37.3 INVOLVEMENT OF ANGIOTENSIN II TYPE 1 RECEPTOR (AT1R) IN SCHIZOPHRENIA: A NEW TARGET FOR DRUG REPURPOSING

BACKGROUND: In the last decades, associations between angiotensin-converting enzyme gene polymorphism and susceptibility to schizophrenia were demonstrated. Brain renin-angiotensin system (RAS) is related to neuroinflammatory alterations mainly related to the activation of microglial angiotensin II type 1 receptor (AT1R). Hence, the dysregulation of brain RAS is associated with changes in glutamate release, reactive oxygen species (ROS) formation and activation of pro-inflammatory pathways, events also related to the pathophysiology of schizophrenia. In fact, a progressive increase in microglial activation from adolescence to adulthood was observed in schizophrenia patients, while in the plasma increased levels of interleukin (IL)-1β, IL-6, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and soluble IL-2 receptor (sIL-2R) were detected. In the brain, AT1R activates NF-kB, a transcription factor for pro-inflammatory cytokines and ROS. Based on the possible involvement of RAS in schizophrenia in the present study we sought to evaluate the expression of AT1R, NF-kB and cytokines in the hippocampus of mice neonatally challenged with the virus mimetic poly I:C and exposed to peripubertal stress, a neurodevelopmental two-hit model of schizophrenia. As secondary outcome we treated periadolescent animals with candesartan, an AT1R antagonist, to verify the prevention of schizophrenia symptoms and neurobiological alterations. METHODS: Male Swiss mice were challenged from the 5th to the 7th postnatal days (PN) with poly I:C 2 mg/kg or sterile saline, intraperitoneally. The animals were exposed during adolescence to unpredictable stress (US), on alternate days, from PN 35th to 42nd or not (NS). Another group of animals received oral doses of 0.3 mg/kg candesartan or saline from PN30-50. On PN70 the animals were submitted to behavioral determinations related to positive- (prepulse inhibition of the startle reflex – PPI), negative- (social interaction test) and cognitive-like (Y maze test) schizophrenia symptoms. Some animals were dissected for hippocampal removal and determination of immune-inflammatory alterations. RESULTS: Our results showed that the exposure to PolyI:C+US induced schizophrenia-related symptoms namely, PPI deficit, decreased social contacts and working memory impairment when compared to saline-treated mice. These behavioral alterations were accompanied by increased hippocampal expression of IBA1 (a marker of microglial activation), AT1R, NF-kB, IL-4, IL-6, TNFα and pro-oxidative alterations. The AT1R blocker, candesartan, prevented the behavioral and most of the neuroimmune alterations induced by PolyI:C+US exposure. CONCLUSIONS: In conclusion, immune-inflammatory mechanisms related to AT1R activation seems to be involved in schizophrenia neurobiology, being this receptor an important target for drug repurposing in this mental disorder. Finally, these are novel evidences not published yet.