The benefit of mineralocorticoid receptor blockade in the treatment of experimental autoimmune encephalomyelitis mice

Abstract

Research on the effects of the mineralocorticoid receptor (MR) suggested a role in innate and adaptive immune responses. The inflammatory profile is directly linked to MR activation in several pathologies such as cardiovascular diseases, autoimmunity, chronic renal disease and obesity. MR is a high-affinity receptor binding both mineralocorticoids and glucocorticoids. In this study, we explored the pharmacological modulation of MR with the mineralocorticoid agonist deoxycorticosterone (DOCA) and the antagonist spironolactone (SPIRO) on corticosterone levels in plasma, neuroinflammation, myelin status and neurodegeneration in the spinal cord of mice with experimental autoimmune encephalomyelitis (EAE) model of Multiple Sclerosis. Animals were treated from day 1 until sacrificed on day 17 post-induction, and experimental groups were divided into: EAE+DOCA (0.75 mg/kg s.c every 3 days), EAE+DOCA+SPIRO (Spironolactone: 25 mg/kg i.p daily), vehicle-treated EAE (EAE+VEH) and Control (CTRL). Administration of DOCA or vehicle to EAE conducted to similar neuropathological alterations. The MR antagonist (a) significantly decreased inflammatory parameters TLR4, IL-1β and microglial CD11b mRNAs and showed a tendency to reduced osteopontin, b) reduced the % of infiltrated cellular and demyelinated area, as well as the reactive gliosis (GFAP+ area and number of IBA1 + cells) vs EAE+DOCA (c) increased the area of the neuronal marker NeuN vs EAE+DOCA and EAE+VEH groups (d) improved functional performance in the rotarod test and clinical signs vs EAE+DOCA. Interestingly, plasma corticosterone was increased in EAE+VEH and EAE+DOCA vs CTRL, while SPIRO administration raised even more corticosterone levels. This hypercorticosteronemia had functional consequences, because the glucocorticoid receptor (GR) and the target gene serum glucocorticoid regulated kinase 1 (SGK1) mRNAs expression were also increased vs DOCA alone. We hypothesized that MR blockage with SPIRO downregulated inflammation-related spinal cord pathology whereas excess glucocorticoids circulating in the EAE+DOCA+SPIRO group may contribute to anti-inflammatory effects.