The Ameliorative Effects of AT2 Receptor Activation with the Hexapeptide Novokinin on Streptozotocin-induced Model of Alzheimer's Disease in SHR

Abstract

Alzheimer's disease (AD), a form of dementia, presents a global concern. This study investigates the connection between hypertension and AD and the effects of the peptide novokinin (NVK), an AT2 receptor agonist in spontaneously hypertensive rats (SHRs). The brain's renin-angiotensin system (RAS) influences cognitive and emotional processes, suggesting potential intersections with AD. Streptozotocin (STZ), administered intracerebroventricularly (ICV), is used as a model of late-onset Alzheimer's disease. This model reveals a memory impairment associated with an insulin-resistant brain state, marked by neuroinflammatory processes contributing to cognitive deficits, oxidative stress, and reduced cerebral energy metabolism. NVK is an angiotensin AT2 receptor agonist, studied for its potential neuroprotective role. Female SHRs were used to investigate the effects of STZ-ICV (twice) and chronic NVK-ICV. NVK was administered for 14 days ICV using osmotic minipumps (ALZET®). The control group exhibited strain-typical increased exploratory activity, reduced anxiety in new environments, and impaired spatial memory, as expected for SHRs. The STZ-ICV negative control group showed signs of impaired memory and object recognition. In the `Open Field’ test, STZ-treated groups with and without NVK-ICV displayed heightened exploratory behaviour. Data from the `Elevated plus maze' test showed decreased anxiety in the STZ-ICV group while combining STZ and NVK normalized the anxiety behaviour. In the `T-maze' test, STZ-ICV-treated rats made fewer correct decisions. The STZ+NVK group exhibited enhanced spatial memory and improved anxiety-like behaviour in novel environments, potentially attributable to the proposed neuroprotective effects of NVK. These findings emphasize the association of RAS in the progression of AD and the potential protective role of the brain's AT2 receptors in this type of dementia.