S produced and released by oligodendrocytes, thereby protecting the brain against extravascular hemoglobin toxicity [112]. Expression of haptoglobin is increased around the hematoma in animal models of ICH. Haptoglobin-deficient mice are more vulnerable to ICH-induced brain injury, and mice with haptoglobin overexpression are less susceptible to injury [112]. Sulforaphane, an NF-E2-related factor2 n-Phenylpiperazine-1-carboxamide (Nrf2) activator, increases haptoglobin in the brain and reduces brain injury following ICH [112]. In addition, sulforaphane treatment increases expression of Nrf2-mediated antioxidant genes, such as catalase, superoxide dismutase, and glutathioneS-transferase, in the brain after ICH [113]. The antioxidative effects of sulforphane are correlated with reduction of brain damage, measured by brain edema, blood rain barrier impairment, cortical apoptosis, and motor deficits [114]. Peroxisome proliferator-activated receptor (PPAR) plays an important role in augmenting phagocytosis and promoting hematoma absorption [36,37]. PPAR is a ligand-dependent transcription factor that regulates the expression PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/11834444 of several target genes, such as scavenger receptor CD36 [36,37]. CD36, a class B scavenger receptor,Fang et al. Journal of Neuroinflammation 2013, 10:27 http://www.jneuroinflammation.com/content/10/1/Page 7 ofis important for phagocytic activity [115,116]. Treatment with PPAR agonists, such as rosiglitazone and 15d-PGJ2, increases expression of CD36 and promotes phagocytosis of RBCs by microglia/phagocytes in both in vitro and in vivo models of ICH [36,37], and anti-CD36 antibodies prevent PPAR agonist-induced increases in phagocytosis [37]. In addition, in an animal model, treatment of ICH with PPAR agonists accelerated hematoma resolution and reduced neurological deficits [36,37]. ROS are produced after ICH and contribute to ICH pathogenesis [4,5,13,34]. In addition, phagocytosis generates a large amount of ROS that can damage macrophages and 4-dichloro-8-fluoroquinazoline 7-Methyl-[1 neurons. PPAR also plays an important role in protecting microglia/macrophages from oxidative damage via upregulation of the antioxidant catalase [36,37]. PPAR agonists upregulate catalase expression in microglia in vitro and in vivo after ICH, enhance phagocytosis in vitro and increase hematoma absorption in vivo [37]. The PPAR-mediated upregulation of catalase reduces oxidative stress, as demonstrated by a significant reduction of extracellular hydrogen peroxide in cultured microglia [37]. Phagocytosis of RBCs by microglia is also enhanced by upregulation of catalane, as demonstrated by the finding that addition of exogenous catalane to the culture media promotes phagocytosis [37]. PPAR can also induce neuroprotection after ICH via anti-inflammatory effects. In both in vitro and in vivo experiments, PPAR activators reduced expression of proinflammatory genes, including TNF-, IL-1,MMP9, and inducible nitric oxide synthase [37]. PPAR is known to inhibit DNA binding of NF-B [34,55], which controls expression of proinflammatory cytokines and enzymes, suggesting that the anti-inflammatory effect of PPAR probably results from inhibition of NF-B [37,117].TLR4 signaling in hematoma resolutionConclusions and perspectives Increasing evidence has shown that TLR4 signaling plays important roles in PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/8833965 ICH-induced inflammatory brain injury by stimulating activation of microglial cells, infiltration of leukocytes, and production of 5-Bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine cytokines and chemokines [28,31]. The TLR4 signaling pathway involved in ICHinduced inflammatory.