Ketamine induced long-term astrocyte plasticity in a region-dependent and oxidative stress-independent manner involving AT 1 -R activation

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

Congreso; Federation of European Neuroscience Societies Virtual Forum 2020; 2020

Federation of European Neuroscience Societies

Astrocytes play an essential role in the genesis, maturation and regulation of theneurovascular unit. Multiple evidences support that astrocyte reactivity is in closerelation with neurovascular unit dysfunction, oxidative stress and inflammation,providing a particular scenario for the development of mental disorders. Ketamine hasbeen proposed as a single-use antidepressant treatment in major depression and itsantidepressant effects have been associated with anti-inflammatory properties.However, Ketamine long-lasting effects over the neurovascular unit components remainunclear. Angiotensin II AT 1 receptor (AT- 1 R) blockers have anti-inflammatory,antioxidant and neuroprotective effects. The present work aims to evaluate the key roleof AT 1 -R in the development of Ketamine long-term and acute effects over astrocytesresponse extended to other neurovascular unit components, in the Prefrontal cortex andventral tegmental area. Male Wistar rats were administered with AT 1 -R antagonistCandesartan/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 foroxidative 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 increasedoxidative stress and neuronal activation elicited by Ketamine Challenge; which wereprevented by the AT 1 -R blockade. Ketamine Challenge-induced region-dependentdecreased microglial expression and augmented cellular apoptosis do not involved AT 1 -R activation. Overall, we present new evidence about Ketamine long-lasting and acuteeffects over the neurovascular unit that support the AT 1 -R involvement, which would beof great impact in its potential use as an antidepressant.