Oxidative Stress, Metabolic Impairment and Neuroinflammation are Associated With Target Organ Damage in SHRSP

Stroke-prone spontaneously hypertensive rats (SHRSP) are widely used as a model to study cerebral small vessel disease (CSVD) and its association with chronic hypertension. This study investigated the relationship between metabolic, cardiovascular, and neuronal comorbidities in 32-week-old SHRSP rats versus Wistar-Kyoto (WKY) controls, with a focus on oxidative stress, inflammation, and metabolic alterations. Despite hypertension and cardiac and renal hypertrophy, no significant cerebral vascular changes or microbleeds and no cerebral edema were detected in SHRSP. NMR-based urinary metabolomics revealed reduced gut microbiome-derived metabolites, such as p-cresylglucuronide, hippurate, and phenylacetylglycine, alongside increases in methylamine and dimethylamine. These findings reflect gut dysbiosis and altered microbial composition in hypertensive conditions. Elevated markers of oxidative stress, including thiobarbituric acid-reactive substances, and increased expression of NADPH oxidase (NOX) 2 and NOX4 in peripheral tissues suggested oxidative damage in SHRSP rats. Astrocytic hyperreactivity, indicated by increased expression of glial fibrillary acidic protein in brain cortex and hippocampus, was suggestive of neuroinflammatory responses. Our findings highlight complex interplay between hypertension, metabolism, and neuroinflammation while underscoring the variability in SHRSP models. Key words SHRSP " Neuroinflammation " Oxidative stress " Metabolomics.