Effects of proteosome inhibition following moderate traumatic brain injury in the rat

Linda Daniels, Nancy E. Stagliano, Karell Curbelo, W. Dalton Dietrich, Helen M. Bramlett

Research output: Contribution to journalArticle

Abstract

Objectives: Proteasome inhibition following ischemia has previously been shown to be therapeutically beneficial in experimental models. The efficacy of this treatment strategy may be further tested clinically in a phase II clinical trial. Proteasome inhibition may be neuroprotective via an anti-inflammatory mechanism. Many of the neuropathological consequences of traumatic brain injury (TBI) parallel those of ischemic injury, but to our knowledge proteasome inhibition has not been evaluated in a clinically relevant TBI model. The purpose of this study was to evaluate the neuroprotective effects of proteasome inhibition following traumatic brain injury in the rat. Methodology: The acute effects of VELCADE®, a potent reversible proteasome inhibitor, were evaluated in 20 rats that underwent moderate fluid percussion (FP) brain injury. A single, bolus injection was administered 30 minutes after FP injury and the animals were sacrificed three days later for histopathological analysis. Contusion volume, neuronal survival (NeuN), and axonal damage (β-APP) were quantitatively assessed to evaluate the neuroprotective effects of this treatment strategy. Results: A neuroprotective trend in the VELCADE® group was found, with an increased number of NeuN positive cortical neurons surviving and a decreased number of β-APP immunoreactive axons compared to vehicle treated animals. However, no significant differences between the groups were found. Conclusion: The present findings did not show a significant effect of VELCADE® treatment using the present TBI model and outcome measures. However, alterations in the experimental design including different injury severities and treatment protocols may result in the detection of a more robust effect. The potential of proteasome inhibition as a treatment for secondary injury following TBI should be further assessed.

Original languageEnglish (US)
Pages (from-to)38-45
Number of pages8
JournalInternational Journal of Neuroprotection and Neuroregeneration
Volume3
Issue number1
StatePublished - Oct 1 2006

Keywords

  • MLN-519
  • Proteasome inhibition
  • PS-519
  • Traumatic brain injury
  • VELCADE®

ASJC Scopus subject areas

  • Clinical Neurology
  • Pharmacology

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