Falls and traffic accidents can cause traumatic brain injury (TBI). Assessment of the injury severity is essential to determine the prognosis or the cause of death. Diabetes mellitus (DM) is a common preexisting disease in elderly adults. We hypothesized that preexisting DM exacerbates TBI secondary to prolonged inflammation. In this study, we investigated TBI-induced changes in nerve function and inflammatory cell migration to the injury site, and the extent of brain contusion in KK-Ay (DM) and C57BL/6J (non-DM) mice. A controlled cortical impact device was used to induce TBI in each mouse. The brain contusion volume was measured using magnetic resonance imaging. Nerve function changes were assessed using the following animal behavior tasks: neurological severity score (NSS), Morris water maze, forced swim test, and beam walking. Immunohistochemical examinations of brain sections were performed to assess the infiltration of neutrophils, astrocytes, microglia, and macrophages, and to detect apoptosis. These experiments were performed on post-injury days 1-90 (over five experiments/time-points in each group). Compared with non-DM mice, DM mice showed significantly greater brain contusion volume, greater deterioration in the NSS, and a higher number of neutrophils, macrophages, and apoptotic cells in the brain tissue specimens. This study indicates that the prognosis of normal mice and DM mice differs, even if they acquire a TBI of the same severity. Therefore, it is important to evaluate patients with TBI for DM and other preexisting diseases in order to provide adequate treatment or to determine the correct cause of death.
Get full access to this article
View all access options for this article.
References
1.
ZelinkovaV., BrazinovaA, TaylorM.S., RusnakM., PlancikovaD., MelichovaJ., and MajdanM. (2019). Location of traumatic brain injury-related deaths: epidemiological analysis of 11 European countries. Brain Inj. 33, 830–835.
2.
BandteA., PüschelK., and KrajewskiK. (2018). Traumatic brain injury in high versus low falls in young children and adolescents: a retrospective analysis. J. Neurosurg. Pediatr. 22, 233–237.
3.
KannusP., SievänenH., PalvanenM., JärvinenT., and ParkkariJ. (2005). Prevention of falls and consequent injuries in elderly people. Lancet, 366, 1885–1893.
4.
KibayashiK. (2019). Prevention of head trauma and death in patients with head injuries: A forensic autopsy study. IATSS Res. 43, 71–74.
BlakytnyR, and JudeE. (2005). The molecular biology of chronic wounds and delayed healing in diabetes. Diabet. Med. 23, 594–608.
7.
LioupisC. (2005). Effects of diabetes mellitus on wound healing: an update. J. Wound Care, 14, 84–86.
8.
LustenbergerT., TalvingP., LamL, InabaK., BassM., PluradD., and DemetriadesD. (2013). Effect of diabetes mellitus on outcome in patients with traumatic brain injury: a national trauma databank analysis. Brain Inj. 27, 281–285.
9.
Abou-El-HassanH, DiaB, ChoucairK, EidS.A., NajdiF., BakiL., TalihF., EidA.A., and KobeissyF. (2017). Traumatic brain injury, diabetic neuropathy and altered-psychiatric health: the fateful triangle. Med. Hypotheses, 108, 69–80.
10.
KimE., TolhurstA.T., and ChoS. (2014). Deregulation of inflammatory response in the diabetic condition is associated with increased ischemic brain injury. J. Neuroinflammation, 11, 83.
11.
LiZ.G., BrittonM., SimaA.A., and DunbarJ.C. (2004). Diabetes enhances apoptosis induced by cerebral ischemia. Life Sci, 76, 249–262.
12.
RizkN.N., RafolsJ.A., and DunbarJ.C. (2006). Cerebral ischemia-induced apoptosis and necrosis in normal and diabetic rats: effects of insulin and C-peptide. Brain Res. 1096, 204–212.
13.
Kelly-CobbsA.I., PrakashR., LiW., PillaiB., HafezS., CouchaM., JohnsonM.H., OgbiS.N., FaganS.C., and ErgulA. (2013). Targets of vascular protection in acute ischemic stroke differ in type 2 diabetes. Am. J. Physiol. Heart Circ. Physiol. 304, H806–H815.
14.
ShijoK., GhavimS, HarrisN.G., HovdaD.A., and SuttonaR.L. (2015). Glucose administration after traumatic brain injury exerts some benefits and no adverse effects on behavioral and histological outcomes. Brain Res. 1614, 94–104.
15.
LiT.T., YangW.C., WangY,Z, Tian SunT., CaoH.L., Jian-Feng ChenJ.F., and LiW.Z. (2020). Effects of a high concentration of hydrogen on neurologyical function after traumatic brain injury in diabetic rats. Brain Res, 1730, 1–9.
16.
GyonevaS. and RansohoffR.M. (2015). Inflammatory reaction after traumatic brain injury: Therapeutic potential of targeting cell-cell communication by chemokines. Trends Pharmacol. Sci. 36, 471–480.
17.
ChenL., DengH., CuiH., FangJ., ZuoZ., DengJ., LiY., WangX., and ZhaoL. (2018). Inflammatory responses and inflammation-associated diseases in organs. Oncotarget, 9, 7204–7218.
18.
NishimuraM. Breeding of mice strains for diabetes mellitus. (1969). Exp Animals, 18, 147–157.
19.
KawaiS., TakagiY., KanekoS., and KurosawaT. (2011). Effect of three types of mixed anesthetic agents alternate to ketamine in mice. Exp. Animals, 60, 481–487.
20.
ShimadaR., EzakiJ., and KibayashiK. (2017). Dose-dependent mortality involving convulsions due to subarachnoid Urografin injection in rats. Legal Med. 29, 29–33.
21.
BrodyD.L., DonaldC.M., KessensC.C., YuedeC., ParsadanianM., SpinnerM., KimE., SchwetyeK.E., HoltzmanD.M., and BaylyP.V. (2007). Electromagnetic controlled cortical impact device for precise, graded experimental traumatic brain injury. J. Neurotrauma, 24, 657–673.
22.
ShimadaR., AbeK., FurutaniR., and KibayashiK. (2014). Changes in dopamine transporter expression in the midbrain following traumatic brain injury: an immunohistochemical and in situ hybridization study in a mouse model. Neurol. Res. 36, 239–246.
23.
FlierlM.A., StahelP.F., BeauchampK.M., MorganS.J., SmithW.R., and ShohamiE. (2009). Mouse closed head injury model induced by a weight-drop device. Nat. Protoc. 4, 1328–1337.
24.
TakemiyaT., FumizawaK., YamagataK., IwakuraY., and KawakamiM. (2017). Brain interleukin-1 facilitates learning of a water maze spatial memory task in young mice. Front. Behav. Neurosci. 11, 202.
25.
VorheesC.V. and WilliamsM.T. (2006). Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat. Protoc. 1, 848–858.
26.
PorsoltR.D., BrossardG., HautboisC., and RouxS. (2001). Rodent models of depression: forced swimming and tail suspension behavioral despair tests in rats and mice. Curr. Protoc. Neurosci. 14, 8.10A.1–8.10A.10.
27.
CarterR.J., LioneL.A., HumbyT., MangiariniL., MahalA., BatesG.P., DunnettS.B., and MortonA.J. (1999). Characterization of progressive motor deficits in mice transgenic for the human Huntington's disease mutation. J. Neuroscience, 19, 3248–3257.
28.
CarterR.J., MortonJ., and DunnettS.B. (2001). Motor coordination and balance in rodents. Curr. Protoc. Neurosci. 15, 8.12.1–8.12.14.
29.
AbeK., ShimadaR., OkadaY., and KibayashiK. (2016). Traumatic brain injury decreases serotonin transporter expression in the rat cerebrum. Neurol. Res. 38, 358–363.
30.
KochanekP.M., MarionD.W., ZhangW., SchidingJ.K., WhiteM., PalmerA.M., ClarkR.S.B., O'MalleyM.E., StyrenS.D., HOC., and DeKoskyS. (1995). Severe controlled cortical impact in rats: assessment of cerebral edema, blood flow, and contusion volume. J. Neurotrauma, 12, 1015–1025.
31.
BradleyW.G. Jr. (1993). MR appearance of hemorrhage in the brain. Radiology, 189, 15–26.
32.
SuttonR.L., LescaudronL., and SteinD.G. (1993). Unilateral cortical contusion injury in the rat: vascular disruption and temporal development of cortical necrosis. J. Neurotrauma, 10, 135–149.
33.
ElliottM.B., JallobJ.J., and TumaR.F. (2008). An investigation of cerebral edema and injury volume assessments for controlled cortical impact injury. J. Neuroscience Meth. 168, 320–324.
34.
TureyenK., BowenK., LiangJ., DempseyR.J., and VemugantiR. (2011). Exacerbated brain damage, edema and inflammation in type-2 diabetic mice subjected to focal ischemia. J. Neurochemistry, 116, 499–507.
35.
KarelinaK., SaracB., FreemanL.M., GaierK.R., and WeilZ.M. (2016). Traumatic brain injury and obesity induce persistent central insulin resistance. Eur. J. Neurosci. 43, 1034–1043.
36.
CryanJ.F., ValentinoR.J., and LuckiI. (2005). Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci. Biobehav. Rev. 29, 547–569.
37.
CommonsK.G., CholaniansA.B., BabbJ.A., and EhlingerD.G. (2017). The rodent forced swim test measures stress-coping strategy, not depression-like behavior. ACS Chem. Neurosci. 8, 955–960.
38.
SempleB.D., ZamaniA., RaynerG., ShultzS.R., and JonesN.C. (2019). Affective, neurocognitive and psychosocial disorders associated with traumatic brain injury and post-traumatic epilepsy, Neurobiol. Dis. 123, 27–41.
39.
LimS.W., SungK.C., ShiueY.L., WangC.C., ChioC.C., and KuoJ.R. (2017). Hyperbaric oxygen effects on depression-like behavior and neuroinflammation in traumatic brain injury rats, World Neurosurg. 100,128–137.
40.
SempleB.D., DixitS., ShultzS.R., BoonW.C., and O'BrienT.J. (2017). Sex-dependent changes in neuronal morphology and psychosocial behaviors after pediatric brain injury, Behav. Brain Res. 319, 48–62.
41.
SharmaA.N., ElasedK.M., GarrettT.L., and LucotJ.B. (2010). Neurobehavioral deficits in db/db diabetic mice. Physiol. Behav. 101, 381–388.
42.
Morganti-KossmannM.C., RancanM., OttoV.I., StahelP.F., and KossmannT. (2001). Role of cerebral inflammation after traumatic brain injury: a revisited concept. Shock, 16, 165–177.
43.
SilvaM.T. (2010). When two is better than one: macrophages and neutrophils work in concert in innate immunity as complementary and cooperative partners of a myeloid phagocyte system. J. Leukoc. Biol. 87, 93–106.
44.
SilvaM.T. (2011). Macrophage phagocytosis of neutrophils at inflammatory/infectious foci: a cooperative mechanism in the control of infection and infectious inflammation. J. Leukoc. Biol. 89, 675–683.
45.
SilvaM.T., do ValeA., and dos SantosN.M. (2008). Secondary necrosis in multicellular animals: an outcome of apoptosis with pathogenic implications. Apoptosis, 13, 463–482.
46.
KohT.J. and DiPietroL.A. (2011). Inflammation and wound healing: the role of the macrophage. Expert Rev. Mol. Med. 13, e23.
47.
KhannaS., BiswasS., ShangY., CollardE., AzadA., KauhC., BhaskerV., GordilloG.M., SenC.K., and RoyS. (2010). Macrophage dysfunction impairs resolution of inflammation in the wounds of diabetic mice. PLoS One, 5, e9539.
48.
SwiftM.E., BurnsA.L., GrayK.L., and DiPietroL.A. (2001). Age-related alterations in the inflammatory response to dermal injury. J. Invest. Dermatol. 117, 1027–1035.
49.
NagayachA., PatroN., and PatroI. (2014). Astrocytic and microglial response in experimentally induced diabetic rat brain. Metab. Brain Dis. 29, 747–761.
50.
ChenY. and LiuL. (2012). Modern methods for delivery of drugs across the blood–brain barrier. Adv. Drug Deliv. Rev. 4, 640–665.
51.
WarmkeN., GriffinK.J., and CubbonR.M. (2016). Pericytes in diabetes-associated vascular disease. J. Diabetes Complications, 30, 1643–1650.
52.
WangS., CaoC., ChenZ., BankaitisV., TzimaE., SheibaniN., and BurridgeK. (2012). Pericytes regulate vascular basement membrane remodeling and govern neutrophil extravasation during inflammation. PLoS One 7, 0e45499.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
