Gene expression profile and cytokine analysis in experimental autoimmune encephalomyelitis (EAE) in AVP deficient rats

Abstract

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.

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 , 2018 ; Viñuela-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 , 2012 , 2018 ).…”

“…Moreover, AVP is present in the CSF of patients diagnosed with neurological diseases, such as organic dementia, Parkinson’s disease, and MS ( Sundquist et al, 1983 ). Viñuela-Berni et al (2020) , using the EAE rat model, demonstrated the pivotal role of increased AVP serum levels on BBB permeability, whereas Quintanar-Stephano et al (2012 , 2019) showed the exacerbation of EAE clinical symptoms using desmopressin (dDAVP, a synthetic agonist of the V2 AVP receptors) in low AVP serum levels NIL rats. This is evaluated by the effects of desmopressin, which increases the permeability of the BBB membrane.…”