Naringin exhibits adaptogen-like and neuroprotective effects on mice under chronic stress, reversing cortical neuroinflammation and neurodegeneration

Chronic unpredictable mild stress (CUMS) induces impairment in cortical functional connectivity, which plays an important role in depression and anxiety. It remains unclear if naringin, a natural adaptogen with antidepressant and anxiolytic effects, reverses CUMS-induced depression by normalizing cortical dysfunction. Therefore, this study investigated the adaptogen-like anti-anxiety and antidepressant effects of naringin on mice subjected to CUMS and the underlying mechanisms in the prefrontal cortex (PFC). Adult male Swiss mice (n=9/group) received daily intraperitoneal injections of saline (10 mL/kg) for control and CUMS, naringin (2.5, 5, and 10mg/kg), or fluoxetine (10mg/kg), enduring CUMS for 21 days. Mice were assessed for depression and anxiety via neurobehavioural tests and neurochemical, biochemical and histochemical evaluations in the PFC. The hypothalamic-pituitary-adrenal (HPA) axis was measured by adrenal weight, serum corticosterone, and glucose levels. Naringin treatment reduced CUMS-induced depression, evidenced by higher sucrose consumption and decreased immobility in tests. It also alleviated anxiety-like behaviors in the elevated-plus maze and open-field tests. These effects correlated with lower corticosterone, serum glucose, and adrenal gland size. Naringin increased cortical antioxidant levels while reducing CUMS-induced lipid/nitrergic peroxidation and TNF-α and IL-1β. Both naringin and fluoxetine boosted serotonin, dopamine, and norepinephrine release in the PFC. Additionally, naringin countered CUMS-induced astrogliosis by lowering glial fibrillary acidic protein and upregulating brain-derived neurotrophic factor, with reduced pyknosis in the PFC. Naringin’s antidepressant/anxiolytic effects stem from inhibiting inflammation, oxidative stress, enhancing HPA function, monoamine release, and astrocytic activity in the mouse PFC. • NAR abated CUMS-induced depression and anxiety • NAR’s antidepressant effect involves improved cortical antioxidant system • NAR’s antidepressant effect involves inhibition cortical neuroinflammation • NAR countered CUMS-induced cortical astrogliosis • NAR improved cortical neurogenesis and neurotropism in CUMS mice