Psychopharmacology · 2026
The nonpeptide angiotensin-(1-7) mimic AVE0991 attenuates neuroendocrine and behavioral responses to chronic unpredictable stress.
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Fonseca Maria Luiza Antunes, de Oliveira Amaral Laura Beatriz, Gonçalves Sthéfanie C A, Costa Laura A, de Oliveira Laura Barroso Ferreira, Mourão Flávio A G, Fontes Marco Antônio Peliky, Bader Michael, Santos Robson A S, Campagnole-Santos Maria José, Kangussu Lucas M
Аннотация
RATIONALE: Chronic stress, frequently associated with dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis and reduced neuroplasticity, is a major risk factor for psychiatric disorders such as anxiety and depression.
OBJECTIVE: The present study aimed to validate a 21-day chronic unpredictable stress (CUS) model and to investigate the effects of the Mas receptor agonist AVE0991 on stress-induced behavioral and molecular alterations.
METHODS: Male C57BL/6J mice were exposed to a 21-day CUS protocol. Animals were randomly assigned to four groups: control + saline, CUS + saline, control + AVE0991, and CUS + AVE0991 (3 mg/kg, i.p.). AVE was administered daily during the last two weeks of the stress protocol. Behavioral tests were performed to evaluate anxiety- and depressive-like behaviors, and plasma corticosterone, blood glucose levels, and brain-derived neurotrophic factor (BDNF) levels in the prefrontal cortex, hippocampus, and hypothalamus were measured.
RESULTS: CUS exposure significantly increased plasma corticosterone and glucose levels and induced anxiety- and depressive-like behaviors. Stressed animals also showed reduced BDNF levels in the prefrontal cortex, hippocampus, and hypothalamus. Treatment with AVE0991 attenuated the increase in corticosterone and prevented stress-induced hyperglycemia. Moreover, AVE0991 reduced depressive-like behavior, increased latency to immobility, and improved anxiety-related parameters in the elevated plus maze and open field tests without affecting locomotor activity. AVE0991 also prevented the reduction of BDNF levels in stress-exposed animals.
CONCLUSION: These findings validate the CUS model and demonstrate that activation of the Mas receptor by AVE0991 exerts anxiolytic, antidepressant, and neuroprotective effects, supporting its potential as a therapeutic strategy for stress-related neuropsychiatric disorders.
OBJECTIVE: The present study aimed to validate a 21-day chronic unpredictable stress (CUS) model and to investigate the effects of the Mas receptor agonist AVE0991 on stress-induced behavioral and molecular alterations.
METHODS: Male C57BL/6J mice were exposed to a 21-day CUS protocol. Animals were randomly assigned to four groups: control + saline, CUS + saline, control + AVE0991, and CUS + AVE0991 (3 mg/kg, i.p.). AVE was administered daily during the last two weeks of the stress protocol. Behavioral tests were performed to evaluate anxiety- and depressive-like behaviors, and plasma corticosterone, blood glucose levels, and brain-derived neurotrophic factor (BDNF) levels in the prefrontal cortex, hippocampus, and hypothalamus were measured.
RESULTS: CUS exposure significantly increased plasma corticosterone and glucose levels and induced anxiety- and depressive-like behaviors. Stressed animals also showed reduced BDNF levels in the prefrontal cortex, hippocampus, and hypothalamus. Treatment with AVE0991 attenuated the increase in corticosterone and prevented stress-induced hyperglycemia. Moreover, AVE0991 reduced depressive-like behavior, increased latency to immobility, and improved anxiety-related parameters in the elevated plus maze and open field tests without affecting locomotor activity. AVE0991 also prevented the reduction of BDNF levels in stress-exposed animals.
CONCLUSION: These findings validate the CUS model and demonstrate that activation of the Mas receptor by AVE0991 exerts anxiolytic, antidepressant, and neuroprotective effects, supporting its potential as a therapeutic strategy for stress-related neuropsychiatric disorders.