Ketamine induced long-term astrocyte plasticity in a region-dependent and oxidative stress-independent manner involving AT1-R activation

OCCHIEPPO, VICTORIA BELEN; BASMADJIAN, OSVALDO MARTIN; MARCHESE NATALIA ANDREA; SILVERO C, M. JAZMIN; RODRÍGUEZ, ANAHÍ; BECERRA, MARÍA C.; BAIARDI, GUSTAVO; BREGONZIO CLAUDIA

Glasgow

Congreso; Fens Virtual Forum 2020; 2020

Fens

Astrocytes play an essential role in the genesis, maturation and regulation of the neurovascular unit. Multiple evidences support that astrocyte reactivity is in close relation with neurovascular unit dysfunction, oxidative stress and inflammation, providing a particular scenario for the development of mental disorders. Ketamine has been proposed as a single-use antidepressant treatment in major depression and its antidepressant effects have been associated with anti-inflammatory properties. However, Ketamine long-lasting effects over the neurovascular unit components remain unclear. Angiotensin II AT1 receptor (AT-1R) blockers have anti-inflammatory, antioxidant and neuroprotective effects. The present work aims to evaluate the key role of AT1-R in the development of Ketamine long-term and acute effects over astrocytes response extended to other neurovascular unit components, in the Prefrontal cortex and ventral tegmental area. Male Wistar rats were administered with AT1-R antagonist Candesartan/vehicle (days 1?10) and Ketamine/saline (days 6?10). After 14 days drug-free, at basal conditions or after Ketamine Challenge, the brains were processed for oxidative stress analysis, cresyl violet staining, and immunohistochemistry against glial, neuronal activation and vascular markers. Ketamine induced long-lasting and region-dependent astrocyte reactivity and morphological alterations, concomitant increased oxidative stress and neuronal activation elicited by Ketamine Challenge; which were prevented by the AT1-R blockade. Ketamine Challenge-induced region-dependent decreased microglial expression and augmented cellular apoptosis do not involved AT1-R activation. Overall, we present new evidence about Ketamine long-lasting and acute effects over the neurovascular unit that support the AT1-R involvement, which would be of great impact in its potential use as an antidepressant.