Combination Therapy with Fenofibrate, a Peroxisome Proliferator-Activated Receptor α Agonist, and Simvastatin, a 3-Hydroxy-3-methylglutaryl-Coenzyme A Reductase Inhibitor, on Experimental Traumatic Brain Injury

Abstract

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...

Simvastatin induces cell cycle arrest and inhibits proliferation of bladder cancer cells via PPARγ signalling pathway

“…Importantly, simvastatin activated PPARγ-dependent pathway in heart failure42 and cardiovascular disease43, for example, it attenuated cardiopulmonary-bypass-induced myocardial inflammatory injury by activating PPARγ44. Pharmalogical studies suggested combination therapy with PPARs agonist and simvastatin may have important therapeutic significance45.…”

Statins in Traumatic Brain Injury

“…16,18,19 In cultures of human BBB endothelia, lovastatin and simvastatin were shown to decrease the translocation of both albumin and sucrose, but not normal leukocytes. 20 Microglia (i.e., the resident immune cells of the brain) are implicated in the secretion of glutamate, reactive oxygen species, and other inflammatory mediators, which may exacerbate cerebral edema and secondary neuronal injury.…”

“…Finally, if treatment was delayed by 3 and 8 hours post-injury, benefit in neurologic function was only seen with the fibrate-statin combination. 19 Simvastatin and marrow stem cells have also been shown to improve the functional outcome of rats up to 90 days after experimental TBI, both when used as a monotherapy and synergistically when given sequentially. The synergistic effect may be mediated by increased delivery of marrow stem cells to the peri-contusional area by statin-induced angiogenesis, and subsequent activation and survival of marrow stem cells secondary to trophic factors released from the new blood vessels.…”

“…The palliative effect of statins most likely represents a class effect. Preclinical studies of TBI have used mostly atorvastatin 10 -12,41,43,44,61 and simvastatin, 10,16,19,45,46,59,64,86 which are relatively lipophilic, and therefore have better BBB penetration. 87 Hydrophilic statins have minimal penetration across the BBB.…”

New Insights into the Role of Peroxisome Proliferator-Activated Receptors in Regulating the Inflammatory Response after Tissue Injury

“…In addition, fenofibrate showed antioxidant effects demonstrated by decrease of intracerebral markers of oxidative stress [36]. A study from the same group assessed a synergistical effect of a combination therapy with fenofibrate and simvastatin, a lipid-lowering drug [42]. The administration of these pharmacological compounds in combination after TBI exerted a more sustained neurological recovery than the monotherapies and might have important significance for the treatment of TBI [42].…”