An imbalance in kynurenine pathway metabolism is hypothesized to be associated with dysregulated glutamatergic neurotransmission, which has been proposed as a mechanism underlying the hippocampal volume loss observed in a variety of neurological disorders. Pre-clinical models suggest that the CA2-3 and dentate gyrus hippocampal subfields are particularly susceptible to excitotoxicity after experimental traumatic brain injury. We tested the hypothesis that smaller hippocampal volumes in collegiate football athletes with (n = 25) and without (n = 24) a concussion history would be most evident in the dentate gyrus and CA2-3 subfields relative to nonfootball healthy controls (n = 27). Further, we investigated whether the concentration of peripheral levels of kynurenine metabolites are altered in football athletes. Football athletes with and without a self-reported concussion history had smaller dentate gyrus (p < 0.05, p < 0.10) and CA2-3 volumes (p's < 0.05) relative to healthy controls. Football athletes with and without a concussion history had a trend toward lower (p < 0.10) and significantly lower (p < 0.05) kynurenine levels compared with healthy controls, while athletes with a concussion history had greater levels of quinolinic acid compared with athletes without a concussion history (p < 0.05). Finally, plasma levels of 3-hydroxykynurenine inversely correlated with bilateral hippocampal volumes in football athletes with a concussion history (p < 0.01), and left hippocampal volume was correlated with the ratio of kynurenic acid to quinolinic acid in football athletes without a concussion history (p < 0.05). Our results raise the possibility that abnormalities of the kynurenine metabolic pathway constitute a mechanism for hippocampal volume differences in the context of sports-related brain injury.
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References
1.
SinghR., MeierT.B., KuplickiR., SavitzJ., MukaiI., CavanaghL., AllenT., TeagueT.K., NerioC., PolanskiD., and BellgowanP.S. (2014). Relationship of collegiate football experience and concussion with hippocampal volume and cognitive outcomes. JAMA, 311, 1883–1888.
2.
SavitzJ., DantzerR., WurfelB.E., VictorT.A., FordB.N., BodurkaJ., BellgowanP.S., TeagueT.K., and DrevetsW.C. (2015). Neuroprotective kynurenine metabolite indices are abnormally reduced and positively associated with hippocampal and amygdalar volume in bipolar disorder. Psychoneuroendocrinology, 52, 200–211.
3.
SavitzJ., DrevetsW.C., SmithC.M., VictorT.A., WurfelB.E., BellgowanP.S., BodurkaJ., TeagueT.K., and DantzerR. (2015). Putative neuroprotective and neurotoxic kynurenine pathway metabolites are associated with hippocampal and amygdalar volumes in subjects with major depressive disorder. Neuropsychopharmacology, 40, 463–471.
4.
AmaralM., OuteiroT.F., ScruttonN.S., and GiorginiF. (2013). The causative role and therapeutic potential of the kynurenine pathway in neurodegenerative disease. J. Mol. Med., 91, 705–713.
5.
SchwarczR., BrunoJ.P., MuchowskiP.J., and WuH.Q. (2012). Kynurenines in the mammalian brain: when physiology meets pathology. Nat. Rev. Neurosci., 13, 465–477.
6.
OkudaS., NishiyamaN., SaitoH., and KatsukiH. (1998). 3-Hydroxykynurenine, an endogenous oxidative stress generator, causes neuronal cell death with apoptotic features and region selectivity. J. Neurochem., 70, 299–307.
7.
SchwarczR., WhetsellW.O.Jr., and ManganoR.M. (1983). Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain. Science, 219, 316–318.
8.
StoneT.W., and DarlingtonL.G. (2013). The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders. Br. J. Pharmacol., 169, 1211–1227.
9.
BlightA.R., SaitoK., and HeyesM.P. (1993). Increased levels of the excitotoxin quinolinic acid in spinal cord following contusion injury. Brain Res. 632, 314–316.
10.
BellM.J., KochanekP.M., HeyesM.P., WisniewskiS.R., SinzE.H., ClarkR.S., BlightA.R., MarionD.W., and AdelsonP.D. (1999). Quinolinic acid in the cerebrospinal fluid of children after traumatic brain injury. Crit. Care Med., 27, 493–497.
11.
SinzE.H., KochanekP.M., HeyesM.P., WisniewskiS.R., BellM.J., ClarkR.S., DeKoskyS.T., BlightA.R., and MarionD.W. (1998). Quinolinic acid is increased in CSF and associated with mortality after traumatic brain injury in humans. J. Cereb. Blood Flow Metab., 18, 610–615.
12.
MackayG.M., ForrestC.M., StoyN., ChristofidesJ., EgertonM., StoneT.W., and DarlingtonL.G. (2006). Tryptophan metabolism and oxidative stress in patients with chronic brain injury. Eu. J. Neurol., 13, 30–42.
HicksR.R., SmithD.H., LowensteinD.H., Saint MarieR., and McIntoshT.K. (1993). Mild experimental brain injury in the rat induces cognitive deficits associated with regional neuronal loss in the hippocampus. J. Neurotrauma, 10, 405–414.
15.
LowensteinD.H., ThomasM.J., SmithD.H., and McIntoshT.K. (1992). Selective vulnerability of dentate hilar neurons following traumatic brain injury: a potential mechanistic link between head trauma and disorders of the hippocampus. J. Neurosci., 12, 4846–4853.
16.
GradyM.S., CharlestonJ.S., MarisD., WitgenB.M., and LifshitzJ. (2003). Neuronal and glial cell number in the hippocampus after experimental traumatic brain injury: analysis by stereological estimation. J. Neurotrauma, 20, 929–941.
17.
SmithD.H., LowensteinD.H., GennarelliT.A., and McIntoshT.K. (1994). Persistent memory dysfunction is associated with bilateral hippocampal damage following experimental brain injury. Neurosci. Lett., 168, 151–154.
18.
SandhirR., OnyszchukG., and BermanN.E. (2008). Exacerbated glial response in the aged mouse hippocampus following controlled cortical impact injury. Exp. Neurol., 213, 372–380.
19.
BaldwinS.A., GibsonT., CallihanC.T., SullivanP.G., PalmerE., and ScheffS.W. (1997). Neuronal cell loss in the CA3 subfield of the hippocampus following cortical contusion utilizing the optical disector method for cell counting. J. Neurotrauma, 14, 385–398.
20.
MeierT.B., BellgowanP.S., BergaminoM., LingJ.M., and MayerA.R. (2015). Thinner cortex in collegiate football players with, but not without, a self-reported history of concussion. J. Neurotrauma E-pub ahead of print.
21.
FischlB., SalatD.H., BusaE., AlbertM., DieterichM., HaselgroveC., van der KouweA., KillianyR., KennedyD., KlavenessS., MontilloA., MakrisN., RosenB., and DaleA.M. (2002). Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron, 33, 341–355.
22.
Van LeemputK., BakkourA., BennerT., WigginsG., WaldL.L., AugustinackJ., DickersonB.C., GollandP., and FischlB. (2009). Automated segmentation of hippocampal subfields from ultra-high resolution in vivo MRI. Hippocampus, 19, 549–557.
23.
WierengaL., LangenM., AmbrosinoS., van DijkS., OranjeB., and DurstonS. (2014). Typical development of basal ganglia, hippocampus, amygdala and cerebellum from age 7 to 24. NeuroImage, 96, 67–72.
24.
BoenE., WestlyeL.T., ElvsashagenT., HummelenB., HolP.K., BoyeB., AnderssonS., KarterudS., and MaltU.F. (2014). Smaller stress-sensitive hippocampal subfields in women with borderline personality disorder without posttraumatic stress disorder. J. Psychiatry Neurosci., 39, 127–134.
25.
TeicherM.H., AndersonC.M. and PolcariA. (2012). Childhood maltreatment is associated with reduced volume in the hippocampal subfields CA3, dentate gyrus, and subiculum. Proc. Natl. Acad. Sci. U. S. A., 109, E563–E572.
26.
WangZ., NeylanT.C., MuellerS.G., LenociM., TruranD., MarmarC.R., WeinerM.W., and SchuffN. (2010). Magnetic resonance imaging of hippocampal subfields in posttraumatic stress disorder. Arch. Gen. Psychiatry, 67, 296–303.
27.
McCreaM., HammekeT., OlsenG., LeoP., and GuskiewiczK. (2004). Unreported concussion in high school football players: implications for prevention. Clin. J. Sport Med., 14, 13–17.
28.
McAllisterT.W., FordJ.C., FlashmanL.A., MaerlenderA., GreenwaldR.M., BeckwithJ.G., BolanderR.P., TostesonT.D., TurcoJ.H., RamanR., and JainS. (2014). Effect of head impacts on diffusivity measures in a cohort of collegiate contact sport athletes. Neurology, 82, 63–69.
29.
ZierhutK.C., GrassmannR., KaufmannJ., SteinerJ., BogertsB., and SchiltzK. (2013). Hippocampal CA1 deformity is related to symptom severity and antipsychotic dosage in schizophrenia. Brain, 136, 804–814.
30.
SteinM.B., KoverolaC., HannaC., TorchiaM.G., and McClartyB. (1997). Hippocampal volume in women victimized by childhood sexual abuse. Psychol. Med., 27, 951–959.
31.
KawakamiR., ShinoharaY., KatoY., SugiyamaH., ShigemotoR., and ItoI. (2003). Asymmetrical allocation of NMDA receptor epsilon2 subunits in hippocampal circuitry. Science, 300, 990–994.
32.
ShinoharaY., HiraseH., WatanabeM., ItakuraM., TakahashiM., and ShigemotoR. (2008). Left-right asymmetry of the hippocampal synapses with differential subunit allocation of glutamate receptors. Proc. Natl. Acad. Sci. U. S. A., 105, 19498–19503.
33.
LiuY., WongT.P., AartsM., RooyakkersA., LiuL., LaiT.W., WuD.C., LuJ., TymianskiM., CraigA.M., and WangY.T. (2007). NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J. Neurosci., 27, 2846–2857.
34.
KraemerW.J., TorineJ.C., SilvestreR., FrenchD.N., RatamessN.A., SpieringB.A., HatfieldD.L., VingrenJ.L., and VolekJ.S. (2005). Body size and composition of National Football League players. J. Strength Cond. Res., 19, 485–489.
35.
OdeJ.J., PivarnikJ.M., ReevesM.J., and KnousJ.L. (2007). Body mass index as a predictor of percent fat in college athletes and nonathletes. Med. Sci. Sports Exerc., 39, 403–409.
SinghR., SavitzJ., TeagueT.K., PolanskiD.W., MayerA.R., BellgowanP.S., and MeierT.B. (2015). Mood symptoms correlate with kynurenine pathway metabolites following sports-related concussion. J. Neurol. Neurosurg. Psychiatry. Epub ahead of print.
38.
Colin-GonzalezA.L., MaldonadoP.D., and SantamariaA. (2013). 3-Hydroxykynurenine: an intriguing molecule exerting dual actions in the central nervous system. Neurotoxicology, 34, 189–204.
39.
FukuiS., SchwarczR., RapoportS.I., TakadaY., and SmithQ.R. (1991). Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism. J. Neurochem., 56, 2007–2017.
40.
GuilleminG.J., SmithD.G., SmytheG.A., ArmatiP.J., and BrewB.J. (2003). Expression of the kynurenine pathway enzymes in human microglia and macrophages. Adv. Exp. Med. Biol., 527, 105–112.
41.
GuidettiP., and SchwarczR. (1999). 3-Hydroxykynurenine potentiates quinolinate but not NMDA toxicity in the rat striatum. Eur. J. Neurosci., 11, 3857–3863.
42.
GabbayV., LiebesL., KatzY., LiuS., MendozaS., BabbJ.S., KleinR.G., and GonenO. (2010). The kynurenine pathway in adolescent depression: preliminary findings from a proton MR spectroscopy study. Prog. Neuropsychopharmacol. Biol. Psychiatry, 34, 37–44.
43.
BlaylockR.L., and MaroonJ. (2011). Immunoexcitotoxicity as a central mechanism in chronic traumatic encephalopathy—A unifying hypothesis. Surg. Neurol. Int., 2, 107.
44.
PerkinsM.N., and StoneT.W. (1982). An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Res. 247, 184–187.
45.
Lugo-HuitronR., Blanco-AyalaT., Ugalde-MunizP., Carrillo-MoraP., Pedraza-ChaverriJ., Silva-AdayaD., MaldonadoP.D., TorresI., PinzonE., Ortiz-IslasE., LopezT., GarciaE., PinedaB., Torres-RamosM., SantamariaA., and La CruzV.P. (2011). On the antioxidant properties of kynurenic acid: free radical scavenging activity and inhibition of oxidative stress. Neurotoxicol. Teratol., 33, 538–547.
46.
SumaT., KoshinagaM., FukushimaM., KanoT., and KatayamaY. (2008). Effects of in situ administration of excitatory amino acid antagonists on rapid microglial and astroglial reactions in rat hippocampus following traumatic brain injury. Neurol. Res., 30, 420–429.
47.
HicksR.R., SmithD.H., GennarelliT.A., and McIntoshT. (1994). Kynurenate is neuroprotective following experimental brain injury in the rat. Brain Res. 655, 91–96.
48.
SmithD.H., OkiyamaK., ThomasM.J., and McIntoshT.K. (1993). Effects of the excitatory amino acid receptor antagonists kynurenate and indole-2-carboxylic acid on behavioral and neurochemical outcome following experimental brain injury. J. Neurosci., 13, 5383–5392.
49.
SteinerJ., WalterM., GosT., GuilleminG.J., BernsteinH.G., SarnyaiZ., MawrinC., BrischR., BielauH., Meyer zu SchwabedissenL., BogertsB., and MyintA.M. (2011). Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission?. J. Neuroinflammation, 8, 94.
50.
SavitzJ., DantzerR., MeierT.B., WurfelB.E., VictorT.A., McIntoshS.A., FordB.N., MorrisH.M., BodurkaJ., TeagueT.K., and DrevetsW.C. (2015). Activation of the kynurenine pathway is associated with striatal volume in major depressive disorder. Psychoneuroendocrinology, 62, 54–58.
51.
Bay-RichterC., LinderholmK.R., LimC.K., SamuelssonM., Traskman-BendzL., GuilleminG.J., ErhardtS., and BrundinL. (2015). A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor in depression and suicidality. Brain Behav. Immun., 43, 110–117.
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