title: Sitagliptin attenuates transient cerebral ischemia/reperfusion injury in diabetic rats: implication of the oxidative-inflammatory-apoptotic pathway.
abstract: OBJECTIVE
  Ischemic stroke is a major macrovascular complication of diabetes mellitus. Sitagliptin, a dipeptidyl peptidase-IV inhibitor, was recently shown to improve cognitive functions in diabetic rats; hence the present study was conducted to evaluate its protective effect against transient ischemia-reperfusion (I/R) in diabetic animals.
  
  
  METHODS
  Diabetes was induced by streptozotocin (40 mg/kg). Six weeks later, cerebral I/R was induced by bicommon carotid occlusion for 15 min followed by 1h reperfusion. Sitagliptin (250 mg/kg; p.o.) was administered daily during the last 2 weeks before I/R.
  
  
  RESULTS
  The drug alleviated hippocampal injury inflicted by diabetes and/or I/R injury where it suppressed nuclear factor kappa (NF-κ)B, 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 sitagliptin was depicted, where it reduced neutrophil infiltration, lipid peroxides and nitric oxide associated with replenished reduced glutathione. Decline of excitatory amino acid glutamate content is a main finding which is probably mediated by the NF-κB signaling pathway as well as improved oxidant status. Sitagliptin exerted an anti-apoptotic effect as reflected by the reduction of the mitochondrial matrix component cytochrome -C and the key downstream executioner caspase-3. Histopathological examination corroborated the biochemical data.
  
  
  CONCLUSIONS
  These findings suggest that sitagliptin is endowed with neuroprotective properties which are probably mediated by its antioxidant, anti-inflammatory, and anti-apoptotic mechanisms and hence may provide a novel agent for the management of ischemic stroke in diabetics.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
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.
authors.forename: Hala F
authors.initials: HF
authors.lastname: Zaki
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: Amina S
authors.initials: AS
authors.lastname: Attia
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: Afaf A
authors.initials: AA
authors.lastname: Ain-Shoka
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000517:prevention & control*; D053148:Caspase 3 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D048909:Diabetes Complications / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental; D006624:Hippocampus / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020556:Neutrophil Infiltration / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D018696:Neuroprotective Agents; D011719:Pyrazines; D014230:Triazoles; D016753:Interleukin-10; D045304:Cytochromes c; C505410:Casp3 protein, rat; D053148:Caspase 3; D000068900:Sitagliptin Phosphate
keywords: Apoptosis; Cytokines; Hippocampus; Ischemia/reperfusion; Sitagliptin; Streptozotocin