IntroductionThe experimental autoimmune encephalomyelitis (EAE), the rat paradigm for the human multiple sclerosis (MS), are autoimmune diseases mediated by Th1 and Th17 cells and responsible of the nervous system demyelination and progressive paralysis. It is know that lymphocytes possess AVP receptors and that EAE increases AVP serum levels along the disease. Neurointermediate pituitary lobectomy (NIL) in rats causes AVP and oxytocin permanent low serum levels and decreased humoral and cell‐mediated immune responses. Nevertheless the role of AVP as a direct immune regulatory factor has not been well clarified.ObjectiveTo investigate the effects of AVP deficiency (by NIL), and the treatment with desmopressin (DP, a synthetic analog of AVP) and conivaptan (CNV, an AVP V1a‐V2 receptor antagonist) on the clinical symptoms of EAE, and to determine the serum levels of Interleukine‐2 (IL‐2), IL‐4, IL‐6, IL‐10, IL‐17A, INF‐γ and TNF‐α in the experimental groups.MethodsGroups of female Lewis rats were divided in: (1) Intact control (Control) (2) Control+EAE, (3) Sham‐operated (SHAM), (4) Control+CNV, (5) NIL and (6) NIL+DP. Except the Control the remaining groups were immunized for EAE three weeks post‐NIL. DP and CNV administrations started 3 days before EAE immunizations. Serum cytokines were analyzed by flow cytometry and EAE clinical symptoms were evaluated by a conventional numerical scale.ResultsEAE clinical symptoms, INF‐γ, TNF‐α, and the IL‐2, IL‐6 and IL‐17A were significantly decreased in both NIL and CNV groups, whereas the IL‐4 and IL‐10 increased in the CNV group. In NIL+DP group we found a significant increase in TNF‐α, whereas the IL‐4 was significantly decreased.Conclusions1) The present clinical and molecular findings demonstrate that AVP deficiency and the block of the AVP receptors decreased immune response, and that DP restores the susceptibility of the NIL animals to develop EAE. 2) The results strongly support that acting directly on the AVP receptors, AVP plays an important immuneregulatory role in the generation and maintenance of the immune‐competence, 3) AVP receptors may be therapeutic targets in the treatment of the human MS.Support or Funding InformationSupported by UAA‐PIFF14‐1 and CONACYT‐221262 (AQS). México.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

IntroductionHuman Multiple Sclerosis (MS) is a medically important disease. MS and its experimental autoimmune encephalomyelitis (EAE) paradigm are central nervous system demyelinizing diseases in which the immune system is directly involved. The pursuit for new treatments for MS still as an important goal for research. The use of the EAE animals to study the immune mechanisms that mediate the disease still being the best strategy to deep into the immune‐neuroendocrine interactions during the pathogenesis. Previously we have demonstrated that neurointermediate pituitary lobectomy (NIL) decreases humoral and cell‐mediated immune responses and that AVP is directly involved. Nevertheless, the role of AVP has not been entirely clarified.ObjectiveTo investigate the mechanism by which AVP deficiency (by NIL) and desmopressin (DP, a synthetic analog of AVP) affects the development of the clinical signs, the immune response and gene expression profile in the EAE.MethodsFemale Lewis rats were divided into intact control (IC), EAE immunized, NIL and NIL treated with desmopressin (NIL+DP). Except the IC, the remaining groups were immunized for EAE. The EAE was induced by encephalitogen subcutaneous injection. Animals were sacrificed at the peak of the disease (15 days after immunization). EAE clinical signs, cytokine serum profiles (IL‐17A, IL‐4, IL‐2, IL‐10, IL‐6, TNF‐α and INF‐γ) (flow cytometry) and spleen gene expression profile (microarray) were evaluated. DP treatment started 3 days before immunization.ResultsAs compared with the EAE group, NIL animals developed just a mild clinical signs of EAE and significant decreased IFN‐γ and IL‐17 levels. NIL+DP treated animals restored its susceptibility to EAE clinical signs, whereas no‐significant differences on cytokine levels occurred. Significant differences in gene expression profile among groups were evident; in the NIL group the expression pattern of the TGF‐β pathway was down‐regulated as compared with the EAE group, whereas in the NIL+DP group the same genes were up‐regulated.ConclusionsFindings add novel data indicating that directly AVP plays a crucial role in regulating the immune responses and suggests that AVP receptor blockers may be used for the MS treatment and possibly autoimmune diseases and other inflammatory processes.Support or Funding InformationSupported by UAA‐PIFF14‐1 and CONACYT‐221262 (AQS). México. VVB: CONACT Doctoral scholarship. NMS: CONACYT post doctoral Fellow. México.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Multiple sclerosis (MS) is a chronic demyelinating and neurodegenerative disease that affects the central nervous system. MS is a heterogeneous disorder of multiple factors that are mainly associated with the immune system including the breakdown of the blood-brain and spinal cord barriers induced by T cells, B cells, antigen presenting cells, and immune components such as chemokines and pro-inflammatory cytokines. The incidence of MS has been increasing worldwide recently, and most therapies related to its treatment are associated with the development of several secondary effects, such as headaches, hepatotoxicity, leukopenia, and some types of cancer; therefore, the search for an effective treatment is ongoing. The use of animal models of MS continues to be an important option for extrapolating new treatments. Experimental autoimmune encephalomyelitis (EAE) replicates the several pathophysiological features of MS development and clinical signs, to obtain a potential treatment for MS in humans and improve the disease prognosis. Currently, the exploration of neuro-immune-endocrine interactions represents a highlight of interest in the treatment of immune disorders. The arginine vasopressin hormone (AVP) is involved in the increase in blood−brain barrier permeability, inducing the development and aggressiveness of the disease in the EAE model, whereas its deficiency improves the clinical signs of the disease. Therefore, this present review discussed on the use of conivaptan a blocker of AVP receptors type 1a and type 2 (V1a and V2 AVP) in the modulation of immune response without completely depleting its activity, minimizing the adverse effects associated with the conventional therapies becoming a potential therapeutic target in the treatment of patients with multiple sclerosis.

Epithelial ovarian cancer (EOC) is the most common and lethal of the ovarian neoplasms, frequently it is detected at advanced stages of the disease resulting in 60–70% of the cases in recurrence and less responsive to chemotherapy. Currently the role played by the neurohypophyseal hormone arginine vasopressin (AVP) and its receptors in the development of EOC is unknown. The purpose of this study was to evaluate the action of desmopressin (DDAVP), an AVP V2 receptor agonist on the cell proliferation and cell migration in cells from the OV‐90 cell line. Cell proliferation was evaluated with the proliferation marker Ki67, whereas the cells migration was evaluated by the wound assay. The AVP V1a and V2 receptors expression were assessed by immunofluorescence. Cell cultures were stimulated during 12, 24, 36 and 48 hours with DDAVP (500 to 1500 mM). In order to discard the cytotoxicity of DDAVP on the OV‐90 cell cultures in control and stimulated cultures the Cytotox 96 kit was used. The experiments were performed three times by duplicate. The results showed that the expression of AVP V1a and V2 receptors are present in both DDAVP stimulated and‐non stimulated cultures. On the other hand in comparison with the control cultures, doses of 1000mM of DDAVP significantly (p<0.05) inhibit both cell proliferation and cellular migration. Present results also suggests a possible inhibitory role of DDAVP on proliferation and cellular migration in the OV‐90 cell lines of epithelial ovarian cancer. Support or Funding Information Universidad Autónoma de Aguascalientes PIFF14‐1 and CONACYT 221262. México

Arginine vasopressin (AVP) is a naturally occurring hormone synthesized in the hypothalamus. AVP demonstrates pro-fibrotic effects as it stimulates hepatic stellate cells to secrete transforming growth factor-β (TGF-β) and collagen. Previous work in liver cirrhotic (CCL 4 -induced) hamsters demonstrated that AVP deficiency induced by neurointermediate pituitary lobectomy (NIL) can restore liver function. Therefore, we hypothesized that liver fibrosis would decrease in portocaval anastomosis (PCA) rats, which model chronic liver diseases, when they are treated with the V1a-V2 AVP receptor antagonist conivaptan (CV). In this study, changes in liver histology and gene expression were analysed in five experimental groups: control, PCA, NIL, PCA + NIL and PCA + CV, with NIL surgery or CV treatment administered 8 weeks after PCA surgery. Body weight gain was assessed on a weekly basis, and serum liver function, liver weight and liver glycogen content were assessed following euthanasia. Most PCA-induced phenotypes were reverted to normal levels following AVP-modelled deficiency, though hypoglycemia and ammonium levels remained elevated in the PCA + CV group. Liver histopathological findings showed a significant reversal in collagen content, less fibrosis in the triad and liver septa and increased regenerative nodules. Molecular analyses showed that the expression of fibrogenic genes (TGF-β and collagen type I) decreased in the PCA + CV group. Our findings strongly suggest that chronic NIL or CV treatment can induce a favourable microenvironment to decrease liver fibrosis and support CV as an alternative treatment for liver fibrosis.

The characterization of the functional state of the NIL animals is important to know all the possible physiological implications of the permanent deficiency of the hormones arginine vasopressin (AVP) and oxytocin (OT). In order to obtain knowledge of the unknown relationships of the effects of NIL on pituitary hormones blood level (GH, PRL, ACTH, TSH, LH, AVP and OT), as well as on urine production, water intake and body weight, groups of Intact Control (IC) and NIL male Wistar rats were compared at 3 and 8 weeks post‐surgery. Hormone levels were assessed by ELISA kits.ResultsNIL caused a transient diabetes insipidus; urine production and water intake returned to normal values between 2 to 4 weeks post‐NIL. AVP and OT serum levels in NIL rats were significantly decreased in 80% and 90% at 3 and 8 weeks post‐surgery. GH and TSH, were significantly decreased at 3 but not at 8 weeks post‐NIL. PRL and ACTH serum levels remained unchanged in both times. Final body weights of NIL animals were 20% less than the IC.ConclusionsNIL animals are a good experimental paradigm to study the protracted effects of AVP and OT deficiency. It is possible that the decreased GH serum levels NIL‐induced, caused the less gain of body weight of these animals.Support or Funding InformationSupported by CONACYT‐221262. México (AQS)