Rutin reportedly conveys many beneficial effects, including neuroprotection in brain injury. However, the mechanisms underlying these effects are still not well understood. This study investigates the effect of rutin on potential mechanisms for neuroprotective effects, using the weight-drop model of traumatic brain injury (TBI) in male mice treated either with rutin or a vehicle via intraperitoneal injection 30 min after TBI. After euthanasia and 24 h after TBI, all mice were examined by tests, including neurologic scores, blood-brain barrier permeability, brain water content and neuronal cell death in the cerebral cortex. Results indicate that the levels of cytochrome c, malondialdehyde (MDA) and superoxide dismutase (SOD) were restored by rutin treatment. Rutin treatment resulted in the downregulation of caspase-3 expression in a reduced number of positive cells under terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, and also the improved survival of neurons. Furthermore, pretreatment levels of MDA were restored, while Bcl-2-associated X protein translocation to mitochondria and cytochrome c release into cytosol were reduced by rutin treatment. Our results demonstrate that rutin improves neurological outcome by protecting neural cells against apoptosis via mechanisms that involve the mitochondria following TBI.

Wu Q, Xia SX, Li QQ, Gao Y, Shen X, Ma L, Zhang MY, Wang T, Li YS, Wang ZF, Luo CL, Tao LY: Mitochondrial division inhibitor 1 (Mdivi-1) offers neuroprotection through diminishing cell death and improving functional outcome in a mouse model of traumatic brain injury. Brain Res 2016;1630:134-143.
Kilbaugh TJ, Karlsson M, Duhaime AC, Hansson MJ, Elmer E, Margulies SS: Mitochondrial response in a toddler-aged swine model following diffuse non-impact traumatic brain injury. Mitochondrion 2015;26:19-25.
Ferri P, Angelino D, Gennari L, Benedetti S, Ambrogini P, Del GP, Ninfali P: Enhancement of flavonoid ability to cross the blood-brain barrier of rats by co-administration with α-tocopherol. Food Funct 2015;6:394-400.
Qu J, Zhou Q, Du Y, Zhang W, Bai M, Zhang Z, Xi Y, Li Z, Miao J: Rutin protects against cognitive deficits and brain damage in rats with chronic cerebral hypoperfusion. Br J Pharmacol 2014;171:3702-3715.
Hur SJ, Park SJ, Jeong CH: Effect of buckwheat extract on the antioxidant activity of lipid in mouse brain and its structural change during in vitro human digestion. J Agric Food Chem 2011;59:10699-10704.
Man YG, Zhou RG, Zhao B: Efficacy of rutin in inhibiting neuronal apoptosis and cognitive disturbances in sevoflurane or propofol exposed neonatal mice. Int J Clin Exp Med 2015;8:14397-14409.
Flierl MA, Stahel PF, Beauchamp KM, Morgan SJ, Smith WR, Shohami E: Mouse closed head injury model induced by a weight-drop device. Nat Protoc 2009;4:1328-1337.
Xu J, Wang H, Ding K, Zhang L, Wang C, Li T, Wei W, Lu X: Luteolin provides neuroprotection in models of traumatic brain injury via the Nrf2-ARE pathway. Free Radic Biol Med 2014;71:186-195.
Wagner C, Vargas AP, Roos DH, Morel AF, Farina M, Nogueira CW, Aschner M, Rocha JB: Comparative study of quercetin and its two glycoside derivatives quercitrin and rutin against methylmercury (MeHg)-induced ROS production in rat brain slices. Arch Toxicol 2010;84:89-97.
Bizzozero OA, Ziegler JL, De Jesus G, Bolognani F: Acute depletion of reduced glutathione causes extensive carbonylation of rat brain proteins. J Neurosci Res 2006;83:656-667.
Gao Z, Xu H, Huang K: Effects of rutin supplementation on antioxidant status and iron, copper, and zinc contents in mouse liver and brain. Biol Trace Elem Res 2002;88:271-279.
Antonius D, Mathew N, Picano J, Hinds A, Cogswell A, Olympia J, Brooks T, DiGiacomo M, Baker J, Willer B, Leddy J: Behavioral health symptoms associated with chronic traumatic encephalopathy: a critical review of the literature and recommendations for treatment and research. J Neuropsychiatry Clin Neurosci 2014;26:313-322.
Shafi S, Barnes SA, Rayan N, Kudyakov R, Foreman M, Cryer HG, Alam HB, Hoff W, Holcomb J: Compliance with recommended care at trauma centers: association with patient outcomes. J Am Coll Surg 2014;219:189-198.
Stratton KJ, Clark SL, Hawn SE, Amstadter AB, Cifu DX, Walker WC: Longitudinal interactions of pain and posttraumatic stress disorder symptoms in U.S. military service members following blast exposure. J Pain 2014;15:1023-1032.
Reid MW, Miller KJ, Lange RT, Cooper DB, Tate DF, Bailie J, Brickell TA, French LM, Asmussen S, Kennedy JE: A multisite study of the relationships between blast exposures and symptom reporting in a post-deployment active duty military population with mild traumatic brain injury. J Neurotrauma 2014;31:1899-1906.
Ye Y, Xu H, Zhang X, Li Z, Jia Y, He X, Huang JH: Association between toll-like receptor 4 expression and neural stem cell proliferation in the hippocampus following traumatic brain injury in mice. Int J Mol Sci 2014;15:12651-12664.
Schreiber S, Lin R, Haim L, Baratz-Goldstien R, Rubovitch V, Vaisman N, Pick CG: Enriched environment improves the cognitive effects from traumatic brain injury in mice. Behav Brain Res 2014;271:59-64.
Ghadiri T, Sharifzadeh M, Khodagholi F, Modarres MSM, Hassanzadeh G, Zarrindast MR, Gorji A: A novel traumatic brain injury model for induction of mild brain injury in rats. J Neurosci Methods 2014;233:18-27.
Greene-Schloesser D, Moore E, Robbins ME: Molecular pathways: radiation-induced cognitive impairment. Clin Cancer Res 2013;19:2294-2300.
Roquilly A, Seguin P, Mimoz O, Feuillet F, Rosenczweig E, Chevalier F, Loutrel O, Malledant Y, Sebille V, Asehnoune K: Risk factors for prolonged duration of mechanical ventilation in acute traumatic tetraplegic patients - a retrospective cohort study. J Crit Care 2014;29:313.e7-e13.
Hailer NP: Immunosuppression after traumatic or ischemic CNS damage: it is neuroprotective and illuminates the role of microglial cells. Prog Neurobiol 2008;84:211-233.
Go KL, Lee S, Zendejas I, Behrns KE, Kim JS: Mitochondrial dysfunction and autophagy in hepatic ischemia/reperfusion injury. Biomed Res Int 2015;2015:183469.
Wang WX, Visavadiya NP, Pandya JD, Nelson PT, Sullivan PG, Springer JE: Mitochondria-associated microRNAs in rat hippocampus following traumatic brain injury. Exp Neurol 2015;265:84-93.
Cornelius C, Crupi R, Calabrese V, Graziano A, Milone P, Pennisi G, Radak Z, Calabrese EJ, Cuzzocrea S: Traumatic brain injury: oxidative stress and neuroprotection. Antioxid Redox Signal 2013;19:836-853.
Yan W, Wang HD, Hu ZG, Wang QF, Yin HX: Activation of Nrf2-ARE pathway in brain after traumatic brain injury. Neurosci Lett 2008;431:150-154.
Tyurin VA, Tyurina YY, Kochanek PM, Hamilton R, DeKosky ST, Greenberger JS, Bayir H, Kagan VE: Oxidative lipidomics of programmed cell death. Methods Enzymol 2008;442:375-393.
El HN, Stein KP, Hagel V, Dammann P, Sure U, Mueller O: The role of decompressive craniectomy in children with severe traumatic brain injury. Eur J Trauma Emerg Surg 2014;40:481-487.
Algattas H, Huang JH: Traumatic brain injury pathophysiology and treatments: early, intermediate and late phases post-injury. Int J Mol Sci 2014;15:309-341.
Tang V, Warden J, Cullen N, Rutledge E: Topiramate in traumatic brain injury: adverse effects on cognitive function. J Head Trauma Rehabil 2007;22:409-410.
Sanganahalli BG, Herman P, Hyder F, Kannurpatti SS: Mitochondrial functional state impacts spontaneous neocortical activity and resting state FMRI. PLoS One 2013;8:e63317.
Vervliet T, Parys JB, Bultynck G: Bcl-2 proteins and calcium signaling: complexity beneath the surface. Oncogene 2016, E-pub ahead of print.
Kim R, Emi M, Tanabe K: Role of mitochondria as the gardens of cell death. Cancer Chemother Pharmacol 2006;57:545-553.
Mele M, Alò R, Avolio E, Canonaco M: Bcl-2/Bax expression levels tend to influence AMPAergic trafficking mechanisms during hibernation in Mesocricetus auratus. J Mol Neurosci 2015;55:374-384.
Li YY, Chen D, Watkins SC, Feldman AM: Mitochondrial abnormalities in tumor necrosis factor-alpha-induced heart failure are associated with impaired DNA repair activity. Circulation 2001;104:2492-2497.
Wamstad JB, Norwood KW, Rogol AD, Gurka MJ, Deboer MD, Blackman JA, Buck ML, Kuperminc MN, Darring JG, Patrick PD: Neuropsychological recovery and quality-of-life in children and adolescents with growth hormone deficiency following TBI: a preliminary study. Brain Inj 2013;27:200-208.
Chen J, Wang L, Wu C, Hu Q, Gu C, Yan F, Li J, Yan W, Chen G: Melatonin-enhanced autophagy protects against neural apoptosis via a mitochondrial pathway in early brain injury following a subarachnoid hemorrhage. J Pineal Res 2014;56:12-19.
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