Abstract
Repeated mild traumatic brain injury (rmTBI) poses adversity in the form of neurological deficits. The ignition of long-term neurological aberrations post-TBI is appended with the microbiota gut–brain axis perturbation. Herein, we examined whether quercetin, which is anti-inflammatory and antioxidant flavonoid, serves as a prebiotic and modifies the compromised microbiome gut–brain axis in rmTBI mouse model. Male C57BL/6 mice were subjected to rmTBI for 7 times. The quercetin (50 mg/kg) was administered peroral from the day1 of first injury till 7 days post-injury. The neurobehavioral assessments were performed using return of righting reflex (ROR), rotarod, forced swimming test (FST), elevated zero maze (EZM), novel object recognition test (NORT), and Y-maze. Mice fecal samples, brains, and intestines were collected for molecular studies. Mice underwent rmTBI showed significant neurological deficits in ROR and rotarod test and also exhibited long-term neuropsychiatric aberrations like anxiety- and depression-like phenotypes, and cognitive deficits in EZM, FST, and Y-maze assays, respectively. Repeated peroral administration of quercetin ameliorated these neuropsychiatric problems. Quercetin treatment also restored the increased expression of GFAP and decreased expression of occludin and doublecortin in the frontal cortex and hippocampus of rmTBI mice. The altered levels of acetate and propionate, and microbial phylum abundance in fecal samples were also normalized in the quercetin-treated group. We also noted an improved intestinal permeability indicated by reduced villi rupture, blunting, and mucosal thinning in quercetin-treated mice. We suggest that the neuroprotective effect of quercetin may be mediated via remodeling of the microbiome gut–brain axis in rmTBI mouse model.
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References
Al-Zalabani, A. H., Al-Jabree, A. H., & Zeidan, Z. A. (2019). Is cesarean section delivery associated with autism spectrum disorder? Neurosciences (riyadh, Saudi Arabia), 24, 11–15. https://doi.org/10.17712/NSJ.2019.1.20180303
Angoa-Pérez, M., Zagorac, B., Anneken, J. H., Briggs, D. I., Winters, A. D., Greenberg, J. M., Ahmad, M., Theis, K. R., & Kuhn, D. M. (2020). Repetitive, mild traumatic brain injury results in a progressive white matter pathology, cognitive deterioration, and a transient gut microbiota dysbiosis. Scientific Reports. https://doi.org/10.1038/S41598-020-65972-4
Bansal, V., Costantini, T., Kroll, L., Peterson, C., Loomis, W., Eliceiri, B., Baird, A., Wolf, P., & Coimbra, R. (2009). Traumatic brain injury and intestinal dysfunction: Uncovering the neuro-enteric axis. Journal of Neurotrauma, 26, 1353–1359. https://doi.org/10.1089/NEU.2008.0858
Braniste, V., Al-Asmakh, M., Kowal, C., Anuar, F., Abbaspour, A., Tóth, M., Korecka, A., Bakocevic, N., Guan, N. L., Kundu, P., Gulyás, B., Halldin, C., Hultenby, K., Nilsson, H., Hebert, H., Volpe, B. T., Diamond, B., & Pettersson, S. (2014). The gut microbiota influences blood–brain barrier permeability in mice. Science Translational Medicine. https://doi.org/10.1126/SCITRANSLMED.3009759
Campbell, S., & MacQueen, G. (2004). The role of the hippocampus in the pathophysiology of major depression. Journal of Psychiatry and Neuroscience, 29, 417–426.
Chavarro, J. E., Martín-Calvo, N., Yuan, C., Arvizu, M., Rich-Edwards, J. W., Michels, K. B., & Sun, Q. (2020). Association of birth by cesarean delivery with obesity and type 2 diabetes among adult women. JAMA Network Open, 3, e202605. https://doi.org/10.1001/JAMANETWORKOPEN.2020.2605
Chiaretti, A., Antonelli, A., Riccardi, R., Genovese, O., Pezzotti, P., Di Rocco, C., Tortorolo, L., & Piedimonte, G. (2008). Nerve growth factor expression correlates with severity and outcome of traumatic brain injury in children. European Journal of Paediatric Neurology, 12, 195–204. https://doi.org/10.1016/J.EJPN.2007.07.016
Chuenkitiyanon, S., Vardhanabhuti, N., & Jianmongkol, S. (2012). A potential benefit of quercetin in preserving tight junction integrity. Journal of Epithelial Biology and Pharmacology, 5, 28–31. https://doi.org/10.2174/1875044301205010028
Cole, W. R., & Bailie, J. M. (2016). Neurocognitive and psychiatric symptoms following mild traumatic brain injury. Milton Park: Taylor & Francis Group.
Costa, L. G., Garrick, J. M., Roquè, P. J., & Pellacani, C. (2016). Mechanisms of neuroprotection by quercetin: Counteracting oxidative stress and more. Oxidative Medicine and Cellular Longevity, 2016, 2986796.
Dandekar, M. P., Palepu, M. S. K., Satti, S., Jaiswal, Y., Singh, A. A., Dash, S. P., Gajula, S. N. R., & Sonti, R. (2022). Multi-strain probiotic formulation reverses maternal separation and chronic unpredictable mild stress-generated anxiety- and depression-like phenotypes by modulating gut–microbiome–brain activity in rats. ACS Chemical Neuroscience. https://doi.org/10.1021/ACSCHEMNEURO.2C00143
Donoso, F., Ramírez, V. T., Golubeva, A. V., Moloney, G. M., Stanton, C., Dinan, T. G., & Cryan, J. F. (2019). Naturally derived polyphenols protect against corticosterone-induced changes in primary cortical neurons. International Journal of Neuropsychopharmacology, 22, 765–777. https://doi.org/10.1093/IJNP/PYZ052
Du, G., Zhao, Z., Chen, Y., Li, Z., Tian, Y., Liu, Z., Liu, B., & Song, J. (2016). Quercetin attenuates neuronal autophagy and apoptosis in rat traumatic brain injury model via activation of PI3K/Akt signaling pathway. Molecular Medicine Reports, 38, 1012–1019. https://doi.org/10.1080/01616412.2016.1240393
Du, G., Zhao, Z., Chen, Y., Li, Z., Tian, Y., Liu, Z., Liu, B., & Song, J. (2018). Quercetin protects rat cortical neurons against traumatic brain injury. Molecular Medicine Reports, 17, 7859–7865.
Eltokhi, A., Janmaat, I. E., Genedi, M., Haarman, B. C. M., & Sommer, I. E. C. (2020). Dysregulation of synaptic pruning as a possible link between intestinal microbiota dysbiosis and neuropsychiatric disorders. Journal of Neuroscience Research, 98, 1335–1369. https://doi.org/10.1002/JNR.24616
FitzGerald, M. J., & Spek, E. J. (2020). Microbiome therapeutics and patent protection. Nature Biotechnology, 38, 806–810. https://doi.org/10.1038/S41587-020-0579-Z
Fleminger, S. (2008). Long-term psychiatric disorders after traumatic brain injury. European Journal of Anaesthesiology, 25, 123–130. https://doi.org/10.1017/S0265021507003250
Fleminger, S., Oliver, D. L., Lovestone, S., Rabe-Hesketh, S., & Giora, A. (2003). Head injury as a risk factor for Alzheimer’s disease: The evidence 10 years on; a partial replication. Journal of Neurology, Neurosurgery, and Psychiatry, 74, 857–862. https://doi.org/10.1136/JNNP.74.7.857
Grinkina, N. M., Li, Y., Haber, M., Sangobowale, M., Nikulina, E., Lepre, C., ElSehamy, A. M., Dugue, R., et al. (2016). Righting reflex predicts long-term histological and behavioral outcomes in a closed head model of traumatic brain injury. PLoS ONE, 11, e0161053. https://doi.org/10.1371/JOURNAL.PONE.0161053
Guasch-Ferré, M., Salas-Salvadó, J., Ros, E., Estruch, R., Corella, D., Fitó, M., Martínez-González, M. A., Arós, F., et al. (2017). The PREDIMED trial, Mediterranean diet and health outcomes: How strong is the evidence? Nutrition, Metabolism, and Cardiovascular Diseases, 27, 624–632. https://doi.org/10.1016/J.NUMECD.2017.05.004
Gururaj, G. (2002). Epidemiology of traumatic brain injuries: Indian scenario. Neurological Research, 24, 24–28. https://doi.org/10.1179/016164102101199503
Hoyles, L., Snelling, T., Umlai, U. K., Nicholson, J. K., Carding, S. R., Glen, R. C., & McArthur, S. (2018). Microbiome–host systems interactions: Protective effects of propionate upon the blood-brain barrier. Microbiome. https://doi.org/10.1186/S40168-018-0439-Y
Huo, R., Zeng, B., Zeng, L., Cheng, K., Li, B., Luo, Y., Wang, H., Zhou, C., et al. (2017). Microbiota modulate anxiety-like behavior and endocrine abnormalities in hypothalamic-pituitary-adrenal axis. Frontiers in Cellular and Infection Microbiology, 7, 489. https://doi.org/10.3389/FCIMB.2017.00489/BIBTEX
Jang, H.-M., Lee, K.-E., & Kim, D.-H. (2019). The preventive and curative effects of Lactobacillus reuteri NK33 and bifidobacterium adolescentis NK98 on immobilization stress-induced anxiety/depression and colitis in mice. Nutrients. https://doi.org/10.3390/nu11040819
Jorge, R. E., Robinson, R. G., Starkstein, S. E., & Arndt, S. V. (1993). Depression and anxiety following traumatic brain injury. The Journal of Neuropsychiatry and Clinical Neurosciences, 5, 369–374. https://doi.org/10.1176/JNP.5.4.369
Kale, A., Pişkin, Ö., Baş, Y., Aydln, B. G., Can, M., Elmas, Ö., & Büyükuysal, Ç. (2018). Neuroprotective effects of quercetin on radiation-induced brain injury in rats. Journal of Radiation Research, 59, 404–410. https://doi.org/10.1093/JRR/RRY032
Kane, M. J., Angoa-Pérez, M., Briggs, D. I., Viano, D. C., Kreipke, C. W., & Kuhn, D. M. (2012). A mouse model of human repetitive mild traumatic brain injury. Journal of Neuroscience Methods, 203, 41–49. https://doi.org/10.1016/J.JNEUMETH.2011.09.003
Karimipour, M., Rahbarghazi, R., Tayefi, H., Shimia, M., Ghanadian, M., Mahmoudi, J., & Bagheri, H. S. (2019). Quercetin promotes learning and memory performance concomitantly with neural stem/progenitor cell proliferation and neurogenesis in the adult rat dentate gyrus. International Journal of Developmental Neuroscience, 74, 18–26. https://doi.org/10.1016/J.IJDEVNEU.2019.02.005
Ke, F., Li, H. R., Chen, X. X., Gao, X. R., Huang, L. L., Du, A. Q., Jiang, C., Li, H., & Ge, J. F. (2020). Quercetin alleviates LPS-induced depression-like behavior in rats via regulating BDNF-related imbalance of copine 6 and TREM1/2 in the hippocampus and PFC. Frontiers in Pharmacology, 10, 1544. https://doi.org/10.3389/FPHAR.2019.01544/BIBTEX
Khan, A., Ali, T., Rehman, S. U., Khan, M. S., Alam, S. I., Ikram, M., Muhammad, T., Saeed, K., Badshah, H., & Kim, M. O. (2018). Neuroprotective effect of quercetin against the detrimental effects of LPS in the adult mouse brain. Frontiers in Pharmacology, 9, 1–16. https://doi.org/10.3389/FPHAR.2018.01383/BIBTEX
Kim, E., Lauterbach, E. C., Reeve, A., Arciniegas, D. B., Coburn, K. L., Mendez, M. F., Rummans, T. A., & Coffey, E. C. (2007). Neuropsychiatric complications of traumatic brain injury: A critical review of the literature (A report by the ANPA Committee on research). Journal of Neuropsychiatry and Clinical Neurosciences, 19(2), 106–127. https://doi.org/10.1176/JNP.2007.19.2.106
Kosari-Nasab, M., Shokouhi, G., Ghorbanihaghjo, A., Mesgari-Abbasi, M., & Salari, A. A. (2019). Quercetin mitigates anxiety-like behavior and normalizes hypothalamus-pituitary-adrenal axis function in a mouse model of mild traumatic brain injury. Behavioural Pharmacology, 30, 282–289. https://doi.org/10.1097/FBP.0000000000000480
Ladak, A. A., Enam, S. A., & Ibrahim, M. T. (2019). A review of the molecular mechanisms of traumatic brain injury. World Neurosurgery, 131, 126–132. https://doi.org/10.1016/J.WNEU.2019.07.039
Lewis, K., Lutgendorff, F., Phan, V., Söderholm, J. D., Sherman, P. M., & McKay, D. M. (2010). Enhanced translocation of bacteria across metabolically stressed epithelia is reduced by butyrate. Inflammatory Bowel Diseases, 16(7), 1138–1148. https://doi.org/10.1002/IBD.21177
Li, X., Wang, H., Wen, G., Li, L., Gao, Y., Zhuang, Z., Zhou, M., Mao, L., & Fan, Y. (2018). Neuroprotection by quercetin via mitochondrial function adaptation in traumatic brain injury: PGC-1α pathway as a potential mechanism. Journal of Cellular and Molecular Medicine, 22(2), 883–891. https://doi.org/10.1111/jcmm.13313
Liebisch, G., Ecker, J., Roth, S., Schweizer, S., Öttl, V., Schött, H. F., Yoon, H., Haller, D., Holler, E., Burkhardt, R., & Matysik, S. (2019). Quantification of fecal short chain fatty acids by liquid chromatography tandem mass spectrometry-investigation of pre-analytic stability. Biomolecules. https://doi.org/10.3390/BIOM9040121
Lin, R., Piao, M., & Song, Y. (2019). Dietary quercetin increases colonic microbial diversity and attenuates colitis severity in citrobacter rodentium-infected mice. Frontiers in Microbiology, 10(MAY), 1092. https://doi.org/10.3389/FMICB.2019.01092/BIBTEX
Lowing, J. L., Susick, L. L., Caruso, J. P., Provenzano, A. M., Raghupathi, R., & Conti, A. C. (2014). Experimental traumatic brain injury alters ethanol consumption and sensitivity. Journal of Neurotrauma, 31(20), 1700–1710. https://doi.org/10.1089/NEU.2013.3286
Luo, Y., Zeng, B., Zeng, L., Du, X., Li, B., Huo, R., Liu, L., Wang, H., Dong, M., Pan, J., Zheng, P., Zhou, C., Wei, H., & Xie, P. (2018). Gut microbiota regulates mouse behaviors through glucocorticoid receptor pathway genes in the hippocampus. Translational Psychiatry, 8(1), 1–10. https://doi.org/10.1038/s41398-018-0240-5
Luo, Y., Zou, H., Wu, Y., Cai, F., Zhang, S., & Song, W. (2017). Mild traumatic brain injury induces memory deficits with alteration of gene expression profile. Scientific Reports, 7(1), 1–10. https://doi.org/10.1038/s41598-017-11458-9
Maas, A. I. R., Menon, D. K., Adelson, P. D., Andelic, N., Bell, M. J., Belli, A., Bragge, P., Brazinova, A., Büki, A., & Chesnut, R. M. (2017). Traumatic brain injury: Integrated approaches to improve prevention, clinical care, and research. The Lancet Neurology, 16(12), 987–1048.
Mannix, R., Berkner, J., Mei, Z., Alcon, S., Hashim, J., Robinson, S., Jantzie, L., Meehan, W. P., & Qiu, J. (2017). Adolescent mice demonstrate a distinct pattern of injury after repetitive mild traumatic brain injury. Journal of Neurotrauma, 34(2), 495–504. https://doi.org/10.1089/NEU.2016.4457
Martínez-Lapiscina, E. H., Clavero, P., Toledo, E., Estruch, R., Salas-Salvadó, J., San Julián, B., Sanchez-Tainta, A., Ros, E., Valls-Pedret, C., & Martinez-Gonzalez, M. Á. (2013). Mediterranean diet improves cognition: The PREDIMED-NAVARRA randomised trial. Journal of Neurology, Neurosurgery, and Psychiatry, 84(12), 1318–1325. https://doi.org/10.1136/JNNP-2012-304792
Martinez-Lapiscina, E. H., Clavero, P., Toledo, E., San Julian, B., Sanchez-Tainta, A., Corella, D., Lamuela-Raventos, R. M., Martinez, J. A., & Martinez-Gonzalez, M. A. (2013). Virgin olive oil supplementation and long-term cognition: The PREDIMED-NAVARRA randomized, trial. The Journal of Nutrition, Health & Aging, 17(6), 544–552. https://doi.org/10.1007/S12603-013-0027-6
Matharu, D., Dhotre, D., Balasubramanian, N., Pawar, N., Sagarkar, S., & Sakharkar, A. (2019). Repeated mild traumatic brain injury affects microbial diversity in rat jejunum. Journal of Biosciences. https://doi.org/10.1007/s12038-019-9940-0
Moreno, L. CGe. I., Puerta, E., Suárez-Santiago, J. E., Santos-Magalhães, N. S., Ramirez, M. J., & Irache, J. M. (2017). Effect of the oral administration of nanoencapsulated quercetin on a mouse model of Alzheimer’s disease. International Journal of Pharmaceutics, 517(1–2), 50–57. https://doi.org/10.1016/J.IJPHARM.2016.11.061
Neuberger, E. J., Swietek, B., Corrubia, L., Prasanna, A., & Santhakumar, V. (2017). Enhanced dentate neurogenesis after brain injury undermines long-term neurogenic potential and promotes seizure susceptibility. Stem Cell Reports, 9(3), 972–984. https://doi.org/10.1016/J.STEMCR.2017.07.015
Olsen, A. B., Hetz, R. A., Xue, H., Aroom, K. R., Bhattarai, D., Johnson, E., Bedi, S., Cox, C. S., & Uray, K. (2013). Effects of traumatic brain injury on intestinal contractility. Neurogastroenterology and Motility, 25(7), 593. https://doi.org/10.1111/NMO.12121
Opeyemi, O. M., Rogers, M. B., Firek, B. A., Janesko-Feldman, K., Vagni, V., Mullett, S. J., Wendell, S. G., Nelson, B. P., New, L. A., Mariño, E., Kochanek, P. M., Baylr, H., Clark, R. S. B., Morowitz, M. J., & Simon, D. W. (2021). Sustained dysbiosis and decreased fecal short-chain fatty acids after traumatic brain injury and impact on neurologic outcome. Journal of Neurotrauma, 38(18), 2610–2621. https://doi.org/10.1089/NEU.2020.7506
Peng, L., Li, Z. R., Green, R. S., Holzman, I. R., & Lin, J. (2009). Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. The Journal of Nutrition, 139(9), 1619. https://doi.org/10.3945/JN.109.104638
Porsolt, R. D., Bertin, A., & Jalfre, M. (1977). Behavioral despair in mice: a primary screening test for antidepressants. Archives Internationales De Pharmacodynamie Et De Therapie, 229(2), 327–336.
Rice, M. W., Pandya, J. D., & Shear, D. A. (2019). Gut microbiota as a therapeutic target to ameliorate the biochemical, neuroanatomical, and behavioral effects of traumatic brain injuries. Frontiers in Neurology. https://doi.org/10.3389/FNEUR.2019.00875
Ruiz, P. A., Braune, A., Hölzlwimmer, G., Quintanilla-Fend, L., & Haller, D. (2007). Quercetin inhibits TNF-induced NF-κB transcription factor recruitment to proinflammatory gene promoters in murine intestinal epithelial cells. The Journal of Nutrition, 137(5), 1208–1215. https://doi.org/10.1093/JN/137.5.1208
Schwarzbold, M., Diaz, A., Martins, E. T., Rufino, A., Amante, L. N., Thais, M. E., Quevedo, J., Hohl, A., Linhares, M. N., & Walz, R. (2008). Psychiatric disorders and traumatic brain injury. Neuropsychiatric Disease and Treatment, 4(4), 797. https://doi.org/10.2147/NDT.S2653
Sharma, D. R., Wani, W. Y., Sunkaria, A., Kandimalla, R. J., Sharma, R. K., Verma, D., Bal, A., & Gill, K. D. (2016). Quercetin attenuates neuronal death against aluminum-induced neurodegeneration in the rat hippocampus. Neuroscience, 324, 163–176. https://doi.org/10.1016/J.NEUROSCIENCE.2016.02.055
Shi, T., Bian, X., Yao, Z., Wang, Y., Gao, W., & Guo, C. (2020). Quercetin improves gut dysbiosis in antibiotic-treated mice. Food & Function, 11(9), 8003–8013. https://doi.org/10.1039/D0FO01439G
Sundman, M. H., Chen, N. K., Subbian, V., & Chou, Y. (2017). The bidirectional gut–brain–microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease. Brain, Behavior, and Immunity, 66, 31–44. https://doi.org/10.1016/J.BBI.2017.05.009
Suzuki, T., & Hara, H. (2009). Quercetin enhances intestinal barrier function through the assembly of zonula [corrected] occludens-2, occludin, and claudin-1 and the expression of claudin-4 in Caco-2 cells. The Journal of Nutrition, 139(5), 965–974. https://doi.org/10.3945/JN.108.100867
Tadepalli, S. A., Bali, Z. K., Bruszt, N., Nagy, L. V., Amrein, K., Fazekas, B., Büki, A., Czeiter, E., & Hernádi, I. (2020). Long-term cognitive impairment without diffuse axonal injury following repetitive mild traumatic brain injury in rats. Behavioural Brain Research. https://doi.org/10.1016/J.BBR.2019.112268
Tucker, L. B., Fu, A. H., & McCabe, J. T. (2016). Performance of male and female C57BL/6J mice on motor and cognitive tasks commonly used in pre-clinical traumatic brain injury research. Journal of Neurotrauma, 33(9), 880. https://doi.org/10.1089/NEU.2015.3977
Tucker, L. B., & McCabe, J. T. (2017). Behavior of male and female C57Bl/6J mice is more consistent with repeated trials in the elevated zero maze than in the elevated plus maze. Frontiers in Behavioral Neuroscience, 11, 13. https://doi.org/10.3389/FNBEH.2017.00013/BIBTEX
Urban, R. J., Pyles, R. B., Stewart, C. J., Ajami, N., Randolph, K. M., Durham, W. J., Danesi, C. P., Dillon, E. L., Summons, J. R., Singh, C. K., Morrison, M., Kreber, L. A., Masel, B., Miller, A. L., Wright, T. J., & Sheffield-Moore, M. (2020). Altered fecal microbiome years after traumatic brain injury. Journal of Neurotrauma, 37(8), 1037–1051. https://doi.org/10.1089/NEU.2019.6688
Verma, A. K., & Pratap, R. (2010). The biological potential of flavones. Natural Product Reports, 27(11), 1571–1593. https://doi.org/10.1039/C004698C
Vorhees, C. V., & Williams, M. T. (2006). Morris water maze: Procedures for assessing spatial and related forms of learning and memory. Nature Protocols, 1(2), 848–858. https://doi.org/10.1038/NPROT.2006.116
Wang, Y. Y., Chang, C. Y., Lin, S. Y., Wang, J. D., Wu, C. C., Chen, W. Y., Kuan, Y. H., Liao, S. L., Wang, W. Y., & Chen, C. J. (2020). Quercetin protects against cerebral ischemia/reperfusion and oxygen glucose deprivation/reoxygenation neurotoxicity. The Journal of Nutritional Biochemistry, 83, 108436. https://doi.org/10.1016/J.JNUTBIO.2020.108436
Wu, C. H., Hung, T. H., Chen, C. C., Ke, C. H., Lee, C. Y., Wang, P. Y., & Chen, S. F. (2014). Post-injury treatment with 7,8-dihydroxyflavone, a TrkB receptor agonist, protects against experimental traumatic brain injury via PI3K/Akt signaling. PLoS ONE, 9(11), e113397. https://doi.org/10.1371/JOURNAL.PONE.0113397
Wu, J., Vogel, T., Gao, X., Lin, B., Kulwin, C., & Chen, J. (2018). Neuroprotective effect of dexmedetomidine in a murine model of traumatic brain injury. Scientific Reports. https://doi.org/10.1038/S41598-018-23003-3
Xu, X., Cowan, M., Beraldo, F., Schranz, A., McCunn, P., Geremia, N., Brown, Z., Patel, M., Nygard, K. L., Khazaee, R., Lu, L., Liu, X., Strong, M. J., Dekaban, G. A., Menon, R., Bartha, R., Daley, M., Mao, H., Prado, V., & Brown, A. (2021). Repetitive mild traumatic brain injury in mice triggers a slowly developing cascade of long-term and persistent behavioral deficits and pathological changes. Acta Neuropathologica Communications, 9(1), 1–27. https://doi.org/10.1186/S40478-021-01161-2
Yang, S., Zhou, H., Wang, G., Zhong, X. H., Shen, Q. L., Zhang, X. J., Li, R. Y., Chen, L. H., Zhang, Y. H., & Wan, Z. (2020). Quercetin is protective against short-term dietary advanced glycation end products intake induced cognitive dysfunction in aged ICR mice. Journal of Food Biochemistry, 44(4), e13164. https://doi.org/10.1111/JFBC.13164
Yang, T., Kong, B., Gu, J. W., Kuang, Y. Q., Cheng, L., Yang, W. T., Xia, X., & Shu, H. F. (2014). Anti-apoptotic and anti-oxidative roles of quercetin after traumatic brain injury. Cellular and Molecular Neurobiology, 34(6), 797–804. https://doi.org/10.1007/S10571-014-0070-9
Yao, R. Q., Qi, D. S., Yu, H. L., Liu, J., Yang, L. H., & Wu, X. X. (2012). Quercetin attenuates cell apoptosis in focal cerebral ischemia rat brain via activation of BDNF–TrkB–PI3K/Akt signaling pathway. Neurochemical Research, 37(12), 2777–2786. https://doi.org/10.1007/S11064-012-0871-5
Zabenko, Y. Y., & Pivneva, T. A. (2016). Flavonoid quercetin reduces gliosis after repetitive mild traumatic brain injury in mice. Fiziolohichnyi Zhurnal (kiev, Ukraine : 1994), 62(5), 50–56. https://doi.org/10.15407/FZ62.05.050
Zhao, Z., Loane, D. J., Murray, M. G., Stoica, B. A., & Faden, A. I. (2012). Comparing the predictive value of multiple cognitive, affective, and motor tasks after rodent traumatic brain injury. Journal of Neurotrauma, 29(15), 2475–2489. https://doi.org/10.1089/NEU.2012.2511
Zhu, C. S., Grandhi, R., Patterson, T. T., & Nicholson, S. E. (2018). A review of traumatic brain injury and the gut microbiome: Insights into novel mechanisms of secondary brain injury and promising targets for neuroprotection. Brain Sciences. https://doi.org/10.3390/BRAINSCI8060113
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The authors (RB, MRB, TP, NS, LV, SG, and MPD) would like to thank NIPER, Hyderabad, for providing all the resources and DoP, Ministry of Chemicals and Fertilizers, Government of India, for providing fellowship.
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MPD thanks funding from the DST-SERB, File number SRG/2020/002439.
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RB executed behavioral studies and prepared the manuscript draft; MRB assisted in molecular studies and making a manuscript draft; TP and NS assisted in behavioral studies and animals sacrifice; LV and SG helped in SCFAs estimation; and MPD contributed to study design, data interpretation, and manuscript edits.
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Balasubramanian, R., Bazaz, M.R., Pasam, T. et al. Involvement of Microbiome Gut–Brain Axis in Neuroprotective Effect of Quercetin in Mouse Model of Repeated Mild Traumatic Brain Injury. Neuromol Med 25, 242–254 (2023). https://doi.org/10.1007/s12017-022-08732-z
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DOI: https://doi.org/10.1007/s12017-022-08732-z