We and others have demonstrated that fibrates [peroxisome proliferator-activated receptor (PPAR)␣ agonists] and statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) exerted neuroprotective and pleiotropic effects in experimental models of traumatic brain injury (TBI). Because the combination of statins and fibrates synergistically enhanced PPAR␣ activation, we hypothesized that the combination of both drugs may exert more important and/or prolonged beneficial effects in TBI than each alone. In this study, we examined the combination of fenofibrate with simvastatin, administered 1 and 6 h after injury, on the consequences of TBI. First, our dose-effect study demonstrated that the most efficient dose of simvastatin (37.5 mg/kg) reduced post-traumatic neurological deficits and brain edema. Then, the effects of the combination of fenofibrate (50 mg/kg) and simvastatin (37.5 mg/kg), given p.o. at 1 and 6 h after TBI, were evaluated on the TBI consequences in the early and late phase after injury. The combination exerted more sustained neurological recovery-promoting and antiedematous effects than monotherapies, and it synergistically decreased the post-traumatic brain lesion. Furthermore, a delayed treatment given p.o. at 3 and 8 h after TBI with the combination was still efficient on neurological deficits induced by TBI, but it failed to reduce the brain edema at 48 h. The present data represent the first demonstration that the combination of fenofibrate and simvastatin exerts prolonged and synergistic neuroprotective effects than each drug alone. Thus, these results may have important therapeutic significance for the treatment of TBI. Traumatic brain injury (TBI) remains one of the leading causes of death and disability in industrialized countries. Despite numerous studies on animal models of TBI that investigated therapeutic strategies, no neuroprotective therapy is currently available (Bramlett and Dietrich, 2004). TBI leads to important and deleterious neuroinflammation, as evidenced by edema, free radicals, cytokine production, induction of nitric-oxide synthase and cyclooxygenase type 2, and leukocyte infiltration. Strategies blocking each inflammatory and oxidative mediator have been shown to induce neuroprotective, anti-inflammatory and antioxidative effects after brain injury (Ray et al., 2002). Drugs that were able to modulate only one molecular pathway implicated in inflammation or oxidative stress induced beneficial effects in experimental studies, but they failed in clinical trials. Thus, one key to success in neuroprotection would be to simultaneously modulate many pathophysiological pathways with pharmacological agent inducing pleiotropic effects.One pleiotropic strategy is to activate peroxisome proliferator-activated receptor (PPAR) ␣. PPAR␣ is one of the three subtypes of the nuclear receptor PPAR family, which can be activated by natural ligands, such as polyunsaturated fatty acids, and synthetic ligands (drugs belonging to fibrate's family). PPARs are implicated in several...

Recent evidence supports a crucial role for matrix metalloproteinase-9 (MMP-9) in blood-brain barrier (BBB) disruption and vasogenic edema formation after traumatic brain injury (TBI). Although the exact causes of MMP-9 upregulation after TBI are not fully understood, several arguments suggest a contribution of the enzyme poly(ADP-ribose)polymerase (PARP) in the neuroinflammatory response leading to MMP-9 activation. The objectives of this study were to evaluate the effect of PARP inhibition by 3-aminobenzamide (3-AB) (1) on MMP-9 upregulation and BBB integrity, (2) on edema formation as assessed by magnetic resonance imaging (MRI), (3) on neuron survival as assessed by (1)H magnetic resonance spectroscopy ((1)H-MRS), and (4) on neurological deficits at the acute phase of TBI. Western blots and zymograms showed blunting of MMP-9 upregulation 6 h after TBI. BBB permeability was decreased at the same time point in 3-AB-treated rats compared to vehicle-treated rats. Cerebral MRI showed less "free" water in 3-AB-treated than in vehicle-treated rats 6 h after TBI. MRI findings 24 h after TBI indicated predominant cytotoxic edema, and at this time point no significant differences were found between 3-AB- and vehicle-treated rats with regard to MMP-9 upregulation, BBB permeability, or MRI changes. At both 6 and 24 h, neurological function was better in the 3-AB-treated than in the vehicle-treated rats. These data suggest that PARP inhibition by 3-AB protected the BBB against hyperpermeability induced by MMP-9 upregulation, thereby decreasing vasogenic edema formation 6 h after TBI. Furthermore, our data confirm the neuroprotective effect of 3-AB at the very acute phase of TBI.

Simvastatin could be a new therapy for reducing posttraumatic edema by preventing damage to tight junctions and neutrophil infiltration into the parenchyma, thus preserving blood-brain barrier integrity.