s-trans-trans-farnesylthiosalicylic-acid and Brain-Injuries

Ras proteins play a role in receptor-mediated signaling pathways and are activated after traumatic brain injury. S-trans-trans-farnesylthiosalicylic acid (FTS), a synthetic Ras inhibitor, acts primarily on the active, GTP-bound form of Ras and was shown to improve neurobehavioral outcome after closed head injury (CHI) in mice. To gain a better understanding of the neuroprotective mechanism of FTS, we used diffusion-weighted imaging (DWI) in a rat model of CHI. Apparent diffusion coefficients (ADC) and transverse relaxation times (T2) were measured in injured rat brains after treatment with vehicle or FTS (5 mg/kg). Neuroprotection by FTS was also assessed in terms of the neurological severity score. One week after injury, significantly better recovery was observed in the FTS-treated rats than in the controls (p = 0.0191). T2 analysis of the magnetic resonance images revealed no differences between the two groups. In contrast, they differed significantly in ADC, particularly at 24 h post-CHI (p < 0.05): in the vehicle-treated rats ADC had decreased to approximately 26% below baseline, whereas it had increased to about 10% above baseline in the FTS-treated rats. As the magnitude of ADC reduction is strongly linked to blood perfusion deficit, these results suggest that the neuroprotective mechanism of FTS might be related to an improvement in cerebral perfusion. We propose that FTS, which is currently being tested in humans for anti-cancer indications, should also be considered as a new strategy for the management of head injury.

Topics: Animals; Brain Injuries; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Farnesol; Male; Motor Activity; ras Proteins; Rats; Recovery of Function; Salicylates; Time Factors

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.

Topics: Animals; Brain Injuries; Disease Models, Animal; Enzyme Inhibitors; Farnesol; Guanosine Triphosphate; Head Injuries, Closed; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Neuroprotective Agents; ras Proteins; Receptors, N-Methyl-D-Aspartate; Recovery of Function; Salicylates