Phenylbutyrate improves recognition memory and increases dendritic spines in the prefrontal cortex and hippocampus in hypertensive female rats

Abstract Hypertension and aging are two major global health challenges. They frequently coexist, presenting with aging-related neuronal alterations which are exacerbated under hypertensive conditions. In the present study, we utilized female, 12-month-old spontaneously hypertensive (SH) rats as a translational animal model of combined hypertension and aging. Phenylbutyrate (PB), a compound with reported anti-inflammatory and neuroprotective properties was evaluated for its effects on recognition memory and dendritic architecture. PB treatment significantly improved both short- and long-term recognition memory, as assessed by the novel object recognition test. At the structural level, PB increased dendritic spine density in the prefrontal cortex (PFC) and in multiple subregions of the dorsal hippocampus, including CA1, CA3, and the dentate gyrus. Moreover, PB selectively enhanced the proportion of mature spine phenotypes, increasing mushroom and bifurcated spines in the PFC and hippocampal subregions examined. Together, these findings indicate that PB mitigates recognition memory decline and preserves dendritic spine density and morphology in cortico-hippocampal circuits in this animal model. Our results support PB as a potential therapeutic strategy for neurocognitive dysfunction associated with the comorbidity of hypertension and aging.