AT1R antagonism can reverse age-dependent hypertension-related neuroinflammation and cognitive impairment in male Sprague Dawley rats

Title: AT₁R antagonism can reverse age-dependent hypertension-related neuroinflammation and cognitive
impairment in male Sprague Dawley rats

Authors: Kayla M. Nist, M.S., and Richard D. Wainford, Ph.D.

AIM: We hypothesize paraventricular nucleus (PVN)-specific blood brain barrier (BBB) disruption and
neuroinflammation increase age-related hypertension and sympathoexcitation, promoting cognitive impairment,
that can be attenuated by an Angiotensin II Type 1 Receptor (AT₁R)-dependent mechanism in male but not
female Sprague Dawley (SD) rats.

METHODS: In male and female SD rats aged 3, 8 and 16 months old (MO) (N=6/gp) and 16 MO male rats
treated with losartan (21 days; sc 3 mg/kg/day; N=6/gp) or hydrochlorothiazide (14 days; sc 4 mg/kg/day;
N=6/gp), blood pressure (femoral artery cannulation), sympathetic tone to the vasculature (iv hexamethonium)
and plasma NE (ELISA) was measured. Cognitive performance was assessed by the novel object recognition
task. BBB disruption was assessed via FITC extravasation and IHC/IF was performed for microglia (CD11b/c),
astrocytes (GFAP), IL-6 and TNF-⍺ in the PVN.

RESULTS: Aged male, but not female, SD rats develop hypertension, sympathoexcitation, and cognitive
impairment. PVN neuroinflammation, proinflammatory cytokine production and BBB disruption increased in
male, but not female rats with age. While losartan and hydrochlorothiazide significantly lowered BP to similar
extents, only losartan reduced sympathoexcitation, attenuated BBB disruption and neuroinflammation, and
reversed impairments in recognition memory in aged male rats.

CONCLUSIONS: Female sex steroids may prevent the development of age-dependent HTN which is associated
with PVN neuroinflammation. In agreement with recent clinical findings, lowering blood pressure with an AT₁R
antagonism improved cognitive function and, thus, an AT₁R antagonism represents a new therapeutic approach
to improve cognitive function in aging and hypertensive populations. Further, these findings suggest an AT₁R
antagonist may enhance cognitive performance in a more beneficial manner than thiazide diuretics.