1. ^*Department of Pharmacology, School of Pharmacy, The Hebrew University, Jerusalem, Israel
2. ^†Pediatric Intensive Care Unit, Hadassah Medical Center, The Hebrew University, Jerusalem, Israel
3. ^‡Department of Neurobiochemistry, Tel-Aviv University, Tel-Hashomer, Israel
4. ^§Department of Neurosurgery, Chaim Sheba Medical Center, Tel-Hashomer, Israel
5. Department of Functional Imaging, Lawrence Berkeley National Laboratory, Berkeley, California, U.S.A.

Correspondence: Esther Shohami, Department of Pharmacology, School of Pharmacy, The Hebrew University of Jerusalem, 91120 Jerusalem, Israel. E-mail: esty@cc.huji.ac.il

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 nontoxic Ras inhibitors such as FTS may qualify as neuroprotective drugs.