Brain AT1 Receptor Involvement in Cognitive Decline and Neuroinflammation in Streptozotocin-Treated Rats

Abstract

Neuroinflammation and oxidative stress are involved in neuropathologies related to learning and memory decline. Angiotensin II contributes to neuroinflammation through angiotensin II type 1 receptors (AT1-R), leading to oxidative stress and release of pro-inflammatory mediators. This study aimed to evaluate the role of brain angiotensin II, via AT1-R, in streptozotocin-induced cognitive decline and neuroinflammation. For this purpose, male Wistar rats were treated with the AT1-R blocker candesartan cilexetil (3 mg/kg) for 25 days. On days 12 and 14, the animals received an intraventricular injection of streptozotocin (3 mg/kg) each day. On day 25, they were tested for spatial, working, and declarative memory through the Morris water maze, holeboard, and novel object recognition tests, respectively. The oxidative stress marker, malondialdehyde, was measured in isolated brain microvessels. Cerebrospinal fluid was collected for tumor necrosis factor-α determination. The volume of the lateral ventricles was evaluated for morphological changes. The AT1-R blocker pretreatment prevented streptozotocin-induced declines in declarative and working memory. No changes in spatial and long-term memory were observed. Streptozotocin increased malondialdehyde in isolated microvessels and tumor necrosis factor-α levels, which were prevented by candesartan administration. All these findings are consistent with the involvement of AT1-R in early streptozotocin-induced changes, with behavioral and inflammatory/morphological outcomes likely mediated by overlapping yet partially distinct mechanisms.