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Acta Neurochirurgica
Published in: Acta Neurochirurgica 10/2008

01-10-2008 | Clinical Article

Brain metabolic and hemodynamic effects of cyclosporin A after human severe traumatic brain injury: a microdialysis study

Authors: Anna Teresa Mazzeo, Óscar Luís Alves, Charlotte B. Gilman, Ronald L. Hayes, Christos Tolias, K. Niki Kunene, M. Ross Bullock

Published in: Acta Neurochirurgica | Issue 10/2008

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Abstract

Background

Mitochondrial dysfunction is a major limiting factor in neuronal recovery following traumatic brain injury. Cyclosporin A (CsA) has been recently proposed for use in the early phase after severe head injury, for its ability to preserve mitochondrial bioenergetic state, potentially exerting a neuroprotective effect. The aim of this study was, therefore, to evaluate the effect of CsA on brain energy metabolism, as measured by cerebral microdialysis, and on cerebral hemodynamics, in a group of severely head injured patients.

Methods

Fifty adult patients with a severe head injury were enrolled in this randomized, double-blind, placebo-controlled study. Patients received 5 mg/kg of CsA over 24 h, or placebo, within 12 h of the injury. A microdialysis probe was placed in all patients, who were managed according to standard protocols for the treatment of severe head injury.

Findings

The most robust result of this study was that, over most of the monitoring period, brain dialysate glucose was significantly higher in the CsA treated patients than in placebo. Both lactate and pyruvate were also significantly higher in the CsA group. Glutamate concentration and lactate/pyruvate ratio were significantly higher in the placebo group than in CsA treated patients, respectively 1 to 2 days, and 2 to 3 days after the end of the 24-h drug infusion. The administration of CsA was also associated with a significant increase in mean arterial pressure (MAP) and cerebral perfusion pressure (CPP).

Conclusions

The administration of CsA in the early phase after head injury resulted in significantly higher extracellular fluid glucose and pyruvate, which may be evidence of a beneficial effect. The early administration of CsA was also associated with a significant increase in MAP and CPP and such a potentially beneficial hemodynamic effect might contribute to a neuroprotective effect.
Literature
1.
Albensi BC, Sullivan PG, Thompson MB, Scheff SW, Mattson MP (2000) Cyclosporin ameliorates traumatic brain-injury-induced alterations of hippocampal synaptic plasticity. Exp Neurol 162:385–389PubMedCrossRef
2.
Alessandri B, Rice AC, Levasseur J, DeFord M, Hamm RJ, Bullock MR (2002) Cyclosporin A improves brain tissue oxygen consumption and learning/memory performance after lateral fluid percussion injury in rats. J Neurotrauma 19:829–841PubMedCrossRef
3.
Alves OL, Doyle AJ, Clausen T, Gilman C, Bullock R (2003) Evaluation of topiramate neuroprotective effect in severe TBI using microdialysis. Ann N Y Acad Sci 993:25–34PubMed
4.
Ankarcrona M, Dypbukt JM, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton SA, Nicotera P (1995) Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron 15:961–973PubMedCrossRef
5.
6.
Brain Trauma Foundation Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS (2007) Guidelines for the management of severe traumatic brain injury. IX. Cerebral perfusion thresholds. J Neurotrauma 24:S59–S64
7.
Buki A, Okonkwo DO, Povlishock JT (1999) Postinjury cyclosporin A administration limits axonal damage and disconnection in traumatic brain injury. J Neurotrauma 16:511–521PubMed
8.
Bullock R, Zauner A, Woodward JJ, Myseros J, Choi SC, Ward JD, Marmarou A, Young HF (1998) Factors affecting excitatory amino acid release following severe human head injury. J Neurosurg 89:507–518PubMed
9.
Bullock MR, Lyeth BG, Muizelaar JP (1999) Current status of neuroprotection trials for traumatic brain injury: lessons from animal models and clinical studies. Neurosurgery 45:207–217PubMedCrossRef
10.
Cesarini KG, Enblad P, Ronne-Engstrom E, Marklund N, Salci K, Nilsson P, Hardemark HG, Hillered L, Persson L (2002) Early cerebral hyperglycolysis after subarachnoid haemorrhage correlates with favourable outcome. Acta Neurochir 144:1121–1131CrossRef
11.
Chaurasia CS (1999) In vivo microdialysis sampling: theory and applications. Biomed Chromatogr 13:317–332PubMedCrossRef
12.
Christians U, Gottschalk S, Miljus J, Hainz C, Benet LZ, Leibfritz D, Serkova N (2004) Alterations in glucose metabolism by cyclosporin in rat brain slices link to oxidative stress: interactions with mTOR inhibitors. Br J Pharmacol 143:388–396PubMedCrossRef
13.
Danovitch GM (2005) Immunosuppressive medications and protocols for kidney transplantation. In: Danovitch GM (ed) Handbook of kidney transplantation. Lippincott Williams & Wilkins, Philadelphia, pp 72–134
14.
Domanska-Janik K, Buzanska L, Dluzniewska J, Kozlowska H, Sarnowska A, Zablocka B (2004) Neuroprotection by cyclosporin A following transient brain ischemia correlates with the inhibition of the early efflux of cytochrome c to cytoplasm. Mol Brain Res 121:50–59PubMedCrossRef
15.
Dusik JR, Glenn TC, Lee WN, Vespa PM, Kelly DF, Lee SM, Hovda DA, Martin NA (2007) Increased pentose phosphate pathway flux after clinical traumatic brain injury: a [1,2-13C2] glucose labeling study in humans. J Cereb Blood Flow Metab 27:1593–602CrossRef
16.
Enblad P, Valtysson J, Andersson J, Lilja A, Valind S, Antoni G, Langstrom B, Hillered L, Persson L (1996) Simultaneous intracerebral microdialysis and positron emission tomography in the detection of ischemia in patients with subarachnoid hemorrhage. J Cereb Blood Flow Metab 16:637–644PubMedCrossRef
17.
Enblad P, Frykholm P, Valtysson J, Silander HC, Andersson J, Fasth KJ, Watanabe Y, Langstrom B, Hillered L, Persson L (2001) Middle cerebral artery occlusion and reperfusion in primates monitored by microdialysis and sequential positron emission tomography. Stroke 32:1574–1580PubMed
18.
Fiskum G (2000) Mitochondrial participation in ischemic and traumatic neural cell death. J Neurotrauma 17:843–855PubMedCrossRef
19.
Friberg H, Ferrand-Drake M, Bengtsson F, Halestrap AP, Wieloch T (1998) Cyclosporin A, but not FK506, protects mitochondria and neurons against hypoglycemic damage and implicates the mitochondrial permeability transition in cell death. J Neurosci 18:5151–5159PubMed
20.
Gardiner SM, March JE, Kemp PA, Fallgren B, Bennett T (2004)) Regional haemodynamic effects of cyclosporin A, tacrolimus and sirolimus in rats. Br J Pharmacol 141:634–643CrossRef
21.
Goodman JC, Valadka AB, Gopinath SP, Uzura M, Robertson CS (1999) Extracellular lactate and glucose alterations in the brain after head injury measured by microdialysis. Crit Care Med 27:1965–1973PubMedCrossRef
22.
Gunter TE, Gunter KK, Sheu SS, Gavin CE (1994) Mitochondrial calcium transport: physiological and pathological relevance. Am J Physiol 267:C313–C339PubMed
23.
Katsura K, Ekholm A, Siesjo BK (1992) Tissue PCO2 in brain ischemia related to lactate content in normo- and hypercapnic rats. J Cereb Blood Flow Metab 12:270–280PubMed
24.
Kett-White R, Hutchinson PJ, Al-Rawi PG, Gupta AK, Pickard JD, Kierkpatrick PJ (2002) Adverse cerebral events detected after subarachnoid hemorrhage using brain oxygen and microdialysis probes. Neurosurgery 50:1213–1222PubMedCrossRef
25.
Kosch M, Hausberg M, Suwelack B (2003) Studies on effects of calcineurin inhibitor withdrawal on arterial distensibility and endothelial function in renal transplant recipients. Transplantation 76:1516–1519PubMedCrossRef
26.
Koura SS, Doppenberg EM, Marmarou A, Choi S, Young HF, Bullock R (1998) Relationship between excitatory amino acid release and outcome after severe human head injury. Acta Neurochir Suppl 71:244–246PubMed
27.
Hlatky R, Valadka AB, Goodman JC, Contant CF, Robertson CS (2004) Patterns of energy substrates during ischemia measured in the brain by microdialysis. J Neurotrauma 21:894–906PubMedCrossRef
28.
Hillered L, Persson L, Ponten U, Ungerstedt U (1990) Neurometabolic monitoring of the ischaemic human brain using microdialysis. Acta Neurochir (Wien) 102:91–97CrossRef
29.
Hillered L, Vespa PM, Hovda DA (2005) Translational neurochemical research in acute human brain injury: the current status and potential future for cerebral microdialysis. J Neurotrauma 22:3–41PubMedCrossRef
30.
Hillered L, Persson L, Nilsson P, Ronne-Engstrom E, Enblad P (2006) Continuous monitoring of cerebral metabolism in traumatic brain injury: a focus on cerebral microdialysis. Curr Opin Crit Care 12:112–118PubMedCrossRef
31.
Hutchinson PJ, Gupta AK, Fryer TF, Al-Rawi PG, Chatfield DA, Coles JP, O’Connell MT, Kett-White R, Minhas PS, Aigbirhio FI, Clark JC, Kirkpatrikck PJ, Menon DK, Pickard JD (2002) Correlation between cerebral blood flow, substrate delivery, and metabolism in head injury: a combined microdialysis and triple oxygen positron emission tomography study. J Cereb Blood Flow Metab 22:735–745PubMedCrossRef
32.
Johnston AJ, Steiner LA, Coles JP, Chatfield DA, Fryer TD, Smielewski P, Hutchinson PJ, O’Connell MT, Al-Rawi PG, Aigbirihio FI, Clark JC, Pickard JD, Gupta AK, Menon DK (2005) Effect of cerebral perfusion pressure augmentation on regional oxygenation and metabolism after head injury. Crit Care Med 33:189–195PubMedCrossRef
33.
Langemann H, Mendelowitsch A, Landolt H, Alessandri B, Gratzl O (1995) Experimental and clinical monitoring of glucose by microdialysis. Clin Neurol Neurosurg 97:149–155PubMedCrossRef
34.
Langemann H, Alessandri B, Mendelowitsch A, Feuerstein T, Landolt H, Gratzl O (2001) Extracellular levels of glucose and lactate measured by quantitative microdialysis in the human brain. Neurol Res 23:531–536PubMedCrossRef
35.
Li PA, Uchino H, Elmer E, Siesjo BK (1997) Amelioration by cyclosporin A of brain damage following 5 or 10 min of ischemia in rats subjected to preischemic hyperglycemia. Brain Res 753:133–140PubMedCrossRef
36.
Lifshitz J, Sullivan PG, Hovda DA, Wieloch T, Mcintosh TK (2004) Mitochondrial damage and dysfunction in traumatic brain injury. Mitochondrion 4:705–713PubMedCrossRef
37.
Lungu AO, Jin ZG, Yamawaki H, Tanimoto T, Wong C, Berk B (2004) Cyclosporin A inhibits flow-mediated activation of endothelial nitric-oxide synthase by altering cholesterol content in caveolae. J Biol Chem 279:48794–48800PubMedCrossRef
38.
Marklund N, Salci K, Lewen A, Hillered L (1997) Glycerol as a marker for post-traumatic membrane phospholipid degradation in rat brain. Neuroreport 8:1457–1461PubMedCrossRef
39.
Marrif H, Juurlink BH (1999) Astrocytes respond to hypoxia by increasing glycolytic capacity. J Neurosci Res 57:255–260PubMedCrossRef
40.
Matsumoto S, Friberg H, Ferrand-Drake M, Wieloch T (1999) Blockade of the mitochondrial permeability transition pore diminishes infarct size in the rat after transient middle cerebral artery occlusion. J Cereb Blood Flow Metab 19:736–741PubMedCrossRef
41.
Mazzeo AT, Kunene N, Gilman C, Hamm R, Bullock R (2006) Severe human traumatic brain injury, but not cyclosporin A treatment, depresses activated T lymphocytes early after injury. J Neurotrauma 23:962–975PubMedCrossRef
42.
Menzel M, Doppenberg EM, Zauner A, Soukup J, Reinert MM, Bullock R (1999) Increased inspired oxygen concentration as a factor in improved brain tissue oxygenation and tissue lactate levels after severe human head injury. J Neurosurg 91:1–10PubMed
43.
Meyerson BA, Linderoth B, Karlsson H, Ungerstedt U (1990) Microdialysis in the human brain: extracellular measurements in the thalamus of parkinsonian patients. Life Sci 46:301–308PubMedCrossRef
44.
Nishiyama A, Kobori H, Fukui T, Zhang GX, Yao L, Rahman M, Hitomi H, Kiyomoto H, Shokoji T, Kimura S, Kohno M, Abe Y (2003) Role of angiotensin II and reactive oxygen species in cyclosporin A-dependent hypertension. Hypertension 42:754–760PubMedCrossRef
45.
Okonkwo DO, Povlishock JT (1999) An intrathecal bolus of cyclosporin A before injury preserves mitochondrial integrity and attenuates axonal disruption in traumatic brain injury. J Cereb Blood Flow Metab 19:443–451PubMedCrossRef
46.
Okonkwo DO, Buki A, Siman R, Povlishock JT (1999) Cyclosporin A limits calcium-induced axonal damage following traumatic brain injury. Neuroreport 10:353–358PubMedCrossRef
47.
Okonkwo DO, Melon DE, Pellicane AJ, Mutlu LK, Rubin DG, Stone JR, Helm GA (2003) Dose–response of cyclosporin A in attenuating traumatic axonal injury in rat. NeuroReport 14:463–466PubMedCrossRef
48.
Peerdeman SM, Girbes ARJ, Polderman KH, Vandertop WP (2003) Changes in cerebral interstitial glycerol concentration in head-injured patients; correlation with secondary events. Intensive Care Med 29:1825–1828PubMedCrossRef
49.
Pellerin L, Magistretti PJ (1994) Glutamate uptake into astrocytes stimultes aerobic glycolysis: A mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci U S A 91:10625–10629PubMedCrossRef
50.
Persson L, Valtysson J, Enblad P, Warme PE, Cesarini K, Lewen A, Hillered L (1996) Neurochemical monitoring using intracerebral microdialysis in patients with subarachnoid hemorrhage. J Neurosurg 84:606–616PubMed
51.
Pettus EH, Povlishock JT (1996) Characterization of a distinct set of intra-axonal ultrastructural changes associated with traumatically induced alteration in axolemmal permeability. Brain Res 722:1–11PubMedCrossRef
52.
Povlishock JT, Pettus EH (1996) Traumatically induced axonal damage: evidence for enduring changes in axolemmal permeability with associated cytoskeletal change. Acta Neurochir Suppl 66:81–86PubMed
53.
Reinstrup P, Stahl N, Mellergard P, Uski T, Ungerstedt U, Nordstrom C-H (2000) Intracerebral microdialysis in clinical practice: baseline values for chemical markers during wakefulness, anesthesia, and neurosurgery. Neurosurgery 47:701–709PubMedCrossRef
54.
Robertson CS (2001) Management of cerebral perfusion pressure after traumatic brain injury. Anesthesiology 95:1513–1517PubMedCrossRef
55.
Roullet JB, Xue H, McCarron DA, Holcomb S, Bennett WM (1994) Vascular mechanism of cyclosporin-induced hypertension in the rat. J Clin Invest 93:2244–2250PubMedCrossRef
56.
Sanchez-Lozada LG, Gamba G, Bolio A, Jimenez F, Herrera-Acosta J, Bobadilla NA (2000) Nifedipine prevents changes in nitric oxide synthase mRNA levels induced by cycloporine. Hypertension 36:642–647PubMed
57.
Scheff SW, Sullivan PG (1999) Cyclosporin A significantly ameliorates cortical damage following experimental traumatic brain injury in rodents. J Neurotrauma 16:783–792PubMed
58.
Schneweis S, Grond M, Staub F, Brinker G, Neveling M, Dohmen C, Graf R, Heiss WD (2001) Predictive value of neurochemical monitoring in large middle cerebral artery infarction. Stroke 32:1863–1867PubMed
59.
Schulz MK, Wang LP, Tange M, Bjerre P (2000) Cerebral microdialysis monitoring: determination of normal and ischemic cerebral metabolisms in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 93:808–814PubMed
60.
Shaltout HA, Abdel-Rahman AA (2003) Cyclosporin induces progressive attenuation of baroreceptor heart rate response and cumulative pressor response in conscious unrestrained rats. J Pharmacol Exp Ther 305:966–973PubMedCrossRef
61.
Shiga Y, Onodera H, Matsuo Y, Kogure K (1992) Cyclosporin A protects against ischemia–reperfusion injury in the brain. Brain Res 595:145–148PubMedCrossRef
62.
Signoretti S, Marmarou A, Tavazzi B, Dunbar J, Amorini AM, Lazzarino G, Vagnozzi R (2004) The protective effect of Cyclosporin A upon N-acetylaspartate and mitochondrial dysfunction following experimental diffuse traumatic brain injury. J Neurotrauma 21:1154–1167PubMed
63.
Skjoth-Rasmussen J, Schultz M, Kristensen SR, Bjerre P (2004) Delayed neurological deficits detected by an ischemic pattern in the extracellular cerebral metabolites in patients with aneurismal subarachnoid hemorrhage. J Neurosurg 100:8–15PubMed
64.
Stahl N, Mellergard P, Hallström A, Ungerstedt U, Nordstrom CH (2001) Intracerebral microdialysis and bedside biochemical analysis in patients with fatal traumatic brain lesions. Acta Anaesthesiol Scand 45:977–985PubMedCrossRef
65.
Starkov AA, Chinopoulos C, Fiskum G (2004) Mitochondrial calcium and oxidative stress as mediators of ischemic brain injury. Cell Calcium 36:257–264PubMedCrossRef
66.
Staub F, Graf R, Gabel P, Kochling M, Klug N, Heiss WD (2000) Multiple interstitial substances measured by microdialysis in patients with subarachnoid hemorrhage. Neurosurgery 47:1106–1116PubMedCrossRef
67.
Sullivan PG, Thompson MB, Schdeff SW (1999) Cyclosporin A attuenuates acute mitochondrial dysfunction following traumatic brain injury. Exp Neurol 160:226–234PubMedCrossRef
68.
Sullivan PG, Rabchevsky AG, Hicks RR, Gibson TR, Fletcher-Turner A, Scheff SW (2000) Dose–response curve and optimal dosing regimen of cyclosporin A after traumatic brain injury in rats. Neuroscience 101:289–295PubMedCrossRef
69.
Sullivan PG, Thompson M, Scheff SW (2000) Continuous infusion of cyclosporin A postinjury significantly ameliorates cortical damage following traumatic brain injury. Exp Neurol 161:631–637PubMedCrossRef
70.
Sullivan PG, Rabchevsky AG, Waldmeier PC, Springer JE (2005) Mitochondrial permeability transition in CNS trauma: cause or effect of neuronal cell death? J Neurosci Res 79:231–239PubMedCrossRef
71.
Tolias CM, Reinert M, Seiler R, Gilman C, Scharf A, Bullock MR (2004) Normobaric hyperoxia-induced improvement in cerebral metabolism and reduction in intracranial pressure in patients with severe head injury: a prospective historical cohort-matched study. J Neurosurg 101:435–444PubMed
72.
Uchino H, Elmer E, Uchino K, Li PA, He QP, Smith ML, Siesjo BK (1998) Amelioration by cyclosporin A of brain damage in transient forebrain ischemia in the rat. Brain Res 812:216–226PubMedCrossRef
73.
Uchino H, Minamikawa-Tachino R, Kristian T, Perkins G, Narazaki M, Siejo BK, Shibasaki F (2002) Differential neuroprotection by cyclosporin A and FK506 following ischemia corresponds with differing abilities to inhibit calcineurin and the mitochondrial permeability transition. Neurobiol Dis 10:219–233PubMedCrossRef
74.
75.
Valadka AB, Goodman JC, Gopinath SP, Uzura M, Robertson CS (1998) Comparison of brain tissue oxygen tension to microdialysis-based measures of cerebral ischemia in fatally head-injured patients. J Neurotrauma 15:509–519PubMed
76.
Valtysson J, Persson L, Hillered L (1998) Extracellular ischemia markers in repeated global ischaemia and secondary hypoxaemia monitored by microdialysis in rat brain. Acta Neurochir 140:387–395CrossRef
77.
Vespa PM, McArthur D, O’Phelan K, Glenn T, Etchepare M, Kelly D, Bergsneider M, Martin NA (2003) Persistently low extracellular glucose correlates with poor outcome 6 months after human traumatic brain injury despite a lack of increased lactate: a microdialysis study. J Cereb Blood Flow Metab 23:865–877PubMedCrossRef
78.
Vespa P, Bergsneider M, Hattori N, wu H-M, Huang S-C, Martin NA, Glenn TC, McArthur DL, Hovda DA (2005) Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study. J Cereb Blood Flow Metab 25:763–774PubMedCrossRef
79.
Wang, X (2001) The expanding role of mitochondria in apoptosis. Genes Dev 15:2922–2933PubMed
80.
Xiong Y, Gu Q, Peterson PL, Muizelaar JP, Lee CP (1997) Mitochondrial dysfunction and calcium perturbation induced by traumatic brain injury. J Neurotrauma 14:23–34PubMed
81.
Yoshimoto T, Siesjo BK (1999) Posttreatment with the immunosuppressant cyclosporin A in transient focal ischemia. Brain Res 839:283–291PubMedCrossRef
82.
Yu G, Hess DC, Borlongan CV (2004) Combined cyclosporine-A and methylprednisolone treatment exerts partial and transient neuroprotection against ischemic stroke. Brain Res 1018:32–37PubMedCrossRef
83.
Zauner A, Bullock R (1995) The role of excitatory amino acids in severe brain trauma: opportunities for therapy: a review. J Neurotrauma 12:547–554PubMed
Metadata
Title
Brain metabolic and hemodynamic effects of cyclosporin A after human severe traumatic brain injury: a microdialysis study
Authors
Anna Teresa Mazzeo
Óscar Luís Alves
Charlotte B. Gilman
Ronald L. Hayes
Christos Tolias
K. Niki Kunene
M. Ross Bullock
Publication date
01-10-2008
Publisher
Springer Vienna
Published in
Acta Neurochirurgica / Issue 10/2008
Print ISSN: 0001-6268
Electronic ISSN: 0942-0940
DOI
https://doi.org/10.1007/s00701-008-0021-7

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