Fenofibrate Increases Heme Oxygenase 1 Expression and Astrocyte Proliferation While Limits Neuronal Injury During Intracerebral Hemorrhage

Abstract

Peroxisome proliferator-activated receptors alpha (PPARα) is a therapy target in atherosclerosis and cardiovascular diseases. However, anti-inflammatory effects of PPARα in intracerebral hemorrhage (ICH) remain unknown. We investigated the anti-inflammatory effects of fenofibrate, a ligand of PPARα, in ICH rat model. We found that engagement of fenofibrate increased nissl body and astrocytes, and reduced the neuronal damage, which was observed in paraffin section of ICH rat brain. Fenofibrate also promoted the proliferation of astrocytes that were isolated from adult rat brain. Fenofibrate significantly upregulated heme oxygenase 1 (HO-1) at protein and mRNA levels in human glioblastoma LN-18 cells and rat brain astrocytes respectively, but nuclear factor kappalight- chain-enhancer of activated B cells (NFκB) was downregulated after fenofibrate treatment. Results showed that fenofibrate-induced upregulation of HO-1 expression were inhibited after LN-18 cells were transfected with 50nM small interfering RNA (siRNAs) for 48 hours to knockdown PPARα. Further studies in rat astrocytes confirmed the rescue effects of PPARα silence against fenofibrate induced upregulation of HO-1 expression. Our data indicated that fenofibrate benefits neuronal protection through increasing HO-1 expression level and decreasing NFκB expression in PPARα-dependent manner. In conclusion, PPARα and HO-1 may function as significant targets to protect the brain during ICH.

Induction of Mild Hyperbilirubinemia: Hype or Real Therapeutic Opportunity?

“…Due to its function in UCB hepatic uptake, interference with OATP1B1 by compounds/substances that used this transporter for their transport may result in significant elevation of bilirubin concentrations ( Table 2). This, indeed, was reported in human Hypolipidemics as niacin, 43 fibrates, 44 studies on subjects with hypercholesterolemia treated with statins 48 with micromolar, thus clinically significant increase of bilirubin concentrations. Quite surprisingly, a low dose of ursodeoxycholic acid (500 mg) commonly used for the treatment of cholestatic liver diseases increases serum bilirubin concentrations by 30%, via suppression of transcription factor hepatic nuclear factor 1α-mediated OATP1B1 inhibition.…”

“…A large number of clinically used therapeutics has been reported to induce HMOX1, an activity that may at least partially account for their therapeutic effect ( Table ) . Among others, these drugs include nonsteroidal anti‐inflammatory drugs such as coxibs or acetylsalicylic acid, hypolipidemics such as niacin, fibrates, or statins . In fact, atorvastatin and rosuvastatin treatment was demonstrated in mice to increase not only plasma bilirubin concentrations (by 30–70%) but also to increase cardiac bilirubin content (by 77–119%), suggesting a real therapeutic potential.…”

The Protective Role of Heme Oxygenase-1 in Atherosclerotic Diseases

“…Although the relevance of pharmacological or gene therapy with HO-1 to atherosclerotic disease in humans has yet to be established, the overall outcome of the preclinical studies carried out clearly points to HO-1 as a potential therapeutic target in atherosclerotic diseases. It is also of interest that the anti-atherogenic effects of statins (HMG-CoA reductase inhibitors) and fibrates (PPAR ligands) are partly mediated through HO-1 induction [102,103,104]. A number of natural antioxidant compounds contained in foods and plants, such as curcumin and caffeic acid phenethyl ester (polyphenols), and sulforaphane (isothiocyanates), have been demonstrated to be effective inducers of HO-1 and exert defensive actions against oxidative stress-related diseases.…”

Heme Oxygenase 1 in the Nervous System: Does It Favor Neuronal Cell Survival or Induce Neurodegeneration?

“…In a mice model of selective HO-1 overexpression in astrocytes, a significant neuroprotection after acute intracerebral hemorrhage has been proved [83,84] and, in the same context, systemic hemin administration reduces blood brain barrier (BBB) damage and improves neurological recovery [85]. Furthermore, animal treatments aiming at HO-1 up-regulation, through the modulation of Nrf2 [86,87] or PPARα [88], confirm HO-1 induction as protective response against post-hemorrhagic neuronal dysfunctions. However, it is important to note that HO-1 up-regulation after brain hemorrhage seems to follow a specific time course, with the early events that can be protective against oxidative stress, whereas late stage overexpression may result in dysfunctions and toxicity [89].…”