Abstract
The purposes of this study were (1) to document the histopathological consequences of moderate traumatic brain injury (TBI) in anesthetized Sprague-Dawley rats, and (2) to determine whether posttraumatic brain hypothermia (30°C) would protect histopathologically. Twenty-four hours prior to TBI, the fluid percussion interface was positioned over the right cerebral cortex. On the 2nd day, fasted rats were anesthetized with 70% nitrous oxide, 1% halothane, and 30% oxygen. Under controlled physiological conditions and normothermic brain temperature (37.5°C), rats were injured with a fluid percussion pulse ranging from 1.7 to 2.2 atmospheres. In one group, brain temperature was maintained at normothermic levels for 3 h after injury. In a second group, brain temperature was reduced to 30°C at 5 min post-trauma and maintained for 3 h. Three days after TBI, brains were perfusion-fixed for routine histopathological analysis. In the normothermic group, damage at the site of impact was seen in only one of nine rats. In contrast, all normothermic animals displayed necrotic neurons within ipsilateral cortical regions lateral and remote from the impact site. Intracerebral hemorrhagic contusions were present in all rats at the gray-white interface underlying the injured cortical areas. Selective neuronal necrosis was also present within the CA3 and CA4 hippocampal subsectors and thalamus. Post-traumatic brain hypothermia significantly reduced the overall sum of necrotic cortical neurons (519±122 vs 952±130, mean ±SE, P=0.03, Kruskal-Wallis test) as well as contusion volume (0.50±0.14 vs 2.14±0.71 mm3, P=0.004). These data document a consistent pattern of histopathological vulnerability following normothermic TBI and demonstrate hypothermic protection in the post-traumatic setting.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Adams JH, Gennarelli TA, Graham DI (1982) Brain damage in non-missle head injury: observations in man and subhuman primates. In: Thomas Smith W, Cavanagh JB (eds) Recent advances in neuropathology. Churchill Livingstone, Edinburgh, pp 165–190
Adams JH, Doyle D, Graham DI, Lawrence AE, McLellan DR (1986) Gliding contusions in nonmissle head injury in humans. Arch Pathol Lab Med 10: 485–486
Auer RN, Siesjo BK (1988) Biological differences between ischemia, hypoglycemia and epilepsy. Ann Neurol 24: 699–707
Bullock R, Maxwell WL, Graham DI, Teasdale GM, Adams JH (1991) Glial swelling following human cerebral contusion: an ultrastructural study. J Neurol Neurosurg Psychiatry 54: 427–434
Busto R., Dietrich WD, Globus MY-T, Valdes I, Scheinberg P, Ginsberg MD (1987) Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 7: 729–738
Busto R, Dietrich WD, Globus MY-T, Ginsberg MD (1989) Postichemic moderate hypothermia inhibits CA1 hippocampal ischemic neuronal injury. Neurosci Lett 101: 299–304
Busto R, Globus MY-T, Dietrich WD, Martinez E, Valdes I, Ginsberg MD (1989) Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke 20: 904–910
Chan PH, Schmidley JW, Fishman RA, Longar SM (1984) Brain injury, edema, and vascular permeability changes induced by oxygen-derived free radicals. Neurology 34: 315–320
Chopp M, Chen H, Dereski MO, Garcia JH (1991) Mild hypothermic intervention after graded ischemic stress in rats. Stroke 22: 37–43
Clifton GL, Jiang JY, Lyeth BG, Jenkins LW, Hamm RJ, Hayes RL (1991) Marked protection by moderate hypothermia after experimental tramatic brain injury. J Cereb Blood Flow Metab 11: 114–121
Cortez SC, McIntosh TK, Noble LJ (1989) Experimental fluid percussion brain injury: vascular disruption and neuronal and glial alterations. Brain Res 482: 272–282
Dietrich WD (1992) The importance of brain temperature in cerebral injury. J Neurotrauma 9[Suppl 2]: 476–485
Dietrich WD, Busto R, Halley M, Valdes I (1990) The importance of brain temperature in alterations of the blood-brain barrier following cerebral ischemia. J Neuropathol Exp Neurol 49: 486–497
Dietrich WD, Busto R, Valdes I, Loor Y (1990) Effects of normothermic versus mild hyperthermic forebrain ischemia in rats. Stroke 21: 1318–1325
Dietrich WD, Halley M, Valdes I, Busto R (1991) Interrelationships between increased vascular permeability and acute neuronal injury damage following temperature controlled brain ischemia in rats. Acta Neuropathol 81: 615–625
Dietrich WD, Busto R, Globus MY-T, Ginsberg MD (1993) Intraischemic but not postichemic brain hypothermia protects chronically following forebrain ischemia in rats. J Cereb Blood Flow Metab 13: 541–549
Dixon CE, Lyeth BG, Povlishock JT, Findling RL, Hamm RJ, Marmarou A, Young HF, Hayes RL (1987) A fluid percussion model of experimental brain injury in the rat. J Neurosurg 67: 110–119
Ellis EF, Chao J, Heizer ML (1989) Brain kininogen following experimental brain injury: evidence for a secondary event. J Neurosurg 71: 437–442
Faden AI, Demediuk P, Panter SS, Vink R (1989) The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244: 798–800
Gennarelli TA, Thibault LE (1985) Biological models of head injury. In: Becker DP, Povlishock JT (eds) Central nervous system status report. NINCDS Publication, Richmond, pp 391–404
Ginsberg MD, Sternau LL, Globus MY-T, Dietrich WD, Busto R (1992) Therapeutic modulation of brain temperature: relevance to ischemic brain injury. Cerebrovasc Brain Metab Rev 4: 189–225
Graham DI, Adams JH, Doyle D (1978) Ischemic brain damage in fatal non-missile head injury. J. Neurol Sci 39: 213–234
Green EJ, Dietrich WD, van Dijk F, Busto R, Markgraf CG, McCabe PM, Ginsberg MD, Schneiderman N (1992) Protective effects of neural hypothermia on behavior following global cerebral ischemia. Brain Res 580: 197–204
Hamm RJ, Dixon CE, Gbadebo DM, Singha AK, Jenkins LW, Lyeth BG, Hayes RL (1992) Cognitive deficits following traumatic brain injury produced by controlled cortical impact. J Neurotrauma 9: 11–20
Hayes RL, Jenkins LW, Lyeth BG, Balster RL, Robinson SE, Miller LP, Clifton GL, Young HF (1988) Pretreatment with phencyclidine, and N-methyl-d-aspartate receptor antagonist, attenuates long-term behavioral deficits in the rat produced by traumatic brain injury. J Neurotrauma 5: 287–302
Hayes RL, Jenkins JW, Lyeth BG (1991) Neurotransmittermediated mechanisms of traumatic brain injury: acethycholine and excitatory amino acids. J Neurotrauma 9[Suppl 1]: 173–187
Hoffman WE, Werner C, Baughman VL, Thomas C, Miletich DJ, Albrecht RF (1991) Postischemic treatment with hypothermia improves outcome from incomplete cerebral ischemia in rats. J Neurosurg Anesthesiol 3: 34–38
Holbourn AHS (1945) The mechanics of brain injury. Br Med Bull 3: 147–149
Hova DA, Becker DB, Katayama Y (1992) Secondary injury and acidosis. J Neurotrauma 9[Suppl 1] S47-S60
Ishige N, Pitts LH, Berry I, Carlson SG, Nishimura MC, Moseley ME, Weinstein PR (1987) The effect of hypoxia on traumatic head injury in rats: alterations in neurologic function, brain edema, and cerebral blood flow. J Cereb Blood Flow Metab 7: 759–767
Jenkins A, Maxwell WL, Graham DI (1989) Experimental intracerebral haematoma in the rat: sequential light microscopic changes. Neuropathol Appl Neurobiol 15: 477–486
Jenkins LW, Lyeth BG, LeWelt W, Moszynski K, DeWitt DS, Balster RL, Miller LP, Clifton GL, Young HF, Hayes RL (1988) Combined pre-trauma scopolamine and phencyclidine attenuates post-traumatic increased sensitivity to delayed secondary ischemia. J Neurotrauma 5: 275–287
Jenkins LW, Moszynski K, Lyeth BG, Lewelt W, DeWitt DS, Allen A, Dixon CE, Povlishock JT, Majewski TJ, Clifton GL, Young HF, Becker DP, Hayes RL (1989) Increased vulnerability of the mildly traumatized brain to cerebral ischemia: the use of controlled secondary ischemia as a research tool to identify common or different mechanisms contributing to mechanical and ischemic brain injury. Brain Res 477: 211–224
Jiang YJ, Lyeth BG, Clifton GL, Jenkins LW, Hamm RJ, Hayes RL (1991) Relationship between body and brain temperature in traumatically brain-injured rodents. J Neurosurg 74: 492–496
Jiang JY, Lyeth BG, Kapasi MZ, Jenkins LW, Povlishock JT (1992) Moderate hypothermia reduces blood-brain barrier disruption following traumatic brain injury in the rat. Acta Neuropathol 84: 495–500
Katayama Y, Becker DP, Tamura T, Hovda DA (1990) Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury. J Neurosurg 73: 889–900
Kawamata T, Katayama Y, Hovda DA, Yoshino A, Becker DB (1992) Administration of excitatory amino acid antagonists via microdialysis attenuates the increase in glucose utilization seen following concussive brain injury. J Cereb Blood Flow Metab 12: 12–24
Kotapka MJ, Gennarelli TA, Graham DI, Adams JH, Thibault LE, Ross DT, Ford I (1991) Selective vulnerability of hippocampal neurons in acceleration-induced experimental head injury. J Neurotrauma 8: 247–258
Lazorthes G, Campan L (1958) Hypothermia in the treatment of craniocerebral traumatism. J Neurosurg 15: 162–167
Linderberg R, Freytag E (1960) The mechanics of cerebral contusion. Arch Pathol 69: 440–469
Lindsberg PJ, Hallenbeck JM, Feuerstein G (1991) Plateletactivating factor in stroke and brain injury. Ann Neurol 30: 117–129
Lyeth BG, Jenkins LW, Hamm RJ, Dixon CD, Phillips LL, Clifton GL, Young HF, Hayes RL (1990) Prolonged memory impairment in the absence of hippocampal cell death following traumatic brain injury in the rat. Brain Res 526: 249–258
Lyeth BG, Jiang JY, Robinson SE, Goo H, Jenkins LW, Hayes RL (1991) Hypothermia blunts acetylcholine increase in CSF in traumatically brain injured rats. Soc Neurosci Abstr 17: 165
Lyeth BG, Jiang JY, Shanliang L (1993) Behavioral protection by moderate hypothermia initiated after experimental traumatic brain injury. J Neurotrauma 10: 57–64
McIntosh TK, Vink R, Noble L, Yamakami I, Soares H, Faden AL (1989) Traumatic brain injury in the rat: characterization of a lateral fluid-percussion model. Neuroscience 28: 233–244
McIntosh TK, Vink R, Soares H, Hayes RL, Simmon R (1989) Effects of N-methyl-d-aspartate receptor blocker MK-801 on neurologic function after experimental brain injury. J Neurotrauma 6: 247–250
Meldrum BS, Brierley JB (1972) Neuronal loss and gliosis in the hippocampus following repetitive epileptic seizures induced in adolescent baboons by allylglyine. Brain Res 48: 361–365
Meldrum BS, Corsellis JAN (1984) Epilepsy, in: Adams JH, Corsellis JAN, Duchen LW, (eds) Greenfield's Neuropathology, 4th edn. Wiley-Medical Publications, New York, pp 921–950
Mitchell DE, Adams JH (1973) Primary focal impact damage to the brain stem in blunt head injury. Does it exist. Lancet II: 215–218
Nilsson P, Hillered L, Ponten U, Ungerstedt U (1990) Changes in cortical extracellular levels of energy related metabolites and amino acids following concussive brain injury. J Cereb Blood Flow Metab 10: 631–637
Povlishock JT, Dietrich WD (1992) The blood-brain barrier in brain injury: an overview. In: Globus MY-T, Dietrich WD (eds) The role of neurotransmitters in brain injury. Plenum Publishing, New York, pp 265–269
Povlishock JT, Becker DP, Sullivan HG, Miller JD (1978) Vascular permeability alterations to horseradish peroxidase in experimental brain injury. Brain Res 153: 223–239
Ribas GC, Jane JA (1992) Traumatic contusions and intracerebral hematomas. J Neurotrauma 9[Suppl1] S265-S275
Rosomoff HL (1955) Experimental brain injury during hypothermia. J Neurosurg 16: 177–187
Sedzimir CB (1959) Therapeutic hypothermia in cases of head injury. J Neurosurg 16: 407–414
Seelig JM, Marshall LF (1985) Biomechanics of head injury: clinical aspects. In: Nahum AM, Melvin J (eds) The biomechanics of trauma. Appleton-Century-Crofts, Norwalk, pp 225–269
Sloviter RS (1983) Epileptic brain damage in rats induced by electrical stimulation of the perforant path. 1. Acute electrophysiological and light microscopic studies. Brain Res Bull 10: 675–697
Taft WC, Yang K, Dixon CE, Clifton GL, Hayes RL (1993) Hypothermia attenuates the loss of hippocampal microtubuleassociated protein 2 (MAP2) following traumatic brain injury. J Cereb Blood Flow Metab 13: 796–802
Yamakami I, McIntosh TK (1989) Effects of traumatic brain injury on regional cerebral blood flow in rats as measured with radiolabeled micropheres. J Cereb Blood Flow Metab 9: 117–124
Yoshino A, Hovda DA, Kawamata T, Katayama Y, Becker DB (1991) Dynamic changes in local cerebral glucose utilization following cerebral concussion in rats: evidence of a hyper-and subsequent hypometabolic state. Brain Res 561: 106–119
Yoshino A, Hovda DA, Katayama Y, Kawamata T, Becker DB (1992) Hippocampal CA3 lesion prevents postconcussive metabolic dysfunction in CA1. J Cereb Blood Flow Metab 12: 996–1006
Young W (1988) Secondary CNS injury. J Neurotrauma 5: 219–221
Yuan X-Q, Prough DS, Smith TL, Dewitt DS (1988) The effects of traumatic brain injury on regional cerebral blood flow in rats. J Neurotrauma 5: 289–301
Zilles L, (1985) The cortex of the rat. A stereotaxic atlas. Springer-Verlag, Berlin Heidelberg New York Tokyo
Author information
Authors and Affiliations
Additional information
Supported by USPHS Grants NS30291 and NS27127
Rights and permissions
About this article
Cite this article
Dietrich, W.D., Alonso, O., Busto, R. et al. Post-traumatic brain hypothermia reduces histopathological damage following concussive brain injury in the rat. Acta Neuropathol 87, 250–258 (1994). https://doi.org/10.1007/BF00296740
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00296740