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Rationale: Emerging evidence indicates that persistent alcohol consumption escalates psychosocial trauma achieved by social defeat stress (SDS)-induced neurobiological changes and behavioral outcomes. Treatment with compounds with neuroprotective functions is believed to reverse ethanol (EtOH)-aggravated SDS-induced behavioral impairments., Objectives: We investigated the outcomes of diosgenin treatment, a phytosteroidal sapogenin in mice co-exposed to repeated SDS and EtOH administration., Methods: During a period of 14 days, SDS male mice were repeatedly administered EtOH (20%, 10 mL/kg) orally from days 8-14 (n = 9). Within days 1-14, SDS mice fed with EtOH were simultaneously treated with diosgenin (25 and 50 mg/kg) or fluoxetine (10 mg/kg) by oral gavage. Locomotor, cognitive-, depressive-, and anxiety-like behaviors were assessed. Adrenal weight, serum glucose, and corticosterone levels were assayed. Brain markers of oxido-inflammatory, neurochemical levels, monoamine oxidase-B, and acetylcholinesterase activities were measured in the striatum, prefrontal cortex, and hippocampus., Results: The anxiety-like behavior, depression, low stress resilience, social, and spatial/non-spatial memory decline exhibited by SDS mice exposed to repeated EtOH administration were alleviated by diosgenin (25 and 50 mg/kg) and fluoxetine, illustrated by increased dopamine and serotonin concentrations and reduced monoamine oxidase-B and acetylcholinesterase activities in the prefrontal cortex, hippocampus, and striatum. Diosgenin attenuated SDS + EtOH interaction induced corticosterone release and adrenal hypertrophy, accompanied by reduced TNF-α, IL-6, malondialdehyde, and nitrite levels in the striatum, prefrontal cortex, and hippocampus. Diosgenin increased glutathione, superoxide dismutase, and catalase levels in SDS + EtOH-exposed mice., Conclusions: Our data suggest that diosgenin reverses SDS + EtOH interaction-induced behavioral changes via normalization of hypothalamic-pituitary-adrenal axis, neurochemical neurotransmissions, and inhibition of oxidative and inflammatory mediators in mice brains., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Social defeat stress (SDS) due to changes in biochemical functions has been implicated in the pathogenesis of affective and cognitive disorders. Employing pharmacological approach with adaptogens in the management and treatment of psychosocial stress is increasingly receiving scientific attention. In this study, we investigated the neuroprotective effect of rutin, a bioflavonoid with neuroprotective and anti-inflammatory functions on neurobehavioral and neuro-biochemical changes in mice exposed to SDS. Groups of mice named the intruder mice received normal saline (10 mL/kg), rutin (5, 10, and 20 mg/kg, i.p.), and ginseng (50 mg/kg, i.p.) daily for 14 days, and then followed by 10 min daily SDS (physical/psychological) exposures to aggressor mice from days 7-14. Investigations consisting of neurobehavioral (locomotion, memory, anxiety, and depression) phenotypes, neuro-biochemical (oxidative, nitrergic, cholinergic, and pro-inflammatory cytokines) levels in discrete brain regions, and hypothalamic-pituitary-adrenal (HPA) axis consisting adrenal weight, corticosterone, and glucose concentrations were assessed. Rutin restored the neurobehavioral deficits and reduced the activity of acetylcholinesterase in the brains. Adrenal hypertrophy, increased serum glucose and corticosterone levels were significantly attenuated by rutin. SDS-induced release of tumor necrosis factor-alpha and interleukin-6 in the striatum, prefrontal cortex, and hippocampus were also suppressed by rutin in a brain-region-dependent manner. Moreover, SDS-induced oxidative stress characterized by low antioxidants (glutathione, superoxide-dismutase, catalase) and lipid peroxidation and nitrergic stress were reversed by rutin in discrete brain regions. Collectively, our data suggest that rutin possesses an adoptogenic potential in mice exposed to SDS via normalization of HPA, oxidative/nitrergic, and neuroinflammatory inhibitions. Thus, may be adopted in the management of neuropsychiatric syndrome due to psychosocial stress., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)