Role of endogenous ligands for the peroxisome proliferators activated receptors alpha in the secondary damage in experimental spinal cord trauma

Genovese, Tiziana; Mazzon, Emanuela; Paola, Rosanna Di; Cannavò, Giuseppe; Muià, Carmelo; Bramantı, Placido; Cuzzocrea, Salvatore

doi:10.1016/j.expneurol.2005.03.003

Cited by 51 publications

(52 citation statements)

References 54 publications

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“…These results are in agreement with our previous observations indicating that PPAR-␣KO mice are more susceptible to the induction of inflammation, possibly due to a less efficient physiological anti-inflammatory control exerted by endogenous GCs (Delerive et al, 1999;Lovett-Racke et al, 2004;Genovese et al, 2005;Okamoto et al, 2005). We here confirm these observations for some of the inflammatory parameters such as cell tissue infiltrate, TNF-␣ production, iNOS, and COX-2 activity.…”

Section: Discussionsupporting

confidence: 83%

Peroxisome Proliferator-Activated Receptor-α Contributes to the Anti-Inflammatory Activity of Glucocorticoids

Cuzzocrea¹,

Bruscoli²,

Mazzon³

et al. 2007

Mol Pharmacol

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Glucocorticoids (GCs) are effective anti-inflammatory agents widely used in the therapeutic approach to treatment of acute and chronic inflammatory diseases. Previous results suggest that peroxisome proliferator-activated receptor-␣ (PPAR-␣), an intracellular transcription factor activated by fatty acids, plays a role in the control of inflammation. With the aim of characterizing the role of PPAR-␣ in GC-mediated anti-inflammatory activity, we tested the efficacy of dexamethasone (DEX), a synthetic GC specific for glucocorticoid receptor, in an experimental model of lung inflammation, carrageenan-induced pleurisy, comparing mice lacking PPAR-␣ (PPAR-␣KO) with wild-type (WT) mice. We also tested the possible synergism of combined treatment with DEX and clofibrate, a PPAR-␣ agonist. Results indicate that DEX-mediated anti-inflammatory activity is weakened in PPAR-␣KO mice compared with WT controls, and that is increased in WT mice when combined with PPAR-␣ agonist treatment. In particular, DEX was less effective in PPAR-␣KO, compared with WT mice, as evaluated by inhibition of NF-B, of TNF-␣ production, of cell migration, of cycloxygenase-2 (COX-2) and inducible nitric-oxide synthase activation. Interestingly enough, macrophages from PPAR-␣KO were less susceptible to DEX-induced COX-2 inhibition in vitro compared with WT mice. However, PPAR-␣ transfection in PPAR-␣KO macrophages, with consequent receptor expression, resulted in reconstitution of susceptibility to DEX-induced COX-2 inhibition to levels comparable with that obtained in WT macrophages. It is noteworthy that the DEX effect on macrophages in vitro was significantly increased in WT cells when combined with PPAR-␣ agonist treatment. These results indicate that PPAR-␣ can contribute to the anti-inflammatory activity of GCs.

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Section: Discussionsupporting

confidence: 83%

Peroxisome Proliferator-Activated Receptor-α Contributes to the Anti-Inflammatory Activity of Glucocorticoids

Cuzzocrea¹,

Bruscoli²,

Mazzon³

et al. 2007

Mol Pharmacol

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“…The time of 24 h after SCI was chosen in agreement with other studies (Genovese et al, 2005). MPO activity was defined as the quantity of enzyme degrading 1 mmol of peroxide/min at 371C and was expressed in milliunits/g of wet tissue.…”

Section: Measurement Of Tnf-a and Il-1bmentioning

confidence: 99%

Neutralization of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Reduces Spinal Cord Injury Damage in Mice

Cantarella

Benedetto

Scollo

et al. 2010

Neuropsychopharmacol

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Spinal cord injury (SCI) is a major cause of disability, its clinical outcome depending mostly on the extent of damage in which proapoptotic cytokines have a crucial function. In particular, the inducers of apoptosis belonging to TNF receptor superfamily and their respective ligands are upregulated after SCI. In this study, the function of the proapoptotic cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in SCI-induced damage was investigated in the mouse. SCI resulted in severe trauma, characterized by prominent inflammation-related damage and apoptosis. Immunostaining for TRAIL and its receptor DR5 was found in the white and gray matter of the perilesional area, as also confirmed by western blotting experiments. Immunoneutralization of TRAIL resulted in improved functional recovery, reduced apoptotic cell number, modulation of molecules involved in the inflammatory response (FasL, TNF-a, IL-1b, and MPO), and the corresponding signaling (caspase-8 and -3 activation, JNK phosphorylation, Bax, and Bcl-2 expression). As glucocorticoid-induced TNF receptor superfamily-related protein (GITR) activated by its ligand (GITRL) contributes to SCI-related inflammation, interactions between TRAIL and GITRL were investigated. SCI was associated with upregulated GITR and GITRL expression, a phenomenon prevented by anti-TRAIL treatment. Moreover, the expression of both TRAIL and DR5 was reduced in tissues from mice lacking the GITR gene (GITR À/À ) in comparison with wild-type mice suggesting that TRAIL-and GITRL-activated pathways synergise in the development of SCI-related inflammatory damage. Characterization of new targets within such molecular systems may constitute a platform for innovative treatment of SCI.

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“…We also showed that after SCI, TZDs act directly by stimulating PPAR␥. A recent study showed that PPAR␣-knockout mice show less neutrophil infiltration and neuronal damage after SCI (Genovese et al, 2005). Currently several dual agonists that can activate both PPAR␥ and PPAR␣ are under development, and in the future these compounds might help prevent the detrimental effects of SCI by curtailing inflammation at the level of transcription.…”

Section: Discussionmentioning

confidence: 99%

Thiazolidinedione Class of Peroxisome Proliferator-Activated Receptor γ Agonists Prevents Neuronal Damage, Motor Dysfunction, Myelin Loss, Neuropathic Pain, and Inflammation after Spinal Cord Injury in Adult Rats

Park

Yi²,

Miranpuri³

et al. 2006

J Pharmacol Exp Ther

215

177

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Thiazolidinediones (TZDs) are potent synthetic agonists of the ligand-activated transcription factor peroxisome proliferatoractivated receptor-␥ (PPAR␥). TZDs were shown to induce neuroprotection after cerebral ischemia by blocking inflammation. As spinal cord injury (SCI) induces massive inflammation that precipitates secondary neuronal death, we currently analyzed the therapeutic efficacy of TZDs pioglitazone and rosiglitazone after SCI in adult rats. Both pioglitazone and rosiglitazone (1.5 mg/kg i.p.; four doses at 5 min and 12, 24, and 48 h) significantly decreased the lesion size (by 57 to 68%, p Ͻ 0.05), motor neuron loss (by 3-to 10-fold, p Ͻ 0.05), myelin loss (by 66 to 75%, p Ͻ 0.05), astrogliosis (by 46 to 61%, p Ͻ 0.05), and microglial activation (by 59 to 78%, p Ͻ 0.05) after SCI. TZDs significantly enhanced the motor function recovery (at 7 days after SCI, the motor scores were 37 to 45% higher in the TZD groups over the vehicle group; p Ͻ 0.05), but the treatment was effective only when the first injection was given by 2 h after SCI. At 28 days after SCI, chronic thermal hyperalgesia was decreased significantly (by 31 to 39%; p Ͻ 0.05) in the pioglitazone group compared with the vehicle group. At 6 h after SCI, the pioglitazone group showed significantly less induction of inflammatory genes [interleukin (IL)-6 by 83%, IL-1␤ by 87%, monocyte chemoattractant protein-1 by 75%, intracellular adhesion molecule-1 by 84%, and early growth response-1 by 67%] compared with the vehicle group (p Ͻ 0.05 in all cases). Pioglitazone also significantly enhanced the post-SCI induction of neuroprotective heat shock proteins and antioxidant enzymes. Pretreatment with a PPAR␥ antagonist, 2-chloro-5-nitro-N-phenyl-benzamide (GW9662), prevented the neuroprotection induced by pioglitazone.Peroxisome proliferator-activated receptor (PPAR) and retinoid X receptor are ligand-activated transcription factors of the nuclear hormone receptor superfamily. Upon ligand binding, PPAR forms a heterodimeric complex with retinoid X receptor that binds to the cis-acting sequences (peroxisome proliferator response element) on DNA to initiate or repress the transcription of target genes (Blanquart et al., 2003). PPAR exists as three isoforms (␣, ␥, and ␦/␤) that control many cellular functions including lipid metabolism, glucose absorption, and cell growth and differentiation (Escher and Wahli, 2000). 15-Deoxy-⌬-12,14-prostaglandin J 2 (15-d-PGJ 2 ) is the natural agonist and thiazolidinediones (TZDs) (troglitazone, ciglitazone, rosiglitazone, and pioglitazone) are potent synthetic agonists of PPAR␥. Of these, troglitazone was removed from the market because of hepatotoxicity, whereas rosiglitazone and pioglitazone are currently ap-

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Role of endogenous ligands for the peroxisome proliferators activated receptors alpha in the secondary damage in experimental spinal cord trauma

Cited by 51 publications

References 54 publications

Peroxisome Proliferator-Activated Receptor-α Contributes to the Anti-Inflammatory Activity of Glucocorticoids

Peroxisome Proliferator-Activated Receptor-α Contributes to the Anti-Inflammatory Activity of Glucocorticoids

Neutralization of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Reduces Spinal Cord Injury Damage in Mice

Thiazolidinedione Class of Peroxisome Proliferator-Activated Receptor γ Agonists Prevents Neuronal Damage, Motor Dysfunction, Myelin Loss, Neuropathic Pain, and Inflammation after Spinal Cord Injury in Adult Rats

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