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Improvement of Cerebral Metabolism Mediated by Ro5-4864 is Associated with Relief of Intracranial Pressure and Mitochondrial Protective Effect in Experimental Brain Injury

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ABSTRACT

Purpose

To investigate the possible impact of reduction of mitochondrial membrane permeabilization by modulation of the 18 kDa translocator protein mediated by Ro5-4864 over post-traumatic cerebral edema and metabolic crisis.

Methods

Cerebral microdialysis and intracranial pressure (ICP) monitoring were performed in Sprague–Dawley rats treated by intraperitoneal injection of either dimethylsulfoxide (vehicle) or Ro5-4864 following cortical contusion and further correlated with quantitative assessment of mitochondrial damage, water content in the injured tissue, modified neurological severity score, and lesion size.

Results

Ro5-4864 resulted in a profound decrease in ICP that correlated with improved cerebral metabolism characterized by significantly higher glucose and pyruvate and lower lactate concentrations in the pericontusional area in comparison with vehicle-treated animals. Reduced ICP correlated with reduced water content in the injured tissue; improved metabolism was associated with reduced mitochondrial damage evidenced by electron microscopy. Both effects were associated with a profound and significant reduction in glycerol release and lesion size, and correlated with improved neurological recovery.

Conclusions

The present study shows that Ro5-4864 has a favorable effect on the fate of injured brain, presumably mediated by improvement of metabolism. It further suggests that improvement of metabolism may contribute to ICP relief.

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Authors and Affiliations

  1. Acute Brain Injury Research Laboratory, Faculty of Medicine, Technion — Israel Institute of Technology, Haifa, Israel

    Jean F. Soustiel, Felix Milman & Menashe Zaaroor

  2. Institute of Pathology, Rambam Medical Center, Faculty of Medicine, Technion — Israel Institute of Technology, Haifa, Israel

    Eugene Vlodavsky

  3. Department of Molecular Pharmacology, Faculty of Medicine, Technion — Israel Institute of Technology, Haifa, Israel

    Moshe Gavish

  4. Department of Neurosurgery, Rambam Medical Center, P.O.B. 9602, Haifa, 31096, Israel

    Jean F. Soustiel

Authors
  1. Jean F. Soustiel
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  2. Eugene Vlodavsky
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  3. Felix Milman
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  4. Moshe Gavish
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  5. Menashe Zaaroor
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Correspondence to Jean F. Soustiel.

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Eugene Vlodavsky made an equal contribution to this work.

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Soustiel, J.F., Vlodavsky, E., Milman, F. et al. Improvement of Cerebral Metabolism Mediated by Ro5-4864 is Associated with Relief of Intracranial Pressure and Mitochondrial Protective Effect in Experimental Brain Injury. Pharm Res 28, 2945–2953 (2011). https://doi.org/10.1007/s11095-011-0463-0

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  • DOI: https://doi.org/10.1007/s11095-011-0463-0

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