The Ras inhibitor S-trans, trans-farnesylthiosalicylic acid exerts long-lasting neuroprotection in a mouse closed head injury model

Esther Shohami*, Ido Yatsiv, Alexander Alexandrovich, Roni Haklai, Galit Elad-Sfadia, Rachel Grossman, Anat Biegon, Yoel Kloog

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Traumatic brain injury activates N-methyl-D-aspartate receptors (NMDAR) inducing activation of the Ras protein (a key regulator of cell growth, survival, and death) and its effectors. Thus, trauma-induced increase in active Ras-GTP might contribute to traumatic brain injury pathology. Based on this hypothesis, a new concept of neuroprotection is proposed, examined here by investigating the effect of the Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS) in a mouse model of closed head injury (CHI). Mice subjected to CHI were treated systemically 1 h later with FTS (5 mg/kg) or vehicle. After 1 h, Ras-GTP in the contused hemisphere showed a significant (3.8-fold) increase, which was strongly inhibited by FTS (82% inhibition) or by the NMDA-receptor antagonist MK-801 (53%). Both drugs also decreased active (phosphorylated) extracellular signal-regulated kinase. FTS prevented the CHI-induced reduction in NMDAR binding in cortical, striatal, and hippocampal regions, measured by [3H]-MK-801 autoradiography, and decreased lesion size by 50%. It also reduced CHI-induced neurologic deficits, indicated by the highly significant (P < 0.0001) 60% increase in extent of recovery. Thus, FTS provided long-term neuroprotection after CHI, rescuing NMDAR binding in the contused hemisphere and profoundly reducing neurologic deficits. These findings suggest that non-toxic Ras inhibitors such as FTS may qualify as neuroprotective drugs.

Original languageEnglish
Pages (from-to)728-738
Number of pages11
JournalJournal of Cerebral Blood Flow and Metabolism
Volume23
Issue number6
DOIs
StatePublished - 1 Jun 2003

Keywords

  • Neuroprotection
  • NMDA receptors
  • Ras
  • S-trans
  • Trans-farnesylthiosalicylic acid (FTS)
  • Traumatic brain injury

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