title: Effects of minocycline plus tissue plasminogen activator combination therapy after focal embolic stroke in type 1 diabetic rats.
abstract: OBJECTIVE
  Poststroke hyperglycemia is associated with resistance to tissue plasminogen activator (tPA) reperfusion, higher risk of intracerebral hemorrhage, and worse neurological outcomes. In this study, we asked whether minocycline combined with intravenous tPA may ameliorate inflammation and brain injury after focal embolic stroke in type 1 diabetic rats.
  
  
  METHODS
  Type 1 diabetic rats were subjected to a focal embolic stroke. Three treatment groups were used: (1) saline at 1.5 hours after stroke; (2) tPA alone at 1.5 hours after stroke; (3) combined minocycline (intravenously) at 1 hour plus tPA at 1.5 hours, and second treatment of minocycline (intraperitoneally) at 12 hours after stroke. Acute brain tissue damages were assessed at 24 hours after stroke. Inflammatory biomarkers interleukin-1β and matrix metalloproteinases 2 and 9 were examined in plasma. Neutrophil infiltration, microglia activation, matrix metalloproteinase activation, and degradation of the tight junction protein claudin-5 were examined in the brain.
  
  
  RESULTS
  Compared with saline or tPA alone treatments, minocycline plus tPA combination therapy significantly reduced brain infarction, intracerebral hemorrhage, and hemispheric swelling at 24 hours after stroke. The combination also significantly suppressed the elevated plasma levels of matrix metalloproteinase-9 and interleukin-1β up to 24 hours after stroke. At 16 hours after stroke, neutrophil infiltration, microglia activation, matrix metalloproteinase-9, and tight junction protein claudin-5 degradation in the peri-infarct brain tissues were also significantly attenuated by the combination therapy.
  
  
  CONCLUSIONS
  Combination therapy with minocycline plus tPA may be beneficial in ameliorating inflammation and reducing infarction, brain swelling, and hemorrhage after ischemic stroke with diabetes mellitus/hyperglycemia.
authors: Departmens of Neurology and Radiology, Harvard Medical School, Boston, MA, USA.
authors: Xiang
authors: X
authors: Fan
authors: Eng H
authors: EH
authors: Lo
authors: Xiaoying
authors: X
authors: Wang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002543:Cerebral Hemorrhage / Q000453:epidemiology / Q000517:prevention & control*; D062507:Claudin-5 / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000150:complications*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000139:chemically induced / Q000150:complications*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D053583:Interleukin-1beta / Q000097:blood; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008911:Minocycline / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012307:Risk Factors; D013311:Streptozocin / Q000009:adverse effects; D020521:Stroke / Q000097:blood / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D062507:Claudin-5; D005343:Fibrinolytic Agents; D053583:Interleukin-1beta; D013311:Streptozocin; D010959:Tissue Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008911:Minocycline