AT 1 ‐R is involved in the development of long‐lasting, region‐dependent and oxidative stress‐independent astrocyte morphological alterations induced by Ketamine

OCCHIEPPO, VICTORIA B.; BASMADJIAN, OSVALDO M.; MARCHESE, NATALIA A.; SILVERO C, M. JAZMIN; RODRÍGUEZ, ANAHÍ; ARMONELLI, SAMANTA; BECERRA, MARÍA C.; BAIARDI, GUSTAVO; BREGONZIO, CLAUDIA

EUROPEAN JOURNAL OF NEUROSCIENCE

WILEY-BLACKWELL PUBLISHING, INC

Año: 2020

0953-816X

Astrocytes play an essential role in the genesis, maturation and regulation of theneurovascular unit. Multiple evidence support that astrocyte reactivity has a closerelationship to neurovascular unit dysfunction, oxidative stress and inflammation,providing a suitable scenario for the development of mental disorders. Ketaminehas been proposed as a single-use antidepressant treatment in major depression, andits antidepressant effects have been associated with anti-inflammatory properties.However, Ketamine long-lasting effects over the neurovascular unit components re-main unclear. Angiotensin II AT1 receptor (AT1-R) blockers have anti-inflammatory,antioxidant and neuroprotective effects. The present work aims to distinguish theacute and long-term Ketamine effects over astrocytes response extended to other neu-rovascular unit components, and the involvement of AT1-R, in prefrontal cortex andventral tegmental area. Male Wistar rats were administered with AT1-R antagonistCandesartan/Vehicle (days 1?10) and Ketamine/Saline (days 6?10). After 14 daysdrug-free, at basal conditions or after Ketamine Challenge, the brains were processedfor oxidative stress analysis, cresyl violet staining and immunohistochemistry forglial, neuronal activation and vascular markers. Repeated Ketamine administrationinduced long-lasting region-dependent astrocyte reactivity and morphological altera-tions, and neuroadaptative changes observed as exacerbated oxidative stress and neu-ronal activation, prevented by the AT1-R blockade. Ketamine Challenge decreasedmicroglial and astrocyte reactivity and augmented cellular apoptosis, independentlyof previous treatment. Overall, AT1-R is involved in the development of neuroadap-tative changes induced by repeated Ketamine administration but does not interferewith the acute effects supporting the potential use of AT1-R blockers as a Ketaminecomplementary therapy in mental disorders.