title: High-density lipoprotein-based therapy reduces the hemorrhagic complications associated with tissue plasminogen activator treatment in experimental stroke.
abstract: OBJECTIVE
  We have previously reported that intravenous injection of high-density lipoproteins (HDLs) was neuroprotective in an embolic stroke model. We hypothesized that HDL vasculoprotective actions on the blood-brain barrier (BBB) may decrease hemorrhagic transformation-associated with tissue plasminogen activator (tPA) administration in acute stroke.
  
  
  METHODS
  We used tPA alone or in combination with HDLs in vivo in 2 models of focal middle cerebral artery occlusion (MCAO) (embolic and 4-hour monofilament MCAO) and in vitro in a model of BBB. Sprague-Dawley rats were submitted to MCAO, n=12 per group. The rats were then randomly injected with tPA (10 mg/kg) or saline with or without human plasma purified-HDL (10 mg/kg). The therapeutic effects of HDL and BBB integrity were assessed blindly 24 hours later. The integrity of the BBB was also tested using an in vitro model of human cerebral endothelial cells under oxygen-glucose deprivation.
  
  
  RESULTS
  tPA-treated groups had significantly higher mortality and rate of hemorrhagic transformation at 24 hours in both MCAO models. Cotreatment with HDL significantly reduced stroke-induced mortality versus tPA alone (by 42% in filament MCAO, P=0.009; by 73% in embolic MCAO, P=0.05) and tPA-induced intracerebral parenchymal hematoma (by 92% in filament MCAO, by 100% in embolic MCAO; P<0.0001). This was consistent with an improved BBB integrity. In vitro, HDLs decreased oxygen-glucose deprivation-induced BBB permeability (P<0.05) and vascular endothelial cadherin disorganization.
  
  
  CONCLUSIONS
  HDL injection decreased tPA-induced hemorrhagic transformation in rat models of MCAO. Both in vivo and in vitro results support the vasculoprotective action of HDLs on BBB under ischemic conditions.
authors: Department of Neurology and Stroke Centre, Bichat University Hospital, Paris, France.
authors: Bertrand
authors: B
authors: Lapergue
authors: Bao Quoc
authors: BQ
authors: Dang
authors: Jean-Philippe
authors: JP
authors: Desilles
authors: Guadalupe
authors: G
authors: Ortiz-Munoz
authors: Sandrine
authors: S
authors: Delbosc
authors: Stéphane
authors: S
authors: Loyau
authors: Liliane
authors: L
authors: Louedec
authors: Pierre-Olivier
authors: PO
authors: Couraud
authors: Mikael
authors: M
authors: Mazighi
authors: Jean-Baptiste
authors: JB
authors: Michel
authors: Olivier
authors: O
authors: Meilhac
authors: Pierre
authors: P
authors: Amarenco
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D002460:Cell Line; D002543:Cerebral Hemorrhage / Q000139:chemically induced* / Q000453:epidemiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D066298:In Vitro Techniques; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000473:pathology; D007275:Injections, Intravenous; D008075:Lipoproteins, HDL / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012307:Risk Factors; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality; D010959:Tissue Plasminogen Activator / Q000009:adverse effects* / Q000627:therapeutic use*
chemical_list: D005343:Fibrinolytic Agents; D008075:Lipoproteins, HDL; D010959:Tissue Plasminogen Activator