Lyoniresinol Attenuates Cobalt-Induced Neurobehavioral Deficits and Inflammatory Responses Associated With NF-κB/GSK3β/JNK Signaling in Rats.

Cobalt exposure, increasingly encountered in industrial and medical contexts, represents a rising neurotoxic threat, yet its underlying mechanisms and effective treatments remain poorly characterized. Here, we investigated the neuroprotective effects of Lyoniresinol, a natural lignan with antioxidant and anti-inflammatory properties, in a rat model of cobalt-induced neurodegeneration. Rats were exposed to cobalt chloride (CoCl₂, 40 mg/kg/day, intraperitoneally) for 14 days, with a subset receiving co-treatment with Lyoniresinol (30 mg/kg/day). Behavioral assessments demonstrated that Lyoniresinol significantly improved spatial memory, recognition memory, anxiety-like behavior, and motor coordination, as evaluated by the Morris water maze, novel object recognition, elevated plus maze, and rotarod test, respectively. Biochemical analyses revealed that Lyoniresinol enhanced antioxidant defense [increased superoxide dismutase (SOD) and reduced glutathione (GSH), reduced Malondialdehyde (MDA)], suppressed pro-inflammatory cytokines [Interlukin-1β (IL-1β), IL-6, tumour necrosis factor-α (TNF-α), C-reactive protein (CRP)], and normalized neurotransmitter levels [dopamine, serotonin, and Gamma-aminobutyric acid (GABA)], indicating restored redox homeostasis and neurochemical balance. Histopathological analysis confirmed preservation of hippocampal neuronal architecture in treated animals. Molecular investigations further demonstrated that Lyoniresinol significantly downregulated the overactivation of Nuclear Factor kappa B (NF-κB), Glycogen synthase kinase-3 beta (GSK3β), and c-Jun N-terminal kinase (JNK) signaling pathways at both mRNA and protein levels, as evidenced by qPCR and Western blot analyses. These findings suggest that Lyoniresinol exerts a broad-spectrum neuroprotective effect against cobalt-induced neurotoxicity by concurrently ameliorating behavioral impairments, oxidative and inflammatory stress, neurotransmitter disruptions, and intracellular signaling dysregulation.