b2 Adrenergic-mediated Reduction of Blood Glutamate Levels and Improved Neurological Outcome After Traumatic Brain Injury in Rats Alexander Zlotnik, MD, PhD,* Yael Klin, MSc,w Benjamin Fredrick Gruenbaum, BS,* Shaun Evan Gruenbaum, MD,z Sharon Ohayon, MD,* Akiva Leibowitz, MD,* Ruslan Kotz, MD,* Michael Dubilet, MD,* Matthew Boyko, MSc,* Yoram Shapira, MD, PhD,* and Vivian I. Teichberg, PhDw Background: Isoflurane-anesthetized rats subjected to traumatic brain injury (TBI) show a transient reduction in blood L-glutamate levels. Having previously observed that isoproter- enol produces a sustained decrease in blood glutamate levels in naive rats, we investigated the possible effects of nonselective and selective b1 and b2 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 mg/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 mg/kg isopro- terenol 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 10mg/kg of metoprolol 60 minutes before TBI or with 50 mg/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 mg/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 b2 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. Key Words: b2 adrenergic receptors, glutamate, recovery, traumatic brain injury (J Neurosurg Anesthesiol 2012;24:30–38) T raumatic brain injury (TBI) is a leading cause of disability and death of young adults in industrialized countries. 1,2 Current estimates suggest that 538.2/100,000 population are living with the consequences of TBI in the United States, with estimates of about 1.5 million new cases in 2003. 3,4 The development of neurochemical, histopathological, and molecular techniques to study human TBI has enabled researchers to begin to elucidate the pathologic sequela after TBI. However, no therapy is currently available that provides complete neuroprotection after TBI. One possible factor that could yield future thera- peutic options is the observation that abnormally high concentrations of L-glutamate are found in the brain’s interstitial fluid and cerebrospinal fluid after TBI. In fact, this excess glutamate in the brain fluids has been observed in several neurodegenerative conditions resulting from acute events such as stroke, bacterial meningitis, and TBI 5–8 and in certain chronic disease states such as glaucoma, amyotrophic lateral sclerosis, and human Received for publication April 24, 2011; accepted August 15, 2011. From the *Division of Anesthesiology, Soroka Medical Center and Ben Gurion University of the Negev, Beer-Sheva; wDepartment of Neurobiology, Weizmann Institute, Rehovot, Israel; and zDepartment of Anesthesiology, Yale University School of Medicine, New Haven, CT. Alexander Zlotnik and Yael Klin contributed equally. The authors have no funding or conflicts of interest to disclose. Reprints: Alexander Zlotnik, MD, PhD, Department of Anesthesiology and Critical Care, Soroka Medical Center, POB 151, Beer Sheva, 84105, Israel (e-mail: zlotnika@bgu.ac.il). Copyright r 2012 by Lippincott Williams & Wilkins LABORATORY INVESTIGATION 30 | www.jnsa.com J Neurosurg Anesthesiol  Volume 24, Number 1, January 2012