse models of myocardial reperfusion injury with genetic and pharmacological depletion of platelet serotonin. These studies were complemented by in vitro serotonin stimulation assays of platelets and leukocytes in mice and men, and by measuring plasma serotonin levels and leukocyte activation in patients with acute coronary syndrome. Results: Platelet-derived serotonin induced neutrophil degranulation with release of myeloperoxidase and hydrogen peroxide (H2O2) and increased expression of membrane-bound leukocyte adhesion molecule CD11b, leading to enhanced inflammation in the infarct area and reduced myocardial salvage. In patients hospitalized with acute coronary syndrome, plasmatic serotonin levels correlated with CD11b expression on neutrophils and myeloperoxidase plasma levels. Long-term serotonin reuptake inhibition - reported to protect patients with depression from cardiovascular events - resulted in the depletion of platelet serotonin stores in mice. These mice displayed a reduction in neutrophil degranulation and preserved cardiac function. In line, patients with depression using serotonin reuptake inhibition, presented with suppressed levels of CD11b surface expression on neutrophils and lower myeloperoxidase levels in blood. Conclusions: Taken together, we identify serotonin as a potent therapeutic target in neutrophil-dependent thromboinflammation during myocardial reperfusion injury.Fil: Mauler, Maximilian. No especifíca;Fil: Herr, Nadine. No especifíca;Fil: Schoenichen, Claudia. No especifíca;Fil: Witsch, Thilo. No especifíca;Fil: Marchini, Timoteo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Härdtner, Carmen. No especifíca;Fil: Koentges, Christoph. No especifíca;Fil: Kienle, Korbinian. Max Planck Institute Of Immunobiology And Epigenetics; AlemaniaFil: Ollivier, Véronique. Inserm; FranciaFil: Schell, Maximilian. No especifíca;Fil: Dorner, Ludwig. No especifíca;Fil: Wippel, Christopher. No especifíca;Fil: Stallmann, Daniela. No especifíca;Fil: Normann, Claus. No especifíca;Fil: Bugger, Heiko. No especifíca;Fil: Walther, Paul. Universitat Ulm; AlemaniaFil: Wolf, Dennis. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Ahrens, Ingo. No especifíca;Fil: Lämmermann, Tim. Max Planck Institute Of Immunobiology And Epigenetics; AlemaniaFil: Ho-Tin-Noé, Benoît. Inserm; FranciaFil: Ley, Klaus. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Bode, Christoph. No especifíca;Fil: Hilgendorf, Ingo. No especifíca;Fil: Duerschmied, Daniel. No especifíca