title: Neuroprotective effects of pioglitazone against transient cerebral ischemic reperfusion injury in diabetic rats: Modulation of antioxidant, anti-inflammatory, and anti-apoptotic biomarkers.
abstract: BACKGROUND
  Recent growing consensus introduced thiazolidinediones, agonists of the nuclear receptor peroxisome proliferator-activated receptor gamma as promising candidates in the management of ischemia in various organs. Thereby, interest was raised to investigate the neuroprotective effects of pioglitazone against transient ischemia/reperfusion (I/R) injury in diabetic rats targeting mainly the oxidative-inflammatory-apoptotic cascades which are involved in this insult.
  
  
  METHODS
  Forebrain ischemia was induced in streptozotocin-diabetic rats by occlusion of the bilateral common carotid arteries for 15min followed by 1h reperfusion. Pioglitazone (10mg/kg; po) was administered daily for 2 weeks prior to I/R.
  
  
  RESULTS
  The drug alleviated hippocampal injury inflicted by diabetes and/or I/R injury where it suppressed nuclear factor kappa (NFκB), and consequently the downstream inflammatory cytokines tumor necrosis factor-α and interleukin-6. In parallel, the anti-inflammatory cytokine interleukin-10 was elevated. Antioxidant potential of pioglitazone was depicted, where it reduced neutrophil infiltration, lipid peroxides, nitric oxide associated with replenished reduced glutathione. Decline of excitatory amino acid glutamate content is a main finding which is probably mediated by the NFκB signaling pathway as well as improved oxidant status. Pioglitazone exerted an anti-apoptotic effect as reflected by the reduction of the cytosolic cytochrome c and the key downstream executioner caspase-3.
  
  
  CONCLUSIONS
  Pioglitazone is endowed with neuroprotective properties which are probably mediated by its antioxidant, anti-inflammatory, and anti-apoptotic mechanisms hence may provide a successful agent for the management of ischemic stroke.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: ayman.elsahar@pharma.cu.edu.eg.
authors.forename: Ayman E
authors.initials: AE
authors.lastname: El-Sahar
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: marwa.safar@pharma.cu.edu.eg.
authors.forename: Marwa M
authors.initials: MM
authors.lastname: Safar
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: hala.fahmy@pharma.cu.edu.eg.
authors.forename: Hala F
authors.initials: HF
authors.lastname: Zaki
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: amina.salem@pharma.cu.edu.eg.
authors.forename: Amina S
authors.initials: AS
authors.lastname: Attia
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: afaf.ainshoka@pharma.cu.edu.eg.
authors.forename: Afaf A
authors.initials: AA
authors.lastname: Ain-Shoka
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D017536:Carotid Artery, Common; D016207:Cytokines / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D016328:NF-kappa B; D018696:Neuroprotective Agents; D045162:Thiazolidinediones; D018698:Glutamic Acid; D000077205:Pioglitazone
keywords: Apoptosis; Hippocampus; Ischemia/reperfusion; Pioglitazone