Effects of Arginine Vasopressin (AVP) Deficiency, Conivaptan and Desmopressin on Clinical Symptoms and Blood Cytokine Levels in Rats with Experimental Autoimmune Encephalomyelitis

Abstract

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.

Arginine vasopressin hormone receptor antagonists in experimental autoimmune encephalomyelitis rodent models: A new approach for human multiple sclerosis treatment

“…This is evaluated by the effects of desmopressin, which increases the permeability of the BBB membrane. Evidence that AVP deficiency is responsible for the decreased immune response in the EAE rats is strongly supported by the similar decreased severity in the clinical symptoms and brain and spinal cord histopathological lymphocyte infiltrations with conivaptan, a specific V1a-V2 AVP receptors antagonist (Quintanar-Stephano et al, 2012;Quintanar-Stephano et al, 2019, 2018Viñuela-Berni et al, 2020; Figure 2). On the other hand, Bossinger suggested that the administration of OXT in patients with MS during aggravation or remission periods alleviates the symptoms (Bossinger, 1966); however, AVP and OXT can bind to V1a and V2 receptors (Terrillon et al, 2003).…”

“…Experiments on Wistar and Lewis rat strains, subjected to neurointermediate pituitary lobectomy (NIL) induced a permanent decrease in AVP and oxytocin (OXT) serum levels. Immune studies in these animals showed that innate, humoral, and cell mediated immune responses were decreased (not suppressed) (Quintanar-Stephano et al, 2012;Quintanar-Stephano et al, 2019). Experiments in NIL Lewis rats immunized for EAE, showed that NIL animals developed just a mild clinical symptom of EAE, whereas desmopressin administration (an agonist of V2 AVP receptors) restored the susceptibility of these animals to EAE (Quintanar-Stephano et al, 2016, 2018.…”

“…Immune studies in these animals showed that innate, humoral, and cell mediated immune responses were decreased (not suppressed) ( Quintanar-Stephano et al, 2012 ; Quintanar-Stephano et al, 2019 ). Experiments in NIL Lewis rats immunized for EAE, showed that NIL animals developed just a mild clinical symptom of EAE, whereas desmopressin administration (an agonist of V2 AVP receptors) restored the susceptibility of these animals to EAE ( Quintanar-Stephano et al, 2016 , 2012 , 2018 ). Similarly, AVP is involved in some CNS disorders, such as stroke, brain edema, ischemia, and modulation of the IS in EAE ( Hedna et al, 2014 ; Zeynalov et al, 2015 ; Viñuela-Berni et al, 2020 ).…”

“…In more advanced stages, the animals develop hind leg paralysis. Activation of AVP receptors expressed in immune cells increases the levels of pro-inflammatory cytokines (IL-2, IL-6, IL-17, INF-γ, and TNF-α), whereas AVP deficiency (NIL-induced) or blocking of the AVP receptors with a V1a and V2 AVP antagonist (conivaptan) decreases clinical symptoms, pro-inflammatory cytokines, and BBB permeability ( Figure 3 ; ( Quintanar-Stephano et al, 2018 ; Viñuela-Berni et al, 2020 ).…”

“…Desmopressin is a synthetic analog of AVP for V2R. It restores or enhances the levels of IL-1 and IL c-2 in splenic ells in NIL animals, increasing the stimulation of immune response in EAE animals, and conivaptan (a V1aR and V2R antagonist) diminishes the activity of the IS in EAE ( Quintanar-Stephano et al, 2018 ).…”