Isoliquiritigenin attenuates lipopolysaccharide-induced cognitive impairment through antioxidant and anti-inflammatory activity

BACKGROUND: Oxidative stress and neuroinflammation are central pathogenic mechanisms common to many neurological diseases. Isoliquiritigenin (ISL) is a flavonoid in licorice with multiple pharmacological properties, including anti-inflammatory activity, and has demonstrated protective efficacy against acute neural injury. However, potential actions against cognitive impairments have not been examined extensively. We established a rat model of cognitive impairment by intracerebroventricular injection of lipopolysaccharide (LPS), and examined the effects of ISL pretreatment on cognitive function, hippocampal injury, and hippocampal expression of various synaptic proteins, antioxidant enzymes, pro-inflammatory cytokines, and signaling factors controlling anti-oxidant and pro-inflammatory responses. RESULTS: Rats receiving LPS alone demonstrated spatial learning deficits in the Morris water maze test as evidenced by longer average escape latency, fewer platform crossings, and shorter average time in the target quadrant than untreated controls. ISL pretreatment reversed these deficits as well as LPS-induced decreases in the hippocampal expression levels of synaptophysin, postsynaptic density-95, brain-derived neurotrophic factor, superoxide dismutase, glutathione peroxidase, and BCL-2. ISL pretreatment also reversed LPS-induced increases in TUNEL-positive (apoptotic) cells, BAX/BCL-2 ratio, and expression levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and C-C motif chemokine ligand 3. Pretreatment with ISL increased the expression levels of phosphorylated (p)-GSK-3β, nuclear NRF2, HO-1 mRNA, and NQO1 mRNA, and reversed LPS-induced nuclear translocation of nuclear factor (NF)-κB. CONCLUSIONS: ISL protects against LPS-induced cognitive impairment and neuronal injury by promoting or maintaining antioxidant capacity and suppressing neuroinflammation, likely through phosphorylation-dependent inactivation of GSK-3β, enhanced expression of NRF2-responsive antioxidant genes, and suppression of NF-κB-responsive pro-inflammatory genes.