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

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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.

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Acknowledgements

Funding for this study was provided by NIH NINDS grant N. P50 NS 12587-27, and Ross Bullock was supported by the Reynolds, and Lind-Lawrence Foundations.

Oscar L Alves was supported by grant no. SFRH/BD/3421/2000 from Fundação para a Ciência e Tecnologia, and by a Fulbright Fellowship.

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Authors and Affiliations

  1. Department of Neuroscience, Psychiatric and Anesthesiological Sciences, University of Messina, Viale Regina Margherita n. 59, 98121, Messina, Italy

    Anna Teresa Mazzeo

  2. Division of Neurosurgery, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA

    Anna Teresa Mazzeo & Charlotte B. Gilman

  3. Serviço de Neurocirurgia, Centro Hospitalar de Vila Nova de Gaia, Faculdade de Medicina da Universitade do Porto, Porto, Portugal

    Óscar Luís Alves

  4. Department of Anesthesiology, University of Florida, Gainesville, FL, USA

    Ronald L. Hayes

  5. Center of Innovative Research, Banyan Biomarkers, Inc., Alachua, FL, USA

    Ronald L. Hayes

  6. Department of Neurosurgery, Kings College Hospital, London, UK

    Christos Tolias

  7. Department of Computer Information Systems, University of Louisville, Louisville, KY, USA

    K. Niki Kunene

  8. Department of Neurosurgery, University of Miami Miller School of Medicine, Lois Pope LIFE Center, Miami, FL, USA

    M. Ross Bullock

Authors
  1. Anna Teresa Mazzeo
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  2. Óscar Luís Alves
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  3. Charlotte B. Gilman
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  4. Ronald L. Hayes
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  5. Christos Tolias
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  6. K. Niki Kunene
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  7. M. Ross Bullock
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Correspondence to Anna Teresa Mazzeo.

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Comment

This study supports the promising concept of using cerebral microdialysis (MD) in early drug development in the Neuro-ICU setting as proposed by Alves et al (1) for obtaining proof-of-concept, studying surrogate end point markers and pharmacokinetics.

The results support a putative neuroprotective effect of Cyklosporin A (CsA) by showing robust positive effects on local neurochemistry measured by MD and hemodynamics in TBI patients. Further work is needed to establish the CsA effects with global methods (e.g. MRI, PET) and to clarify the mechanisms of the observed effects. Analysis of unbound drug levels in MD samples would also be valuable.

The neurochemical effects of CsA are particularly intriguing in view of the emerging concept of energy metabolic crisis without hypoxia/ischemia being a common phenomenon following TBI and perhaps subarachnoid hemorrhage (2-7). This phenomenon is characterised by a relative shortage of brain glucose and pyruvate perhaps related to competition for glucose between metabolic pathways such as the glycolytic and Pentose Phosphate Pathways (8) contributing to secondary brain damage. The observation that CsA may alleviate this type of energy metabolic crisis by increasing the cerebral MD glucose and pyruvate levels could lead to a higher capacity for endogenous brain repair and improved outcome.

References

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2. 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 21:894–906

3. 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 25:763–774

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8. 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 labelling study in humans. J Cereb Blood Flow Metab 27:1593–602

Lars Hillered

Dept of Neuroscience, Neurosurgery,

Uppsala University Hospital, Uppsala, Sweden

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Mazzeo, A.T., Alves, Ó.L., Gilman, C.B. et al. Brain metabolic and hemodynamic effects of cyclosporin A after human severe traumatic brain injury: a microdialysis study. Acta Neurochir (Wien) 150, 1019–1031 (2008). https://doi.org/10.1007/s00701-008-0021-7

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