Protective effect of thymosin alpha-1 on postnatal systemic inflammation induced learning and memory impairment in mice

Objective To explore the effect of thymosin alpha-1 (Ta1) on postnatal systemic inflammation-induced learning and memory impairment in mice and their relevant mechanism. Methods (1) Twenty-four neonatal C57BL/6 mice were randomly assigned into normal saline group,lipopolysaccharide (LPS, 0.3 mg/kg) group, LPS (0.6 mg/kg) group, and LPS (0.9 mg/kg) group. And the animals were intraperitoneally injected with different doses of LPS or equal volume of saline for 5 days. The variations of body weight, liver weight relative to the body and tumor necrosis factor-α (TNF-α) level in serum and brain tissues were observed to determine the appropriate dose of LPS for simulating neonatal clinical infection. (2) A total of 60 newborn mice were randomly divided into three groups: control group, LPS group and Ta1 treatment group; mice in each group were continuously injected with equal volume saline, LPS (0.6 mg/kg) and Ta1 (0.4 mg/kg)+LPS (0.6 mg/kg) for 5 days. On day 28 and on day 56, Morris water maze was used to measure the spatial learning and memory abilities of mice; the concentrations of TNF-α, interleukin-1β (IL-1β), brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the hippocampus were examined by ELISA, and the expressions of toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) were measured by Western blotting. Results (1) As compared with the normal saline group, the mice in the LPS group (0.6 mg/kg) had significantly slower growth ([2.23±0.22] g vs. [1.18±0.21] g), increased relative liver weight to the body (0.052±0.004 vs. 0.072±0.007) and increased TNF-α levels in serum and brain tissues ([62.01±3.32] pg/mL vs. [151.06±14.51] pg/mL; [186.03±13.24] pg/mL vs. [298.71±41.61] pg/mL, P<0.05). (2) As compared with the LPS group, Ta1 treatment group had significantly shortened average escape latency in place navigation test, prolonged active time in spatial probe test, statistically decreased hippocampal TNF-α, IL-1β, TLR4 and NF-κB levels ([73.32±5.18] pg/mL vs. [58.61±4.03] pg/mL; [99.15±8.30] pg/mL vs. [75.56±6.13] pg/mL; 2.32±0.29 vs. 1.71±0.26; 1.77±0.24 vs. 1.26±0.14) and significantly increased BDNF and NGF levels ([1.33±0.12] pg/mL vs. [1.69±0.25] pg/mL; [41.45±3.47] pg/mL vs. [50.38±5.02] pg/mL, P<0.05). Conclusion Ta1 improves learning and memory functions and alleviates neuro-inflammation in postnatal infection of mice, and the underlying mechanism probably involves in inhibiting TLR4/NF-κB signaling pathway activation and increasing neurotrophic factors. Key words: Infectious disease; Thymosin alpha-1; Learning and memory ability; Brain-derived neurotrophic factor; Nerve growth factor; Toll-like receptor 4; Nuclear factor-κB