Evaluation of antidepressant and sleep-promoting effects of cordycepin in a menopause-like stress model

The menopausal transition is often accompanied by mood disturbances and sleep disorders, exacerbated by estrogen deficiency and chronic stress. Although hormone replacement therapy (HRT) is effective, its use is limited by safety concerns, underscoring the need for non-hormonal alternatives. Cordycepin (3'-deoxyadenosine), a bioactive compound derived from Cordyceps militaris, has demonstrated neuromodulatory and anti-inflammatory properties in various central nervous system models. However, its combined effects on mood and sleep disturbances under menopause-related conditions have not been fully elucidated. In this study, we evaluated the therapeutic potential of cordycepin in ovariectomized rats subjected to chronic immobilization stress (OVX+IMO), a validated preclinical model of menopausal mood and sleep dysregulation. Cordycepin treatment (intraperitoneally) significantly alleviated depressive- and anxiety-like behaviors in multiple behavioral paradigms, including the forced swim test, tail suspension test, and elevated plus maze, comparable to the effects of estradiol. At the neuroendocrine level, cordycepin decreased serum corticosterone and suppressed corticotropin-releasing factor (CRF) and c-fos expression in the hypothalamic paraventricular nucleus, indicating attenuation of hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. Additionally, cordycepin elevated hippocampal and cortical levels of brain-derived neurotrophic factor (BDNF) and serotonin, restored the glutamate/GABA ratio, and increased melatonin concentrations in the hypothalamus. Electrophysiological analyses demonstrated reduced sleep latency and prolonged non-rapid eye movement (NREM) sleep duration, indicating improved sleep initiation and maintenance. These findings suggest that cordycepin exerts antidepressant and sleep-enhancing effects through multi-target modulation of neuroendocrine signaling, neurotransmitter systems, and circadian regulation. Given its efficacy, natural origin, and favorable safety profile, cordycepin emerges as a promising non-hormonal candidate for the management of menopausal mood and sleep disorders.