title: Intravenous brain-derived neurotrophic factor reduces infarct size and counterregulates Bax and Bcl-2 expression after temporary focal cerebral ischemia.
abstract: OBJECTIVE
  Pretreatment with intraventricular brain-derived neurotrophic factor (BDNF) reduces ischemic damage after focal cerebral ischemia. In this experiment we studied the effect of intravenous BDNF delivered after focal cerebral ischemia on neurological outcome, infarct size, and expression of proapoptotic and antiapoptotic proteins Bax and Bcl-2, respectively.
  
  
  METHODS
  With the use of the suture occlusion technique, the right middle cerebral artery in rats was temporarily occluded for 2 hours. Thirty minutes after vessel occlusion, BDNF (300 microg/kg per hour in vehicle; n=12) or vehicle alone (n=13) was continuously infused intravenously for 3 hours. After 24 hours the animals were weighed and neurologically assessed on a 5-point scale. The animals were then killed, and brains underwent either 2,3,5-triphenyltetrazolium chloride staining for assessment of infarct volume or paraffin embedding for morphology and immunohistochemistry (Bax, Bcl-2).
  
  
  RESULTS
  Physiological parameters (mean arterial blood pressure, PO(2), PCO(2), pH, body temperature, glucose) and weight revealed no difference between groups. Neurological deficit was improved in BDNF-treated animals versus controls (P:<0.05, unpaired, 2-tailed t test). Mean+/-SD infarct volume was 229.7+/-97.7 mm(3) in controls and 121.3+/-80.2 mm(3) in BDNF-treated animals (P:<0.05, unpaired, 2-tailed t test). Cortical infarct volume was 155.5+/-78.5 mm(3) in the placebo group and 69.9+/-50.2 mm(3) in the BDNF-treated group (P:<0.05, unpaired, 2-tailed t test). Subcortical infarct volume was 74.1+/-30.6 mm(3) in the placebo group and 51.1+/-26.8 mm(3) in the BDNF-treated group (P:=NS). Bax-positive neurons were significantly reduced in the ischemic penumbra in BDNF-treated animals (P:<0.05, unpaired, 2-tailed t test), whereas Bcl-2-positive neurons were significantly increased in this area (P:<0.001, unpaired, 2-tailed t test).
  
  
  CONCLUSIONS
  This study demonstrates a neuroprotective effect of BDNF when delivered intravenously after onset of focal cerebral ischemia. As shown here, one possible mechanism of action of neuroprotection of BDNF after focal ischemia appears to be counterregulation of Bax/Bcl-2 proteins within the ischemic penumbra.
authors.affiliation: Department of Neurology, University of Heidelberg, Germany. wolf_schaebitz@med.uni-heidelberg.de
authors.forename: W R
authors.initials: WR
authors.lastname: Schäbitz
authors.forename: C
authors.initials: C
authors.lastname: Sommer
authors.forename: W
authors.initials: W
authors.lastname: Zoder
authors.forename: M
authors.initials: M
authors.lastname: Kiessling
authors.forename: M
authors.initials: M
authors.lastname: Schwaninger
authors.forename: S
authors.initials: S
authors.lastname: Schwab
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology* / Q000627:therapeutic use; D004396:Coloring Agents; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D008565:Membrane Proteins / Q000096:biosynthesis; D020768:Middle Cerebral Artery; D009460:Neurologic Examination; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D013194:Staining and Labeling; D013778:Tetrazolium Salts; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
chemical_list: C494774:Bak1 protein, rat; C494828:Bax protein, rat; D019208:Brain-Derived Neurotrophic Factor; D004396:Coloring Agents; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013778:Tetrazolium Salts; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C009591:triphenyltetrazolium