title: β2 adrenergic-mediated reduction of blood glutamate levels and improved neurological outcome after traumatic brain injury in rats.
abstract: BACKGROUND
  Isoflurane-anesthetized rats subjected to traumatic brain injury (TBI) show a transient reduction in blood L-glutamate levels. Having previously observed that isoproterenol produces a sustained decrease in blood glutamate levels in naive rats, we investigated the possible effects of nonselective and selective β1 and β2 adrenergic agonists and antagonists both on blood glutamate levels and on the neurological outcomes of rats subjected to TBI.
  
  
  METHODS
  Rats received either 10 mL/kg of isotonic saline 1 hour after TBI, 50 µg/kg of isoproterenol pretreatment 30 minutes before TBI, 10 mg/kg of propranolol pretreatment 60 minutes before TBI, 10 mg/kg of metoprolol pretreatment 60 minutes before TBI, or 10 mg/kg of butaxamine pretreatment 40 minutes before TBI and 10 minutes before pretreatment with 50 µg/kg isoproterenol or 10 mg/kg of propranolol 60 minutes after TBI. A neurological severity score (NSS) was measured at 1, 24, and 48 hours after TBI. Blood glutamate, blood glucose, mean arterial blood pressure, and heart rate were measured at the time of drug injection, at the time of TBI, 60 minutes after TBI, and 90 minutes after TBI.
  
  
  RESULTS
  Blood glutamate levels decreased spontaneously by 60 minutes after TBI in the control group (P<0.05), reverting to baseline levels by 90 minutes after TBI. A pretreatment with either 10 mg/kg of metoprolol 60 minutes before TBI or with 50 µg/kg of isoproterenol 30 minutes before TBI also reduced blood glutamate levels (P<0.05) both at 90 minutes after TBI and improved the NSS measured 24 and 48 hours after TBI in comparison with the control saline-treated group. However, a 10-mg/kg butoxamine pretreatment 40 minutes before TBI and 10 minutes before pretreatment with 50 µg/kg of isoproterenol or 10 mg/kg of propranolol 60 minutes before TBI neither affected blood glutamate levels across time after TBI nor caused any significant change in the NSS measured 24 and 48 hours after TBI in comparison with the control saline-treated group. A strong correlation (r(2)=0.73) was demonstrated between the percent decrease in blood glutamate levels at 90 minutes after TBI and the percent improvement of NSS measured 24 hours after TBI.
  
  
  CONCLUSIONS
  The results suggest that the transient blood glutamate reduction seen after TBI is the result of a stress response and of the activation of the sympathetic nervous system through the β2 adrenergic receptors, causing an increase of the brain-to-blood efflux of glutamate observed with excess brain glutamate levels after a brain insult. This strongly correlates with the neurological improvement observed 24 hours after TBI.
authors: Division of Anesthesiology, Soroka Medical Center and Ben Gurion University of the Negev, Beer-Sheva, Israel. zlotnika@bgu.ac.il
authors: Alexander
authors: A
authors: Zlotnik
authors: Yael
authors: Y
authors: Klin
authors: Benjamin Fredrick
authors: BF
authors: Gruenbaum
authors: Shaun Evan
authors: SE
authors: Gruenbaum
authors: Sharon
authors: S
authors: Ohayon
authors: Akiva
authors: A
authors: Leibowitz
authors: Ruslan
authors: R
authors: Kotz
authors: Michael
authors: M
authors: Dubilet
authors: Matthew
authors: M
authors: Boyko
authors: Yoram
authors: Y
authors: Shapira
authors: Vivian I
authors: VI
authors: Teichberg
mesh_terms: D058665:Adrenergic beta-1 Receptor Agonists / Q000627:therapeutic use; D058671:Adrenergic beta-1 Receptor Antagonists / Q000627:therapeutic use; D058666:Adrenergic beta-2 Receptor Agonists / Q000627:therapeutic use; D058672:Adrenergic beta-2 Receptor Antagonists / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001930:Brain Injuries / Q000097:blood* / Q000150:complications; D002078:Butoxamine / Q000627:therapeutic use; D018698:Glutamic Acid / Q000097:blood*; D016489:Head Injuries, Closed / Q000097:blood / Q000150:complications; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D007545:Isoproterenol / Q000627:therapeutic use; D008297:Male; D008790:Metoprolol / Q000627:therapeutic use; D009068:Movement / Q000187:drug effects / Q000502:physiology; D009422:Nervous System Diseases / Q000209:etiology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D016896:Treatment Outcome
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D001786:Blood Glucose; D018343:Receptors, Adrenergic, beta-2; D002078:Butoxamine; D018698:Glutamic Acid; D008790:Metoprolol; D007545:Isoproterenol