Berberine attenuates SPS-induced cognitive and affective deficits and corticolimbic injury in Wistar rats via restoration of BDNF and redox–inflammatory balance

BACKGROUND: Single prolonged stress (SPS) is a validated PTSD-like paradigm that causes cognitive and affective dysfunction and corticolimbic injuries due to the dysregulation of the HPA-axis and neurotrophic, redox, and neuroimmune pathways. Berberine is a bioactive isoquinoline alkaloid that demonstrates neuroprotective effects, although its effect on corticolimbic-pathology caused by SPS is yet to be fully characterized. OBJECTIVES: To ascertain whether berberine attenuates SPS-induced neurobehavioral impairments and corticolimbic neuronal damage in Wistar rats. METHODS: Adult male Wistar rats were exposed to SPS (restraint, forced swim, and anesthetic-induced loss of consciousness) and left undisturbed for 7 days to allow stress consolidation. Then, rats were given oral berberine (50 or 200 mg/kg) or fluoxetine (10 mg/kg) in a single daily dose. Behavioral measures were Y-maze spontaneous alternation, Morris water maze, novel object recognition and sucrose preference. ELISA was used to quantify serum corticosterone. BDNF, SOD, catalase, MDA, and IL-1b/IL-6/TNF-a were assayed in the hippocampus and mPFC. CFV and NeuN immunohistochemistry were used to assess neuronal integrity and astrocytic reactivity was assessed using GFAP-immunoreactivity. RESULTS: SPS induced severe deficits in working memory, spatial and recognition memories and reward sensitivity, and high basal corticosterone. It increased lipid peroxidation and pro-inflammatory cytokines while reducing antioxidant enzyme activities in brain tissue homogenates (hippocampus and medial prefrontal cortex). Berberine improved behavioral outcomes and attenuated endocrine, biochemical, and histopathological abnormalities in a dose-dependent manner. CONCLUSION: Berberine attenuates SPS-induced-cognitive/affective dysfunction and corticolimbic-lesion and establishes normalization of basal corticosterone, BDNF recovery, antioxidant defense, lipid peroxidation, cytokine elevations, and astrocytic activation. These findings support berberine as a multi-target candidate for mitigating stress-related-neurotoxicity.