The role of JAK/STAT/SOCS3 signaling in rats with brain damage induced by early alcohol exposure after birth

Abstract

Early postnatal alcohol exposure can have negative impacts on neonatal rat brain development and function. Our research explored the impacts of alcohol exposure from postnatal day 4 to PD9 on Sprague‒Dawley rat pups. Pups were intragastrically administered with either an alcohol milk solution or a pure milk solution twice daily. On PD10, brains were analyzed via histological and biochemical methods. Alcohol exposure led to growth impairment, behavioral abnormalities, and cognitive deficits. It also reduced microglial numbers in the hippocampus while activating the remaining microglia to secrete IL-6. In addition, alcohol induced the upregulation of pro-apoptotic factors and downregulation of the anti-apoptotic protein BCL-2 in the hippocampus by activating the JAK/STAT/SOCS3 signaling pathway. Similar effects were observed in vitro when BV-2 cells were exposed to ethanol and HT-22 cells were exposed to IL-6. The drug AG490, a STAT3 inhibitor, mitigated IL-6-induced JAK/STAT activation and neuronal apoptosis in HT-22 cells. Overall, these findings demonstrate that early-life alcohol exposure triggers an inflammatory microglial response involving the release of IL-6, which activates JAK/STAT signaling, leading to hippocampal neuronal apoptosis and developmental/cognitive impairments. AG490 may disrupt this inflammatory signaling cascade and cause neuronal damage.

Keywords

alcohol exposure / brain damage / JAK/STAT/SOCS3 / neonatal rats / neuroinflammation

References

[1] May PA, Chambers CD, Kalberg WO, et al. Prevalence of fetal alcohol spectrum disorders in 4 US communities. JAMA. 2018;319(5):474-482.

[2] Ehrhart F, Roozen S, Verbeek J, et al. Review and gap analysis: molecular pathways leading to fetal alcohol spectrum disorders. Mol Psychiatr. 2019;24(1):10-17.

[3] Granato A, Dering B. Alcohol and the developing brain: why neurons die and how survivors change. Int J Mol Sci. 2018;19(10):2992.

[4] Wozniak JR, Riley EP, Charness ME. Clinical presentation, diagnosis, and management of fetal alcohol spectrum disorder. Lancet Neurol. 2019;18(8):760-770.

[5] Klintsova AY, Hamilton DA, Mooney SM, Petrenko C. Proceedings of the 2018 annual meeting of the fetal alcohol spectrum disorders study group. Alcohol. 2019;81:47-55.

[6] Popova S, Lange S, Probst C, Gmel G, Rehm J. Estimation of national, regional, and global prevalence of alcohol use during pregnancy and fetal alcohol syndrome: a systematic review and meta-analysis. Lancet Glob Healt. 2017;5(3):e290-e299.

[7] Wilhoit LF, Scott DA, Simecka BA. Fetal alcohol spectrum disorders: characteristics, complications, and treatment. Community Ment Health J. 2017;53(6):711-718.

[8] Denny L, Coles S, Blitz R. Fetal alcohol syndrome and fetal alcohol spectrum disorders. Am Fam Physician. 2017;96(8):515-522.

[9] Drew PD, Kane CJ. Fetal alcohol spectrum disorders and neuroimmune changes. Int Rev Neurobiol. 2014;118:41-80.

[10] Kane CJ, Phelan KD, Drew PD. Neuroimmune mechanisms in fetal alcohol spectrum disorder. Dev Neurobiol. 2012;72(10):1302-1316.

[11] Deak T, Kelliher KT, Wojcik HJ, Gano A. Prenatal and adolescent alcohol exposure programs immunity across the lifespan: CNS-mediated regulation. Pharmacol Biochem Behav. 2022;216:173390.

[12] Noor S, Milligan ED. Lifelong impacts of moderate prenatal alcohol exposure on neuroimmune function. Front Immunol. 2018;9:1107.

[13] Borst K, Dumas AA, Prinz M. Microglia: immune and nonimmune functions. Immunity. 2021;54(10):2194-2208.

[14] Kwon HS, Koh SH. Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener. 2020;9(1):42.

[15] Nayak D, Roth TL, McGavern DB. Microglia development and function. Annu Rev Immunol. 2014;32(1):367-402.

[16] Terreni L, De Simoni MG. Role of the brain in interleukin-6 modulation. Neuroimmunomodulation. 1998;5(3-4):214-219.

[17] West PK, Viengkhou B, Campbell IL, Hofer MJ. Microglia shield the murine brain from damage mediated by the cytokines IL-6 and IFN-α. Front Immunol. 2022;13:1036799.

[18] García-Juárez M, Camacho-Morales A. A. Defining the role of anti- and pro-inflammatory outcomes of interleukin-6 in mental health. Neuroscience. 2022;492:32-46.

[19] Darwish AH, Elgohary TM, Nosair NA. Serum interleukin-6 level in children with attention-deficit hyperactivity disorder (ADHD). J Child Neurol. 2019;34(2):61-67.

[20] Johnson DE, O'Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signaling axis in cancer. Nat Rev Clin Oncol. 2018;15(4):234-248.

[21] Zhu H, Jian Z, Zhong Y, et al. Janus kinase inhibition ameliorates ischemic stroke injury and neuroinflammation through reducing NLRP3 inflammasome activation via JAK2/STAT3 pathway inhibition. Front Immunol. 2021;12:714943.

[22] Wang G, Zhang B, Wang Y, Han S, Wang C. Crocin promotes apoptosis of human skin cancer cells by inhibiting the JAK/STAT pathway. Exp Ther Med. 2018;16(6):5079-5084.

[23] Dodington DW, Desai HR, Woo M. JAK/STAT - emerging players in metabolism. Trends Endocrinol Metab. 2018;29(1):55-65.

[24] Souvenir R, Fathali N, Ostrowski RP, Lekic T, Zhang JH, Tang J. Tissue inhibitor of matrix metalloproteinase-1 mediates erythropoietin-induced neuroprotection in hypoxia ischemia. Neurobiol Dis. 2011;44(1):28-37.

[25] Trengove MC, Ward AC. SOCS proteins in development and disease. Am J Clin Exp Immunol. 2013;2(1):1-29.

[26] Hristova M, Rocha-Ferreira E, Fontana X, et al. Inhibition of signal transducer and activator of transcription 3 (STAT3) reduces neonatal hypoxic-ischemic brain damage. J Neurochem. 2016;136(5):981-994.

[27] Seif F, Khoshmirsafa M, Aazami H, Mohsenzadegan M, Sedighi G, Bahar M. The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell Commun Signal. 2017;15(1):23.

[28] Kim J, Won JS, Singh AK, Sharma AK, Singh I. STAT3 regulation by S-nitrosylation: implication for inflammatory disease. Antioxid Redox Signal. 2014;20(16):2514-2527.

[29] Ruggiero MJ, Boschen KE, Roth TL, Klintsova AY. Sex differences in early postnatal microglial colonization of the developing rat Hippocampus following a single-day alcohol exposure. J Neuroimmune Pharmacol. 2018;13(2):189-203.

[30] Boschen KE, Ruggiero MJ, Klintsova AY. Neonatal binge alcohol exposure increases microglial activation in the developing rat hippocampus. Neuroscience. 2016;324:355-366.

[31] Hickman S, Izzy S, Sen P, Morsett L, El Khoury J. Microglia in neurodegeneration. Nat Neurosci. 2018;21(10):1359-1369.

[32] Kamal H, Tan GC, Ibrahim SF, et al. Alcohol use disorder, neurodegeneration, Alzheimer's and Parkinson's disease: interplay between oxidative stress, neuroimmune response and excitotoxicity. Front Cell Neurosci. 2020;14:282.

RIGHTS & PERMISSIONS

2024 2024 The Authors. Pediatric Discovery published by John Wiley & Sons Australia, Ltd on behalf of Children's Hospital of Chongqing Medical University.