Attenuation of acute and chronic damage following traumatic brain injury in copper, zinc—superoxide dismutase transgenic mice

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  • 1 Departments of Neurological Surgery, Neurology, and Pediatrics, School of Medicine, University of California, San Francisco, California; and the Department of Neurosurgery, Tohoku University School of Medicine, Sendai, Japan
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✓ To elucidate the role of oxygen-derived free radicals and superoxide dismutase in traumatic brain injury (TBI), blood-brain barrier (BBB) permeability, brain edema, behavioral function, and necrotic cavity volume (CV) were evaluated after TBI using nontransgenic (nTg) mice and heterozygous and homozygous transgenic (Tg) mice with a 1.5- (Tg1.5x), 3.1- (Tg3.1x) and five- (Tg5x) fold increase in human copper, zinc—superoxide dismutase (CuZn-SOD) activity.

Traumatic brain injury was produced by the weight-drop method. Evans blue dye leakage 4 hours after injury was attenuated in a CuZn-SOD dose-dependent manner with decreases of 18.6%, 40.9%, and 48.8%, in the Tg1.5x, Tg3.1x, and Tg5x groups, respectively. The water content 6 hours after injury in the Tg3.1x (79.64%) and Tg5x (79.45%) groups was significantly lower than in nTg mice (81.37%). There was an initial decrease in body weight and in motor performance, as measured by beam walk and beam balance tasks undertaken 1 day after TBI. However, the average reduction in beam balance and beam walk performance deficits and changes in body weight postinjury were significantly ameliorated in Tg mice. The CV was significantly smaller in Tg mice than in nTg mice (p < 0.01). These results indicate that superoxide radicals play a deleterious role following TBI. Furthermore, Tg mice provide a useful model for demonstrating the beneficial role of an antioxidant enzyme in TBI without the confounding effect of pharmacokinetics, toxicity, and BBB permeability associated with exogenous agents.

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Contributor Notes

Address reprint requests to: Pak H. Chan, Ph.D., Departments of Neurological Surgery and Neurology, University of California, 521 Parassus Avenue, C-224, San Francisco, California 94143–0651.
  • 1.

    Becker DP, , Miller JD, & Ward JD, et al: The outcome from severe head injury with early diagnosis and intensive management. J Neurosurg 47:491502, 1977 Becker DP, Miller JD, Ward JD, et al: The outcome from severe head injury with early diagnosis and intensive management. J Neurosurg 47:491–502, 1977

    • Search Google Scholar
    • Export Citation
  • 2.

    Beckman JS, , Beckman TW, & Chen J, et al: Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 87:16201624, 1990 Beckman JS, Beckman TW, Chen J, et al: Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 87:1620–1624, 1990

    • Search Google Scholar
    • Export Citation
  • 3.

    Beckman JS, , Carson M, & Smith CD, et al: ALS, SOD and peroxynitrite. Nature 364:584, 1993 (Letter) Beckman JS, Carson M, Smith CD, et al: ALS, SOD and peroxynitrite. Nature 364:584, 1993 (Letter)

    • Search Google Scholar
    • Export Citation
  • 4.

    Betz AL: Identification of hypoxanthine transport and xanthine oxidase activity in brain capillaries. J Neurochem 44:574579, 1985 Betz AL: Identification of hypoxanthine transport and xanthine oxidase activity in brain capillaries. J Neurochem 44:574–579, 1985

    • Search Google Scholar
    • Export Citation
  • 5.

    Braughler JM, , Hall ED, & Means ED, et al: Evaluation of an intensive methylprednisolone sodium succinate dosing regimen in experimental spinal cord injury. J Neurosurg 67:102105, 1987 Braughler JM, Hall ED, Means ED, et al: Evaluation of an intensive methylprednisolone sodium succinate dosing regimen in experimental spinal cord injury. J Neurosurg 67:102–105, 1987

    • Search Google Scholar
    • Export Citation
  • 6.

    Chan PH: The role of oxygen radicals in brain injury and edema, in Chow CK (ed): Cellular Antioxidant Defense Mechanisms. Boca Raton, FL: CRC Press, 1988, Vol 3, pp 89109 Chan PH: The role of oxygen radicals in brain injury and edema, in Chow CK (ed): Cellular Antioxidant Defense Mechanisms. Boca Raton, FL: CRC Press, 1988, Vol 3, pp 89–109

    • Search Google Scholar
    • Export Citation
  • 7.

    Chan PH, , Chu L, & Chen SF, et al: Reduced neurotoxicity in transgenic mice overexpressing human copper-zinc-superoxide dismutase. Stroke 21 (Suppl 11):III80III82, 1990 Chan PH, Chu L, Chen SF, et al: Reduced neurotoxicity in transgenic mice overexpressing human copper-zinc-superoxide dismutase. Stroke 21 (Suppl 11):III80–III82, 1990

    • Search Google Scholar
    • Export Citation
  • 8.

    Chan PH, , Longar S, & Fishman RA: Phospholipid degradation and edema development in cold-injured rat brain. Brain Res 277:329337, 1983 Chan PH, Longar S, Fishman RA: Phospholipid degradation and edema development in cold-injured rat brain. Brain Res 277:329–337, 1983

    • Search Google Scholar
    • Export Citation
  • 9.

    Chan PH, , Longar S, & Fishman RA: Protective effects of liposome-entrapped superoxide dismutase on posttraumatic brain edema. Ann Neurol 21:540547, 1987 Chan PH, Longar S, Fishman RA: Protective effects of liposome-entrapped superoxide dismutase on posttraumatic brain edema. Ann Neurol 21:540–547, 1987

    • Search Google Scholar
    • Export Citation
  • 10.

    Chan PH, , Yang GY, & Chen SF, et al: Cold-induced brain edema and infarction are reduced in transgenic mice overexpressing CuZn-superoxide dismutase. Ann Neurol 29:482486, 1991 Chan PH, Yang GY, Chen SF, et al: Cold-induced brain edema and infarction are reduced in transgenic mice overexpressing CuZn-superoxide dismutase. Ann Neurol 29:482–486, 1991

    • Search Google Scholar
    • Export Citation
  • 11.

    Clifton GL, , Jiang JY, & Lyeth BG, et al: Marked protection by moderate hypothermia after experimental traumatic brain injury. J Cereb Blood Flow Metab 11:114121, 1991 Clifton GL, Jiang JY, Lyeth BG, et al: Marked protection by moderate hypothermia after experimental traumatic brain injury. J Cereb Blood Flow Metab 11:114–121, 1991

    • Search Google Scholar
    • Export Citation
  • 12.

    Cuevas P, , Reimers D, & Carceller F, et al: Ischemic reperfusion injury in rabbit spinal cord: protective effect of superoxide dismutase on neurological recovery and spinal infarction. Acta Anat 137:303310, 1990 Cuevas P, Reimers D, Carceller F, et al: Ischemic reperfusion injury in rabbit spinal cord: protective effect of superoxide dismutase on neurological recovery and spinal infarction. Acta Anat 137:303–310, 1990

    • Search Google Scholar
    • Export Citation
  • 13.

    Demopoulos HB, , Flamm E, & Seligman M, et al: Oxygen free radicals in central nervous system ischemia and trauma, in Autor AP (ed): Pathology of Oxygen. New York: Academic Press, 1982, pp 127155 Demopoulos HB, Flamm E, Seligman M, et al: Oxygen free radicals in central nervous system ischemia and trauma, in Autor AP (ed): Pathology of Oxygen. New York: Academic Press, 1982, pp 127–155

    • Search Google Scholar
    • Export Citation
  • 14.

    Epstein CJ, , Avraham KB, & Lovett M, et al: Transgenic mice with increased Cu/Zn-superoxide dismutase activity: animal model of dosage effects in Down syndrome. Proc Natl Acad Sci USA 84:80448048, 1987 Epstein CJ, Avraham KB, Lovett M, et al: Transgenic mice with increased Cu/Zn-superoxide dismutase activity: animal model of dosage effects in Down syndrome. Proc Natl Acad Sci USA 84:8044–8048, 1987

    • Search Google Scholar
    • Export Citation
  • 15.

    Faden AI, , Demediuk P, & Panter SS, et al: The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244:798800, 1989 Faden AI, Demediuk P, Panter SS, et al: The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244:798–800, 1989

    • Search Google Scholar
    • Export Citation
  • 16.

    Feeney DM, , Boyeson MG, & Linn RT, et al: Responses to cortical injury: I. Methodology and local effects of contusions in the rat. Brain Res 211:6777, 1981 Feeney DM, Boyeson MG, Linn RT, et al: Responses to cortical injury: I. Methodology and local effects of contusions in the rat. Brain Res 211:67–77, 1981

    • Search Google Scholar
    • Export Citation
  • 17.

    Feeney DM, , Gonzalez A, & Law WA: Amphetamine, haloperidol, and experience interact to affect rate of recovery after motor cortex injury. Science 217:855857, 1982 Feeney DM, Gonzalez A, Law WA: Amphetamine, haloperidol, and experience interact to affect rate of recovery after motor cortex injury. Science 217:855–857, 1982

    • Search Google Scholar
    • Export Citation
  • 18.

    Flamm ES, , Demopoulos HB, & Seligman ML, et al: Free radicals in cerebral ischemia. Stroke 9:445447, 1978 Flamm ES, Demopoulos HB, Seligman ML, et al: Free radicals in cerebral ischemia. Stroke 9:445–447, 1978

    • Search Google Scholar
    • Export Citation
  • 19.

    Hall ED, , Andrus PK, & Yonkers PA: Brain hydroxyl radical generation in acute experimental head injury. J Neurochem 60:588594, 1993 Hall ED, Andrus PK, Yonkers PA: Brain hydroxyl radical generation in acute experimental head injury. J Neurochem 60:588–594, 1993

    • Search Google Scholar
    • Export Citation
  • 20.

    Hall ED, & Braughler JM: Central nervous system trauma and stroke. II. Physiological and pharmacological evidence for involvement of oxygen radicals and lipid peroxidation. Free Radic Biol Med 6:303313, 1989 Hall ED, Braughler JM: Central nervous system trauma and stroke. II. Physiological and pharmacological evidence for involvement of oxygen radicals and lipid peroxidation. Free Radic Biol Med 6:303–313, 1989

    • Search Google Scholar
    • Export Citation
  • 21.

    Hall ED, , Yonkers PA, & McCall JM, et al: Effects of the 21-aminosteroid U74006F on experimental head injury in mice. J Neurosurg 68:456461, 1988 Hall ED, Yonkers PA, McCall JM, et al: Effects of the 21-aminosteroid U74006F on experimental head injury in mice. J Neurosurg 68:456–461, 1988

    • Search Google Scholar
    • Export Citation
  • 22.

    Hicks RR, , Smith DH, & Lowenstein DH, et al: Mild experimental brain injury in the rat induces cognitive deficits associated with regional neuronal loss in the hippocampus. J Neurotrauma 10:405414, 1993 Hicks RR, Smith DH, Lowenstein DH, et al: Mild experimental brain injury in the rat induces cognitive deficits associated with regional neuronal loss in the hippocampus. J Neurotrauma 10:405–414, 1993

    • Search Google Scholar
    • Export Citation
  • 23.

    Huie RE, & Padmaja S: The reaction of no with superoxide. Free Radic Res 18:195199, 1993 Huie RE, Padmaja S: The reaction of no with superoxide. Free Radic Res 18:195–199, 1993

    • Search Google Scholar
    • Export Citation
  • 24.

    Ikeda Y, , Anderson JH, & Long DM: Oxygen free radicals in the genesis of traumatic and peritumoral brain edema. Neurosurgery 24:679685, 1989 Ikeda Y, Anderson JH, Long DM: Oxygen free radicals in the genesis of traumatic and peritumoral brain edema. Neurosurgery 24:679–685, 1989

    • Search Google Scholar
    • Export Citation
  • 25.

    Imaizumi S, , Woolworth V, & Fishman RA, et al: Liposome-en-trapped superoxide dismutase reduces cerebral infarction in cerebral ischemia in rats. Stroke 21:13121317, 1990 Imaizumi S, Woolworth V, Fishman RA, et al: Liposome-en-trapped superoxide dismutase reduces cerebral infarction in cerebral ischemia in rats. Stroke 21:1312–1317, 1990

    • Search Google Scholar
    • Export Citation
  • 26.

    Katayama Y, , Becker DP, & Tamura T, et al: Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury. J Neurosurg 73:889900, 1990 Katayama Y, Becker DP, Tamura T, et al: Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury. J Neurosurg 73:889–900, 1990

    • Search Google Scholar
    • Export Citation
  • 27.

    Kinouchi H, , Epstein CJ, & Mizui T, et al: Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn superoxide dismutase. Proc Natl Acad Sci USA 88:1115811162, 1991 Kinouchi H, Epstein CJ, Mizui T, et al: Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn superoxide dismutase. Proc Natl Acad Sci USA 88:11158–11162, 1991

    • Search Google Scholar
    • Export Citation
  • 28.

    Kontos HA, & Povlishock JT: Oxygen radicals in brain injury. Cent Nerv Syst Trauma 3:257263, 1986 Kontos HA, Povlishock JT: Oxygen radicals in brain injury. Cent Nerv Syst Trauma 3:257–263, 1986

    • Search Google Scholar
    • Export Citation
  • 29.

    Kontos HA, & Wei EP: Superoxide production in experimental brain injury. J Neurosurg 64:803807, 1986 Kontos HA, Wei EP: Superoxide production in experimental brain injury. J Neurosurg 64:803–807, 1986

    • Search Google Scholar
    • Export Citation
  • 30.

    Kontos HA, , Wei EP, & Ellis EF, et al: Appearance of superoxide anion radical in cerebral extracellular space during increased prostaglandin synthesis in cats. Circ Res 57:142151, 1985 Kontos HA, Wei EP, Ellis EF, et al: Appearance of superoxide anion radical in cerebral extracellular space during increased prostaglandin synthesis in cats. Circ Res 57:142–151, 1985

    • Search Google Scholar
    • Export Citation
  • 31.

    Muizelaar JP, , Marmarou A, & Young HF, et al: Improving the outcome of severe head injury with the oxygen radical scavenger polyethylene glycol-conjugated superoxide dismutase: a phase II trial. J Neurosurg 78:375382, 1993 Muizelaar JP, Marmarou A, Young HF, et al: Improving the outcome of severe head injury with the oxygen radical scavenger polyethylene glycol-conjugated superoxide dismutase: a phase II trial. J Neurosurg 78:375–382, 1993

    • Search Google Scholar
    • Export Citation
  • 32.

    Nilsson P, , Hillered L, & Pontén U, et al: Changes in cortical extracellular levels of energy-related metabolites and amino acids following concussive brain injury in rats. J Cereb Blood Flow Metab 10:631637, 1990 Nilsson P, Hillered L, Pontén U, et al: Changes in cortical extracellular levels of energy-related metabolites and amino acids following concussive brain injury in rats. J Cereb Blood Flow Metab 10:631–637, 1990

    • Search Google Scholar
    • Export Citation
  • 33.

    Shi YP, , Huang TT, & Carlson EJ, et al: The mapping of transgenes by fluorescence in situ hybridization on G-banded mouse chromosomes. Mamm Genome 5:337341, 1994 Shi YP, Huang TT, Carlson EJ, et al: The mapping of transgenes by fluorescence in situ hybridization on G-banded mouse chromosomes. Mamm Genome 5:337–341, 1994

    • Search Google Scholar
    • Export Citation
  • 34.

    Siesjo BK, , Agardh CD, & Bergtsson F: Free radicals and brain damage. Cerebrovasc Brain Metab Rev 1:165211, 1989 Siesjo BK, Agardh CD, Bergtsson F: Free radicals and brain damage. Cerebrovasc Brain Metab Rev 1:165–211, 1989

    • Search Google Scholar
    • Export Citation
  • 35.

    Smith DH, , Lowenstein DH, & Gennarelli TA, et al: Persistent memory dysfunction is associated with bilateral hippocampal damage following experimental brain injury. Neurosci Lett 168:151154, 1994 Smith DH, Lowenstein DH, Gennarelli TA, et al: Persistent memory dysfunction is associated with bilateral hippocampal damage following experimental brain injury. Neurosci Lett 168:151–154, 1994

    • Search Google Scholar
    • Export Citation
  • 36.

    Soares HD, , Thomas M, & Cloherty K, et al: Development of prolonged focal cerebral edema and regional cation changes following experimental brain injury in the rat. J Neurochem 58:18451852, 1992 Soares HD, Thomas M, Cloherty K, et al: Development of prolonged focal cerebral edema and regional cation changes following experimental brain injury in the rat. J Neurochem 58:1845–1852, 1992

    • Search Google Scholar
    • Export Citation
  • 37.

    Swanson RA, , Morton MT, & Tsao-Wu G, et al: A semiautomated method for measuring brain infarct volume. J Cereb Blood Flow Metab 10:290293, 1990 Swanson RA, Morton MT, Tsao-Wu G, et al: A semiautomated method for measuring brain infarct volume. J Cereb Blood Flow Metab 10:290–293, 1990

    • Search Google Scholar
    • Export Citation
  • 38.

    Tornheim PA, , Prioleau GR, & McLaurin RL: Acute responses to experimental blunt head trauma. Topography of cerebral cortical edema. J Neurosurg 60:473480, 1984 Tornheim PA, Prioleau GR, McLaurin RL: Acute responses to experimental blunt head trauma. Topography of cerebral cortical edema. J Neurosurg 60:473–480, 1984

    • Search Google Scholar
    • Export Citation
  • 39.

    Vink R, , McIntosh TK, & Demeduik P, et al: Decline in intracellular free Mg2+ is associated with irreversible tissue injury after brain trauma. J Biol Chem 263:757761, 1988 Vink R, McIntosh TK, Demeduik P, et al: Decline in intracellular free Mg2+ is associated with irreversible tissue injury after brain trauma. J Biol Chem 263:757–761, 1988

    • Search Google Scholar
    • Export Citation
  • 40.

    Wei EP, , Kontos HA, & Dietrich WD, et al: Inhibition by free radical scavengers and by cyclooxygenase inhibitors of pial arteriolar abnormalities from concussive brain injury in cats. Circ Res 48:95103, 1981 Wei EP, Kontos HA, Dietrich WD, et al: Inhibition by free radical scavengers and by cyclooxygenase inhibitors of pial arteriolar abnormalities from concussive brain injury in cats. Circ Res 48:95–103, 1981

    • Search Google Scholar
    • Export Citation
  • 41.

    Yamakami I, & McIntosh TK: Effects of traumatic brain injury on regional cerebral blood flow in rats as measured with radiolabeled microspheres. J Cereb Blood Flow Metab 9:117124, 1989 Yamakami I, McIntosh TK: Effects of traumatic brain injury on regional cerebral blood flow in rats as measured with radiolabeled microspheres. J Cereb Blood Flow Metab 9:117–124, 1989

    • Search Google Scholar
    • Export Citation
  • 42.

    Yang G, , Chan PH, & Chen J, et al: Human copper-zinc superoxide dismutase transgenic mice are highly resistant to reperfusion injury after focal cerebral ischemia. Stroke 25:165170, 1994 Yang G, Chan PH, Chen J, et al: Human copper-zinc superoxide dismutase transgenic mice are highly resistant to reperfusion injury after focal cerebral ischemia. Stroke 25:165–170, 1994

    • Search Google Scholar
    • Export Citation
  • 43.

    Young W: The post-injury responses in trauma and ischemia: secondary injury or protective mechanism? Cent Nerv Syst Trauma 4:2751, 1987 Young W: The post-injury responses in trauma and ischemia: secondary injury or protective mechanism? Cent Nerv Syst Trauma 4:27–51, 1987

    • Search Google Scholar
    • Export Citation

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