Abstract
This study was conducted to clarify the potential mechanisms of Troxerutin neuroprotection against Lipopolysaccharide (LPS) induced oxidative stress and neuroinflammation through targeting the SIRT1/SIRT3 signaling pathway. To establish a model, a single dose of LPS (500μg/kg body weight) was injected to male Wistar rats intraperitoneally. Troxerutin (100 mg/kg body weight) was injected intraperitoneally for 5 days after induction of the model. Cognitive and behavioral evaluations were performed using Y-maze, single-trial passive avoidance, and novel object recognition tests. The expression of inflammatory mediators, SIRT1/SIRT3, and P53 was measured using the ELISA assay. Likewise, the expression levels of SIRT1/SIRT3 and NF-κB were determined using Western blot assay. Brain acetyl-cholinesterase activity was determined by utilizing the method of Ellman. Reactive oxygen species (ROS) was detected using Fluorescent probe 2, 7-dichlorofluorescein diacetate (DCFH-DA). Furthermore, malondialdehyde (MDA) levels were determined. A single intraperitoneal injection of LPS was led to ROS production, acute neuroinflammation, apoptotic cell death, and inactivation of the SIRT1/SIRT3 signaling pathway. Likewise, ELISA assay demonstrated that post-treatment with Troxerutin considerably suppressed LPS-induced acute neuroinflammation, oxidative stress, apoptosis and subsequently memory impairments by targeting SIRT1/SIRT3 signaling pathway. Western blot assay confirmed ELISA results about SIRT1/SIRT3 and NF-κB proteins. These results suggest that Troxerutin can be a suitable candidate to treat neuroinflammation caused by neurodegenerative disorders.
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Amani H, Ajami M, Nasseri Maleki S, Pazoki-Toroudi H, Daglia M, Tsetegho Sokeng AJ, Di Lorenzo A, Nabavi SF, Devi KP, Nabavi SM (2017) Targeting signal transducers and activators of transcription (STAT) in human cancer by dietary polyphenolic antioxidants. Biochimie 142:63–79
Amani, Hamed, Ebrahim Mostafavi, Hamidreza Arzaghi, Soodabeh Davaran, Abolfazl Akbarzadeh, Omid Akhavan, Hamidreza Pazoki-Toroudi, and Thomas J Webster. 2018. 'Three-dimensional graphene foams: synthesis, properties, biocompatibility, biodegradability, and applications in tissue engineering'. ACS Biomaterials Science & Engineering, 5: 193–214
Amani H, Habibey R, Shokri F, Hajmiresmail SJ, Akhavan O, Mashaghi A, Pazoki-Toroudi H (2019) Selenium nanoparticles for targeted stroke therapy through modulation of inflammatory and metabolic signaling. Sci Rep 9:6044
Badshah H, Ali T, Myeong OK (2016) Osmotin attenuates LPS-induced neuroinflammation and memory impairments via the TLR4/NFκB signaling pathway. J Scientific Reports 6:24493
Baluchnejadmojarad T, Jamali-Raeufy N, Zabihnejad S, Rabiee N, Roghani M (2017a) Troxerutin exerts neuroprotection in 6-hydroxydopamine lesion rat model of Parkinson’s disease: Possible involvement of PI3K/ERβ signaling. J European J Pharmacology 801:72–78
Baluchnejadmojarad T, Kiasalari Z, Afshin-Majd S, Ghasemi Z, Roghani M (2017b) S-allyl cysteine ameliorates cognitive deficits in streptozotocin-diabetic rats via suppression of oxidative stress, inflammation, and acetylcholinesterase. J European J Pharmacology 794:69–76
Block ML, Zecca L, Hong J-S (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. J Nature Reviews Neuroscience:8–57
Bromfield JJ, Iacovides SM (2017) Evaluating lipopolysaccharide-induced oxidative stress in bovine granulosa cells. J Assist Reprod Genet 34:1619–1626
Chen L, Li W, Qi D, Lu L, Zhang Z, Wang D (2018) Honokiol protects pulmonary microvascular endothelial barrier against lipopolysaccharide-induced ARDS partially via the Sirt3/AMPK signaling axis. J Life Sciences 210:86–95
Ellman GL, Diane Courtney K, Jr VA, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. J Biochemical Pharmacology 7:88–95
Esterbauer, Hermann, and Kevin H Cheeseman. (1990). [42] Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. in Methods in enzymology (Elsevier)
Geinisman Y (2000) Structural synaptic modifications associated with hippocampal LTP and behavioral learning. J Cerebral Cortex 10:952–962
Golechha M, Chaudhry U, Bhatia J, Saluja D, Singh D (2011) Naringin protects against kainic acid-induced status epilepticus in rats: evidence for an antioxidant, anti-inflammatory and neuroprotective intervention. J Biological Arya Pharmaceutical Bulletin 34:360–365
Gorina R, Font-Nieves M, Márquez-Kisinousky L, Santalucia T, Planas AM (2011) Astrocyte TLR4 activation induces a proinflammatory environment through the interplay between MyD88-dependent NFκB signaling, MAPK, and Jak1/Stat1 pathways. J Glia 59:242–255
Ian M (2017) The future of genomic medicine involves the maintenance of sirtuin 1 in global populations. Mol Biol 2:00013
Jamali-Raeufy N, Roghani M, Ramazi S, Mansouri M (2014) Administration of Salvianolic Acid B Attenuates Learning and Memory Deficits in Diabetic Rats: Involvement of Oxidative Stress. J Basic and Clinical Pathophysiology 2:43–50
Jamali-Raeufy N, Roghani M, Nikbakht F, Ramazi S, Zavvary F (2015) Salvianolic acid improves status epilepticus and learning and memory deficiency in rat model of temporal lobe epilepsy. J Basic and Clinical Pathophysiology 3:39–46
Jiang D-Q, Wang Y, Li M-X, Ma Y-J, Wang Y (2017) SIRT3 in neural stem cells attenuates microglia activation-induced oxidative stress injury through mitochondrial pathway. J Frontiers in Cellular Neuroscience 11:7
Kessler, M, G Ubeaud, T Walter, F Sturm, and L Jung. (2002). Free radical scavenging and skin penetration of troxerutin and vitamin derivatives, J Dermatological Treatment 13: 133–41
Martins IJ (2018) Bacterial lipopolysaccharides and neuron toxicity in neurodegenerative diseases. Neurol Neurosurg 1:1–3
Na J-Y, Song K, Kim S, Kwon J (2016) Rutin protects rat articular chondrocytes against oxidative stress induced by hydrogen peroxide through SIRT1 activation. Biochem Biophys Res Commun 473:1301–1308
Okun E, Griffioen KJ, Mattson MP (2011) Toll-like receptor signaling in neural plasticity and disease. J Trends Neurosciences 34:269–281
Panat NA, Singh BG, Maurya DK, Sandur SK, Ghaskadbi SS (2016) Troxerutin, a natural flavonoid binds to DNA minor groove and enhances cancer cell killing in response to radiation. J Chemico-Biological Interactions 251:34–44
Park BS, Lee J-O (2013) Recognition of lipopolysaccharide pattern by TLR4 complexes. J Experimental Molecular Medicine 45:e66
Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong J-S, Knapp DJ, Crews FT (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. J Glia 55:453–462
Salminen A, Kauppinen A, Suuronen T, Kaarniranta K (2008) SIRT1 longevity factor suppresses NF-κB-driven immune responses: regulation of aging via NF-κB acetylation? J Bioessays 30:939–942
Salminen A, Hyttinen JMT, Kaarniranta K (2011) AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan. J Mol Med 89:667–676
Shah SA, Khan M, Jo M-H, Jo MG, Amin FU, Kim MO (2017) Melatonin stimulates the SIRT 1/Nrf2 signaling pathway counteracting lipopolysaccharide (LPS)-induced oxidative stress to rescue postnatal rat brain. J CNS Neuroscience Therapeutics 23:33–44
Song J-H, Lee J-W, Shim B, Lee C-Y, Choi S, Kang C, Sohn N-W, Shin J-W (2013) Glycyrrhizin alleviates neuroinflammation and memory deficit induced by systemic lipopolysaccharide treatment in mice. J Molecules 18:15788–15803
Stephenson J, Nutma E, van der Valk P, Amor S (2018) Inflammation in CNS neurodegenerative diseases. J Immunol 154:204–219
Su K-Y, Yu CY, Chen Y-W, Huang Y-T, Chen C-T, Wu H-F, Chen Y-LS (2014) Rutin, a flavonoid and principal component of Saussurea involucrata, attenuates physical fatigue in a forced swimming mouse model. Int J Med Sci 11:528–537
Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, Mayo MW (2004) Modulation of NF-κB-dependent transcription and cell survival by the SIRT1 deacetylase. J The EMBO J 23:2369–2380
Zanoni I, Ostuni R, Marek LR, Barresi S, Barbalat R, Barton GM, Granucci F, Kagan JC (2011) CD14 controls the LPS-induced endocytosis of Toll-like receptor 4. J Cell 147:868–880
Zhang Z-F, Zhang Y-q, Fan S-H, Zhuang J, Zheng Y-L, Lu J, Wu D-M, Shan Q, Hu B (2015) Troxerutin protects against 2, 2′, 4, 4′-tetrabromodiphenyl ether (BDE-47)-induced liver inflammation by attenuating oxidative stress-mediated NAD+-depletion. J Hazardous Materials 283:98–109
Zhao L, Chen Y-H, Wang H, Ji Y-L, Ning H, Wang S-F, Cheng Z, Lu J-W, Duan Z-H, Xu D-X (2008) Reactive oxygen species contribute to lipopolysaccharide-induced teratogenesis in mice. J Toxicol Sci 103:149–157
Zhào, Hóngyi, Yu Liu, Jing Zeng, Dandan Li, Weiwei Zhang, Yonghua Huang. (2018). Troxerutin and Cerebroprotein Hydrolysate Injection Protects Neurovascular Units from Oxygen-Glucose Deprivation and Reoxygenation-Induced Injury In Vitro, J Evidence-Based Complementary and Alternative Medicine 2018
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The present study was financially supported by research affairs of Iran University of Medical Sciences.
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Jamali-Raeufy, N., Kardgar, S., Baluchnejadmojarad, T. et al. Troxerutin exerts neuroprotection against lipopolysaccharide (LPS) induced oxidative stress and neuroinflammation through targeting SIRT1/SIRT3 signaling pathway. Metab Brain Dis 34, 1505–1513 (2019). https://doi.org/10.1007/s11011-019-00454-9
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DOI: https://doi.org/10.1007/s11011-019-00454-9