title: Thiazolidinedione class of peroxisome proliferator-activated receptor gamma agonists prevents neuronal damage, motor dysfunction, myelin loss, neuropathic pain, and inflammation after spinal cord injury in adult rats.
abstract: Thiazolidinediones (TZDs) are potent synthetic agonists of the ligand-activated transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma). 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 < 0.05), motor neuron loss (by 3- to 10-fold, p < 0.05), myelin loss (by 66 to 75%, p < 0.05), astrogliosis (by 46 to 61%, p < 0.05), and microglial activation (by 59 to 78%, p < 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 < 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 < 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-1beta 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 < 0.05 in all cases). Pioglitazone also significantly enhanced the post-SCI induction of neuroprotective heat shock proteins and antioxidant enzymes. Pretreatment with a PPARgamma antagonist, 2-chloro-5-nitro-N-phenyl-benzamide (GW9662), prevented the neuroprotection induced by pioglitazone.
authors.affiliation: Department of Neurological Surgery, University of Wisconsin, Madison, WI 53792, USA.
authors.forename: Seung-Won
authors.initials: SW
authors.lastname: Park
authors.forename: Jae-Hyuk
authors.initials: JH
authors.lastname: Yi
authors.forename: Guruwattan
authors.initials: G
authors.lastname: Miranpuri
authors.forename: Irawan
authors.initials: I
authors.lastname: Satriotomo
authors.forename: Kellie
authors.initials: K
authors.lastname: Bowen
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Resnick
authors.forename: Raghu
authors.initials: R
authors.lastname: Vemuganti
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D005911:Gliosis / Q000473:pathology / Q000517:prevention & control; D006360:Heat-Shock Proteins / Q000235:genetics; D018836:Inflammation Mediators / Q000276:immunology; D009043:Motor Activity / Q000187:drug effects*; D009046:Motor Neurons / Q000187:drug effects* / Q000473:pathology; D009186:Myelin Sheath / Q000473:pathology*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D047495:PPAR gamma / Q000819:agonists*; D010146:Pain / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D016207:Cytokines; D006360:Heat-Shock Proteins; D018836:Inflammation Mediators; D018696:Neuroprotective Agents; D047495:PPAR gamma; D045162:Thiazolidinediones