AT1-R is involved in the development of long-lasting, region-dependent and oxidative stress-independent astrocyte morphological alterations induced by Ketamine

Abstract

Astrocytes play an essential role in the genesis, maturation and regulation of the neurovascular unit. Multiple evidence support that astrocyte reactivity has a close relationship to neurovascular unit dysfunction, oxidative stress and inflammation, providing a suitable 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 (AT1-R) blockers have anti-inflammatory, antioxidant and neuroprotective effects. The present work aims to distinguish the acute and long-term Ketamine effects over astrocytes response extended to other neurovascular unit components, and the involvement of AT1-R, in 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 for glial, neuronal activation and vascular markers. Repeated Ketamine administration induced long-lasting region-dependent astrocyte reactivity and morphological alterations, and neuroadaptative changes observed as exacerbated oxidative stress and neuronal activation, prevented by the AT1-R blockade. Ketamine Challenge decreased microglial and astrocyte reactivity and augmented cellular apoptosis, independently of previous treatment. Overall, AT1-R is involved in the development of neuroadaptative changes induced by repeated Ketamine administration but does not interfere with the acute effects supporting the potential use of AT1-R blockers as a Ketamine complementary therapy in mental disorders.