Impaired cerebral mitochondrial function after traumatic brain injury in humans

Bon H. Verweij M.D., J. Paul Muizelaar M.D., Ph.D., Federico C. Vinas M.D., Patti L. Peterson M.D., Ye Xiong M.D., Ph.D., and Chuan P. Lee Ph.D.
View More View Less
Restricted access

Purchase Now

USD  $45.00

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $515.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $612.00
Print or Print + Online

Object. Oxygen supply to the brain is often insufficient after traumatic brain injury (TBI), and this results in decreased energy production (adenosine triphosphate [ATP]) with consequent neuronal cell death. It is obviously important to restore oxygen delivery after TBI; however, increasing oxygen delivery alone may not improve ATP production if the patient's mitochondria (the source of ATP) are impaired. Traumatic brain injury has been shown to impair mitochondrial function in animals; however, no human studies have been previously reported.

Methods. Using tissue fractionation procedures, living mitochondria derived from therapeutically removed brain tissue were analyzed in 16 patients with head injury (Glasgow Coma Scale Scores 3–14) and two patients without head injury. Results revealed that in head-injured patients mitochondrial function was impaired, with subsequent decreased ATP production.

Conclusions. Decreased oxygen metabolism due to mitochondrial dysfunction must be taken into account when clinically defining ischemia and interpreting oxygen measurements such as jugular venous oxygen saturation, arteriovenous difference in oxygen content, direct tissue oxygen tension, and cerebral blood oxygen content determined using near-infrared spectroscopy. Restoring mitochondrial function might be as important as maintaining oxygen delivery.

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $515.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $612.00
  • 1.

    Astrup J: Energy-requiring cell functions in the ischemic brain. Their critical supply and possible inhibition in protective therapy. J Neurosurg 56:482497, 1982 Astrup J: Energy-requiring cell functions in the ischemic brain. Their critical supply and possible inhibition in protective therapy. J Neurosurg 56:482–497, 1982

    • Search Google Scholar
    • Export Citation
  • 2.

    Bergsneider M, , Hovda DA, & Shalmon E, et al: Cerebral hyperglycolysis following severe traumatic brain injury in humans: a positron emission tomography study. J Neurosurg 86:241251, 1997 Bergsneider M, Hovda DA, Shalmon E, et al: Cerebral hyperglycolysis following severe traumatic brain injury in humans: a positron emission tomography study. J Neurosurg 86:241–251, 1997

    • Search Google Scholar
    • Export Citation
  • 3.

    Berman RF, , Verweij BH, & Muizelaar JP: Neurobehavioral protection by the neuronal calcium channel blocker Ziconotide in a model of traumatic diffuse brain injury in rats. J Neurosurg 93:821828, 2000 Berman RF, Verweij BH, Muizelaar JP: Neurobehavioral protection by the neuronal calcium channel blocker Ziconotide in a model of traumatic diffuse brain injury in rats. J Neurosurg 93:821–828, 2000

    • Search Google Scholar
    • Export Citation
  • 4.

    Bouma GJ, , Muizelaar JP, & Choi SC, et al: Cerebral circulation and metabolism after severe traumatic brain injury: the elusive role of ischemia. J Neurosurg 75:685693, 1991 Bouma GJ, Muizelaar JP, Choi SC, et al: Cerebral circulation and metabolism after severe traumatic brain injury: the elusive role of ischemia. J Neurosurg 75:685–693, 1991

    • Search Google Scholar
    • Export Citation
  • 5.

    Brodersen P, & Jørgensen EO: Cerebral blood flow and oxygen uptake, and cerebropinal fluid biochemistry in severe coma. J Neurol Neurosurg Psychiatry 37:384391, 1974 Brodersen P, Jørgensen EO: Cerebral blood flow and oxygen uptake, and cerebropinal fluid biochemistry in severe coma. J Neurol Neurosurg Psychiatry 37:384–391, 1974

    • Search Google Scholar
    • Export Citation
  • 6.

    Cormio M, , Valadka AB, & Robertson CS: Elevated jugular venous oxygen saturation after severe head injury. J Neurosurg 90:915, 1999 Cormio M, Valadka AB, Robertson CS: Elevated jugular venous oxygen saturation after severe head injury. J Neurosurg 90:9–15, 1999

    • Search Google Scholar
    • Export Citation
  • 7.

    Cruz J: Brain ischemia in head injury. J Neurosurg 78:522, 1993 (Letter) Cruz J: Brain ischemia in head injury. J Neurosurg 78:522, 1993 (Letter)

    • Search Google Scholar
    • Export Citation
  • 8.

    De Salles AAF, , Muizelaar JP, & Young HF: Hyperglycemia, cerebrospinal fluid lactic acidosis, and cerebral blood flow in severely head-injured patients. Neurosurgery 21:4550, 1987 De Salles AAF, Muizelaar JP, Young HF: Hyperglycemia, cerebrospinal fluid lactic acidosis, and cerebral blood flow in severely head-injured patients. Neurosurgery 21:45–50,, 1987

    • Search Google Scholar
    • Export Citation
  • 9.

    Erecinska M, & Silver IA: Ions and energy in mammalian brain. Progr Neurobiol 43:3771, 1994 Erecinska M, Silver IA: Ions and energy in mammalian brain. Progr Neurobiol 43:37–71, 1994

    • Search Google Scholar
    • Export Citation
  • 10.

    Ernster L: Lipid peroxidation in biological membranes: mechanisms and implications, in Yagi K (ed): Active Oxygens, Lipid Peroxides and Antioxidants. Boca Raton, FL: CRC Press, 1993, pp 130 Ernster L: Lipid peroxidation in biological membranes: mechanisms and implications, in Yagi K (ed): Active Oxygens, Lipid Peroxides and Antioxidants. Boca Raton: FL: CRC Press, 1993, pp 1–30

    • Search Google Scholar
    • Export Citation
  • 11.

    Fineman I, , Hovda DA, & Smith M, et al: Concussive brain injury is associated with a prolongated accumulation of calcium: a 45Ca autoradiographic study. Brain Res 624:94102, 1993 Fineman I, Hovda DA, Smith M, et al: Concussive brain injury is associated with a prolongated accumulation of calcium: a 45Ca autoradiographic study. Brain Res 624:94–102, 1993

    • Search Google Scholar
    • Export Citation
  • 12.

    Gopinath SP, , Robertson CS, & Contant CF, et al: Jugular venous desaturation and outcome after head injury. J Neurol Neurosurg Psychiatry 57:717723, 1994 Gopinath SP, Robertson CS, Contant CF, et al: Jugular venous desaturation and outcome after head injury. J Neurol Neurosurg Psychiatry 57:717–723, 1994

    • Search Google Scholar
    • Export Citation
  • 13.

    Grynkiewicz G, , Poenie M, & Tsien RY: A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260:34403450, 1985 Grynkiewicz G, Poenie M, Tsien RY: A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260:3440–3450, 1985

    • Search Google Scholar
    • Export Citation
  • 14.

    Kiening KL, , Unterberg AW, & Bardt TF, et al: Monitoring of cerebral oxygenation in patients with a severe head injury: brain tissue PO2 versus jugular vein oxygen saturation. J Neurosurg 85:751757, 1996 Kiening KL, Unterberg AW, Bardt TF, et al: Monitoring of cerebral oxygenation in patients with a severe head injury: brain tissue PO2 versus jugular vein oxygen saturation. J Neurosurg 85:751–757, 1996

    • Search Google Scholar
    • Export Citation
  • 15.

    Lee CP, , Sciamanna M, & Peterson P: Intact rat brain mitochondria from a single animal: preparation and properties. Methods Toxicol 2:4149, 1993 Lee CP, Sciamanna M, Peterson P: Intact rat brain mitochondria from a single animal: preparation and properties. Methods Toxicol 2:41–49, 1993

    • Search Google Scholar
    • Export Citation
  • 16.

    Lowry OH, , Rosebrough NJ, & Farr AL, et al: Protein measurement with the folin phenol reagent. J Biol Chem 193:265275, 1951 Lowry OH, Rosebrough NJ, Farr AL, et al: Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275, 1951

    • Search Google Scholar
    • Export Citation
  • 17.

    Muizelaar JP: Brain ischemia in head injury. J Neurosurg 78:522523, 1993 (Letter) Muizelaar JP: Brain ischemia in head injury. J Neurosurg 78:522–523, 1993 (Letter)

    • Search Google Scholar
    • Export Citation
  • 18.

    Muizelaar JP, , Marmarou A, & DeSalles AAF, et al: Cerebral blood flow and metabolism in severely head-injured children. Part 1: Relationship with GCS score, outcome, ICP, and PVI. J Neurosurg 71:6371, 1989 Muizelaar JP, Marmarou A, DeSalles AAF, et al: Cerebral blood flow and metabolism in severely head-injured children. Part 1: Relationship with GCS score, outcome, ICP, and PVI. J Neurosurg 71:63–71, 1989

    • Search Google Scholar
    • Export Citation
  • 19.

    Obrist WD, , Langfitt TW, & Jaggi JL, et al: Cerebral blood flow and metabolism in comatose patients with acute head injury. Relationship to intracranial hypertension. J Neurosurg 61:241253, 1984 Obrist WD, Langfitt TW, Jaggi JL, et al: Cerebral blood flow and metabolism in comatose patients with acute head injury. Relationship to intracranial hypertension. J Neurosurg 61:241–253, 1984

    • Search Google Scholar
    • Export Citation
  • 20.

    Rappaport ZH, , Ransohoff J, & Hass WK: Cerebral metabolism in head trauma. Progr Neurol Surg 10:113, 1981 Rappaport ZH, Ransohoff J, Hass WK: Cerebral metabolism in head trauma. Progr Neurol Surg 10:1–13, 1981

    • Search Google Scholar
    • Export Citation
  • 21.

    Robertson CS, , Narayan RK, & Gokaslan ZL, et al: Cerebral arteriovenous oxygen difference as an estimate of cerebral blood flow in comatose patients. J Neurosurg 70:222230, 1989 Robertson CS, Narayan RK, Gokaslan ZL, et al: Cerebral arteriovenous oxygen difference as an estimate of cerebral blood flow in comatose patients. J Neurosurg 70:222–230, 1989

    • Search Google Scholar
    • Export Citation
  • 22.

    Shalit MN, , Beller AJ, & Feinsod M: Clinical equivalents of cerebral oxygen consumption in coma. Neurology 22:155160, 1972 Shalit MN, Beller AJ, Feinsod M: Clinical equivalents of cerebral oxygen consumption in coma. Neurology 22:155–160, 1972

    • Search Google Scholar
    • Export Citation
  • 23.

    Sharples PM, , Stuart AG, & Matthews DSF, et al: Cerebral blood flow and metabolism in children with severe head injury. Part 1: relation to age, Glasgow coma score, outcome, intracranial pressure, and time after injury. J Neurol Neurosurg Psychiatry 58:145152, 1995 Sharples PM, Stuart AG, Matthews DSF, et al: Cerebral blood flow and metabolism in children with severe head injury. Part 1: relation to age, Glasgow coma score, outcome, intracranial pressure, and time after injury. J Neurol Neurosurg Psychiatry 58:145–152, 1995

    • Search Google Scholar
    • Export Citation
  • 24.

    Siesjö BK: Cerebral circulation and metabolism. J Neurosurg 60:883908, 1984 Siesjö BK: Cerebral circulation and metabolism. J Neurosurg 60:883–908, 1984

    • Search Google Scholar
    • Export Citation
  • 25.

    Siesjö BK: Pathophysiology and treatment of focal cerebral ischemia. Part I: Pathophysiology. J Neurosurg 77:169184, 1992 Siesjö BK: Pathophysiology and treatment of focal cerebral ischemia. Part I: Pathophysiology. J Neurosurg 77:169–184, 1992

    • Search Google Scholar
    • Export Citation
  • 26.

    Siesjö BK: Pathophysiology and treatment of focal cerebral ischemia. Part II: Mechanisms of damage and treatment. J Neurosurg 77:337354, 1992 Siesjö BK: Pathophysiology and treatment of focal cerebral ischemia. Part II: Mechanisms of damage and treatment. J Neurosurg 77:337–354, 1992

    • Search Google Scholar
    • Export Citation
  • 27.

    Tabaddor K, , Bhushan C, & Pevsner PH, et al: Prognostic value of cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) in acute head trauma. J Trauma 12:10531055, 1972 Tabaddor K, Bhushan C, Pevsner PH, et al: Prognostic value of cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) in acute head trauma. J Trauma 12:1053–1055, 1972

    • Search Google Scholar
    • Export Citation
  • 28.

    van Santbrink H, , Maas AIR, & Avezaat CJJ: Continuous monitoring of partial pressure of brain tissue oxygen in patients with severe head injury. Neurosurgery 38:2131, 1996 van Santbrink H, Maas AIR, Avezaat CJJ: Continuous monitoring of partial pressure of brain tissue oxygen in patients with severe head injury. Neurosurgery 38:21–31, 1996

    • Search Google Scholar
    • Export Citation
  • 29.

    Verweij BH, , Muizelaar JP, & Vinas FC, et al: Improvement in mitochondrial dysfunction as a new surrogate efficiency measure for preclinical trials: dose—response and time-window profiles for administration of the calcium channel blocker Ziconotide in experimental brain injury. J Neurosurg 93:829834, 2000 Verweij BH, Muizelaar JP, Vinas FC, et al: Improvement in mitochondrial dysfunction as a new surrogate efficiency measure for preclinical trials: dose—response and time-window profiles for administration of the calcium channel blocker Ziconotide in experimental brain injury. J Neurosurg 93:829–834, 2000

    • Search Google Scholar
    • Export Citation
  • 30.

    Verweij BH, , Muizelaar JP, & Vinas FC, et al: Mitochondrial dysfunction after experimental and human brain injury and its possible reversal with a selective N-type calcium channel antagonist (SNX-111). Neurol Res 19:334339, 1997 Verweij BH, Muizelaar JP, Vinas FC, et al: Mitochondrial dysfunction after experimental and human brain injury and its possible reversal with a selective N-type calcium channel antagonist (SNX-111). Neurol Res 19:334–339, 1997

    • Search Google Scholar
    • Export Citation
  • 31.

    Vinas FC, , Verweij BH, & Muizelaar JP: Invasive monitoring of cerebral oxygenation. Crit Rev Neurosurg 8:3140, 1998 Vinas FC, Verweij BH, Muizelaar JP: Invasive monitoring of cerebral oxygenation. Crit Rev Neurosurg 8:31–40, 1998

    • Search Google Scholar
    • Export Citation
  • 32.

    Xiong Y, , Gu Q, & Peterson PL, et al: Mitochondrial dysfunction and calcium perturbation induced by traumatic brain injury. J Neurotrauma 14:2334, 1997 Xiong Y, Gu Q, Peterson PL, et al: Mitochondrial dysfunction and calcium perturbation induced by traumatic brain injury. J Neurotrauma 14:23–34, 1997

    • Search Google Scholar
    • Export Citation
  • 33.

    Xiong Y, , Peterson PL, & Muizelaar JP, et al: Amelioration of mitochondrial function by a novel antioxidant U-101033E following traumatic brain injury in rats. J Neurotrauma 14:907917, 1997 Xiong Y, Peterson PL, Muizelaar JP, et al: Amelioration of mitochondrial function by a novel antioxidant U-101033E following traumatic brain injury in rats. J Neurotrauma 14:907–917, 1997

    • Search Google Scholar
    • Export Citation
  • 34.

    Xiong Y, , Peterson PL, & Verweij BH, et al: Mitochondrial dysfunction following experimental traumatic brain injury: combined efficacy of SNX-111 and U-101033E. J Neurotrauma 15:531544, 1998 Xiong Y, Peterson PL, Verweij BH, et al: Mitochondrial dysfunction following experimental traumatic brain injury: combined efficacy of SNX-111 and U-101033E. J Neurotrauma 15:531–544, 1998

    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 1330 271 34
Full Text Views 320 49 4
PDF Downloads 198 38 3
EPUB Downloads 0 0 0