title: Tissue plasminogen activator treatment of stroke in type-1 diabetes rats.
abstract: OBJECTIVE
  Diabetes mellitus (DM) is a major stroke risk factor and is associated with poor recovery compared with nondiabetic stroke patients. In the present study, we investigated the effects of tissue plasminogen activator (tPA) treatment of stroke in diabetic and non-diabetic rats.
  
  
  METHODS
  Type-1 diabetes (T1DM) was induced by injection of streptozotocin. Non-T1DM and T1DM rats were subjected to embolic middle cerebral artery occlusion (MCAo) and treated with or without tPA 2h after MCAo. Functional outcomes and immunostaining for advanced glycation endproducts receptor (RAGE), matrix metalloproteinase-9 (MMP-9) and toll-like receptor 4 (TLR4) and Western blotting were performed.
  
  
  RESULTS
  tPA treatment of WT-MCAo rats significantly improved the functional outcome and reduced the lesion volume compared with non-treatment WT-MCAo rats (p<0.05). There was no significant difference between treatment with or without tPA in the WT-MCAo group in brain hemorrhage, BBB leakage and expression of inflammatory mediators, RAGE, MMP-9 and TLR4. However, tPA treatment in T1DM-MCAo rats (T1DM-MCAo+tPA) significantly enlarged brain hemorrhage, augmented BBB leakage, and failed to decrease lesion volume and improve functional outcome after stroke compared to T1DM-MCAo control. tPA treatment also significantly increased the expression of RAGE, MMP-9 and TLR4 in the ischemic brain in T1DM-MCAo rats compared with T1DM-MCAo control rats (p<0.05). Brain hemorrhage was significantly correlated with functional deficit and RAGE and TLR4 expression, respectively.
  
  
  CONCLUSIONS
  Treatment of stroke with tPA increased brain hemorrhage, BBB leakage and failed to improve functional outcome in T1DM rats. The increased inflammatory response may contribute to the failed neuroprotective effects of tPA treatment in T1DM rats.
authors: Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, United States.
authors: R
authors: R
authors: Ning
authors: M
authors: M
authors: Chopp
authors: T
authors: T
authors: Yan
authors: A
authors: A
authors: Zacharek
authors: C
authors: C
authors: Zhang
authors: C
authors: C
authors: Roberts
authors: X
authors: X
authors: Cui
authors: M
authors: M
authors: Lu
authors: J
authors: J
authors: Chen
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology; D015153:Blotting, Western; D002543:Cerebral Hemorrhage / Q000188:drug therapy / Q000473:pathology; D004396:Coloring Agents; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D005070:Evans Blue; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D020127:Recovery of Function; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D004396:Coloring Agents; D005343:Fibrinolytic Agents; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D005070:Evans Blue; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9