Prenatal Ursolic acid Programmes Durable Epigenetic, Neuroendocrine and Neuroinflammatory Resilience against Sequential Early-life and Adult Glucocorticoid Stress in Rats

Abstract

Background: Early-life adversity programmes lifelong vulnerability to stress-related disease, and that vulnerability is compounded when adversity is followed by further challenge in adulthood. Interventions capable of conferring durable resilience remain scarce. We asked whether prenatal ursolic acid, a dietary pentacyclic triterpenoid, protects the rat prefrontal cortex against sequential early-life and adult stress. Methodology: Pregnant Wistar dams received ursolic acid (10 mg kg⁻¹ per day, orally) or vehicle throughout gestation. Male offspring were divided into four groups (n = 12) combining prenatal treatment with maternal separation on postnatal days 2–14. Prefrontal DNMT3a and H2AX transcription was quantified by reverse-transcription PCR, and serum corticosterone and prefrontal interleukin-1β, Nrf2 and brain-derived neurotrophic factor by ELISA. Six offspring from each group then matured to postnatal day 42, when the maternally separated groups received dexamethasone (0.5 mg kg⁻¹ per day for seven days) as a second challenge. Behaviour was assessed by forced swim, novel object recognition and elevated plus maze; structure by Golgi impregnation and haematoxylin and eosin staining. Results: Prenatal ursolic acid approximately doubled DNMT3a and H2AX transcription. Maternal separation raised corticosterone by 50%, more than doubled interleukin-1β and reduced Nrf2 by two-thirds; prenatal exposure abolished each effect. Following the adult challenge, prenatally exposed offspring maintained control-level corticosterone, interleukin-1β, Nrf2 and brain-derived neurotrophic factor, preserved dendritic arborisation, spine density and neuronal cytoarchitecture, and showed unimpaired performance across all three behavioural paradigms. Conclusion: Prenatal ursolic acid programmes durable, multilevel resilience that withstands sequential early-life and adult stress, identifying prenatal nutritional programming as a tractable route to lifelong stress resilience.