Objective To investigate the effects of TAK-242, a specific Toll-like receptor 4 (TLR4) inhibitor, on autism spectrum disorder(ASD)-like behaviors and neuroinflammation in offspring rats induced by maternal immune activation (MIA), so as to provide an experimental basis for early ASD intervention. Methods Thirty pregnant SD rats were randomly divided into control group, LPS, and TAK-242 intervention group (n=10 per group).On gestational day 9.5 (G9.5), the LPS and TAK-242 groups received an intraperitoneal injection of 100μg/kg LPS, while the control group received an equivalent volume of PBS.The TAK-242 group received a pre-injection of 3mg/kg TAK-242 2 hours before LPS administration.Male offspring underwent behavioral tests at 6 - 8 weeks of age to assess their social behavior and cognitive function.Serum levels of IL-6 and TNF-α in the dams and offspring were measured using ELISA.In the offspring, the expression of inflammatory factors in the prefrontal cortex (PFC) was detected by qRT-PCR, while microglial morphology and the expression of the marker Iba-1 were examined by immunohistochemistry. Results Compared with the control group, the LPS group showed significantly elevated serum levels of IL-6 and TNF-α in both dams and offspring (P<0.001).Offspring in the LPS group exhibited ASD-like behavioral abnormalities, including increased marble burying, reduced central zone duration in the open field, decreased social index, and impaired learning and memory (F=9.811, 14.490, 31.750, 5.250, P<0.05).Furthermore, the LPS group demonstrated up-regulated mRNA expression of pro-inflammatory factors and down-regulated mRNA expression of anti-inflammatory factors in the PFC (P<0.001), along with microglial activation (characterized by enlarged cell bodies and shortened processes) and increased Iba-1 expression.TAK-242 intervention significantly ameliorated all these abnormalities (P<0.05). Conclusions TAK-242 ameliorates MIA-induced ASD-like behaviours in offspring by inhibiting the TLR4/NF-κB signalling pathway, potentially through modulating microglial polarization and attenuating neuroinflammation.
Key words
autism spectrum disorder /
TAK-242 /
microglia /
Toll-like receptor 4 /
lipopolysaccharide
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References
[1] Bian Q,Chen Y,Zhang J, et al.Maternal natural killer cells drive neuroimmune disorders in offspring through aberrant secretion of extracellular granzyme B[J].Immunity,2025,58(6):1502-1518.e8.
[2] Yu H, Lin L, Zhang Z, et al.Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study[J].Signal Transduct Target Ther, 2020, 5(1): 209.
[3] Mastenbroek LJM, Kooistra SM, Eggen BJL, et al.The role of microglia in early neurodevelopment and the effects of maternal immune activation[J].Semin Immunopathol, 2024, 46(1-2): 1.
[4] Ono Y, Maejima Y, Saito M, et al.TAK-242, a specific inhibitor of Toll-like receptor 4 signalling, prevents endotoxemia-induced skeletal muscle wasting in mice[J].Sci Rep, 2020, 10(1): 694.
[5] Xie J, Tuo P, Zhang W et al.Inhibition of the TLR4/NF-κB pathway promotes the polarization of LPS-induced BV2 microglia toward the M2 phenotype[J].Neuroreport,2023,34(17):834-844.
[6] 张蓓,王敏囡,尼罗帕,等.产后早期免疫激活对小鼠孤独症样行为和胶质细胞的影响[J].中国儿童保健杂志,2024,32(4):405-411.
Zhang B, Wang MN, Niluopa, et al.Effects of early postpartum immune activation on autism-like behavior and glial cells in mice[J].Chin J Child Health Care, 2024, 32(4): 405-411.(in Chinese)
[7] Xia YM,Guan YQ,Liang JF, et al.TAK-242 improves sepsis-associated acute kidney injury in rats by inhibiting the TLR4/NF-κB signaling pathway.[J].Ren Fail,2024,46(1):2313176.
[8] Norollahi SE, Babaei K, Pashidy-Pour A, et al.Role of the TLR signaling pathway in the pathogenesis of glioblastoma multiforme with an emphasis on immunotherapy[J].Biochem Biophys Rep, 2025, 43: 102149.
[9] Sorge RE, Lacroix-Fralish ML, Tuttle AH, etal.Spinal cord Toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice[J].J Neurosci, 2011, 31(43): 15450-15454.
[10] 林涛.TAK-242通过抑制TLR4-NF-κB通路减轻出血后脑积水的研究[D].济南:山东大学,2022.
Lin T.Pharmacological inhibition of TLR4-NF-κB signaling by TAK-242 attenuates posthemorrhagic hydrocephalus[D].Jinan: Shandong University, 2022.(in Chinese)
[11] Feng Y, Ju Y, Wu Q, et al.TAK-242, a toll-like receptor 4 antagonist, against brain injury by alleviates autophagy and inflammation in rats[J].Open Life Sci, 2023, 18(1): 20220662.
[12] Hughes HK, Rowland ME, Onore CE, et al.Dysregulated gene expression associated with inflammatory and translation pathways in activated monocytes from children with autism spectrum disorder[J].Transl Psychiatry, 2022, 12(1): 39.
[13] Rice TW, Wheeler AP, Bernard GR, et al.A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis[J].Crit Care Med, 2010, 38(8): 1685-1694.
[14] Sultan S, Alhejin N, Serafi R, et al.Does vitamin D deficiency increase the risk of autism spectrum disorder? Linking evidence with theory—A narrative review[J].Psychiatry Int, 2025, 6(1): 22.
[15] Yu H, Lin L, Zhang Z, et al.Targeting NF-κB pathway for the therapy of diseases: Mechanism and clinical study[J].Signal Transduct Target Ther, 2020, 5(1): 209.
[16] Mowry FE, Peaden SC, Stern JE, et al.TLR4 and AT1R mediate blood-brain barrier disruption, neuroinflammation, and autonomic dysfunction in spontaneously hypertensive rats[J].Pharmacol Res, 2021, 174: 105877.
[17] 孙梦菲.基于TLR4/MyD88/NF-κB信号通路探讨汉黄芩素抑制小胶质细胞炎症并保护神经元细胞的实验研究[D].北京:中国中医科学院,2024.
Sun MF.Experimental study on wogonin inhibiting microglial inflammation and protecting neuronal cells with wogonin based on TLR4/MyD88/NF-κB signaling pathway[D].Beijing: China Academy of Chinese Medical Sciences, 2024.(in Chinese)
[18] Wu X, He T, Yang C, et al.Suppressing TLR4 alleviates cerebral injury in heatstroke rats through the modulation of microglial polarization[J].Int J Hyperthermia, 2025, 42(1): 2503312.
[19] Zhang X, Li J, Cao C, et al.Nrf2 activation by neferine mitigates microglial neuroinflammation after subarachnoid hemorrhage through inhibiting TAK1-NF-κB signaling[J].Int Immunopharmacol, 2024, 130: 111693.
[20] Hughes HK, Moreno RJ, Ashwood P.Innate immune dysfunction and neuroinflammation in autismspectrum disorder (ASD)[J].Focus, 2024, 22(2): 229-241.
[21] Paolicelli RC, Sierra A, Stevens B, et al.Microglia states and nomenclature: A field at its crossroads[J].Neuron, 2022, 110(21): 3458-3483.
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