RXR agonist

Adverse events in early life can alter the developmental trajectory of glial cells and neurons in the brain, increasing an individual's risk of developing neuropsychiatric disorders later in life. Retinoid X receptor alpha (RXRα), a member of the nuclear receptor superfamily, has been shown to exert protective effects on the central nervous system when activated. However, whether RXRα plays a role in maternal separation (MS) and the underlying mechanisms remain unclear. In this study, we used MS in BALB/c mice to simulate early-life stress, aiming to investigate the impact of MS on hippocampal neuronal development in mice during early life, as well as the neuroprotective role of RXRα and its mechanisms. The results showed that MS induced hippocampal neuronal damage and inhibited RXRα expression in offspring mice. In contrast, RXRα activation significantly ameliorated hippocampal neuronal damage in MS mice and exerted neuroprotective effects by suppressing oxidative stress, repairing mitochondrial dysfunction, reducing neuronal apoptosis, and promoting mitophagy. Further analysis revealed that bexarotene (an RXR agonist) exerted neuroprotective effects by upregulating the expression levels of RXRα and peroxisome proliferator-activated receptor gamma (PPARγ). In HT22 cells with hydrogen peroxide (H₂O₂)-induced damage, knockdown of PPARγ expression via small interfering RNA (siRNA) significantly attenuated the neuroprotective effect of RXRα activation against neuronal damage. In conclusion, MS impairs the development of hippocampal neurons in offspring mice, which may alter the developmental trajectory of the nervous system and increase the risk of neuropsychiatric disorders in adulthood. Activation of RXRα can effectively alleviate oxidative stress and neuronal damage in the hippocampus by improving mitochondrial dysfunction. Therefore, targeting RXRα holds promise as a potential strategy for treating the consequences of early-life trauma.