A-Adrenergic receptor inhibition affects cerebral glucose metabolism, motor performance, and inflammatory response after traumatic brain injury Eric J. Ley, MD, Morgan A. Clond, BS, Marko Bukur, MD, Ryan Park, BS, Michael Chervonski, BS, Grant Dagliyan, MPH, Dan R. Margulies, MD, Patrick D. Lyden, MD, Peter S. Conti, MD, PhD, and Ali Salim, MD, Los Angeles, California BACKGROUND: The purpose of this study was to evaluate how A-adrenergic receptor inhibition after traumatic brain injury (TBI) alters changes in early cerebral glucose metabolism and motor performance, as well as cerebral cytokine and heat shock protein (HSP) expression. METHODS: Mouse cerebral glucose metabolism was measured by microPET fluorodeoxyglucose uptake and converted into standardized uptake values (SUV). Four groups of C57/Bl6 mice (wild type [WT]) were initially evaluated: sham or TBI, followed by tail vein injection of either saline or a nonselective A-adrenergic receptor inhibitor (propranolol, 4 mg/kg). Then motor performance, cerebral cytokine, and HSP70 expression were studied at 12 hours and 24 hours after sham injury or TBI in WT mice treated with saline or propranolol and in A1-adrenergic/A2-adrenergic receptor knockout (BARKO) mice treated with saline. RESULTS: Cerebral glucose metabolism was significantly reduced after TBI (mean SUV TBI, 1.63 vs. sham 1.97, p G 0.01) and propranolol attenuated this reduction (mean SUV propranolol, 1.89 vs. saline 1.63, p G 0.01). Both propranolol and BARKO reduced motor deficits at 24 hours after injury, but only BARKO had an effect at 12 hours after injury. TBI WT mice treated with saline performed worse than propranolol mice at 24 hours after injury on rotarod (23 vs. 44 seconds, p G 0.01) and rearing (130 vs. 338 events, p = 0.01) results. At 24 hours after injury, sham BARKO and TBI BARKO mice were similar on rotarod (21 vs. 19 seconds, p = 0.53), ambulatory testing (2,891 vs. 2,274 events, p = 0.14), and rearing (129 vs. 64 events, p = 0.09) results. Interleukin 1A expression was affected by BARKO and propranolol after TBI; attenuation of interleukin 6 and increased HSP70 expression were noted only with BARKO. CONCLUSION: A-adrenergic receptor inhibition affects cerebral glucose metabolism, motor performance, as well as cerebral cytokine and HSP expression after TBI. (J Trauma Acute Care Surg. 2012;73: 33Y40. Copyright * 2012 by Lippincott Williams & Wilkins) KEY WORDS: Traumatic brain injury; A-adrenergic receptor; cerebral glucose metabolism; propranolol; knockout. T raumatic brain injury (TBI) is an enormous public health problem with 1.7 million TBI cases per year. 1 An estimated 5.3 million individuals currently live with a TBI-related dis- ability 2 such as memory or motor deficits, psychological dis- orders, sleep disturbances, and seizures. 3Y5 A secondary injury process after the initial insult increases the associated dis- abilities owing to neuronal stress from mechanical pressures, vascular damage, and inflammatory changes. Emerging bench top 6,7 and retrospective clinical 8Y10 evidence suggest that A-adrenergic receptor (BAR) inhibition reduces the cascade of secondary injuries that occur after TBI. BAR signaling is involved in multiple key aspects of TBI including cerebral ion flux, 11,12 energy metabolism, 13Y16 transcription, 14,17 edema, 18 inflammation, 14,19Y21 and cell death. 14,22,23 Electromagnetic, stereotaxic cranial impact devices offer a TBI model that can determine the effect of BAR inhibition by producing a standard graded injury with well-characterized impairments and reproducible, histologically defined lesions. 24 The injury to the left frontoparietal cortex produces specific motor deficits that can serve as key outcome parameters for testing BAR therapeutics or gene knockout. 25 The impact of BAR on cerebral glucose metabolism is of specific interest as the rapid increase and then extended decrease in cerebral glucose metabolism that occurs after TBI are well studied and may be associated with underlying cerebral cell deterioration. 16 Gauging the effect of BAR inhibition on inflammatory med- iators after TBI is a common therapeutic strategy; interleukin 1A (IL-1A) and IL-6 are frequent targets of experimental brain therapy. 21,26Y30 In addition, heat shock protein 72 (HSP72) is regarded as protective after TBI, and elevation is regarded as a positive marker for survival. 31 Using the electromagnetic, stereotaxic cranial impact model, we studied the associated metabolic, motor, and inflammatory disturbances after injury to determine how BAR inhibition alters these changes. We hypothesize that BAR inhibition attenuates the altered cere- bral glucose metabolism, motor deficits, and inflammatory response after TBI. AAST 2011 PLENARY P APER J Trauma Acute Care Surg Volume 73, Number 1 33 Submitted: September 9, 2011; Revised: March 22, 2012; Accepted: March 23, 2012. From the Division of Trauma and Critical Care (E.J.L., M.A.C., M.B., D.R.M., P.D.L., A.S.), Department of Surgery, Cedars-Sinai Medical Center; and Depart- ment of Radiology (R.P., M.C., G.D., P.S.C.), University of Southern California, Los Angeles, California. This study was part of the podium presentation at the 70th meeting of the American Association for the Surgery of Trauma, Chicago, Illinois, on September 17, 2011. Address for reprints: Eric J. Ley, MD, Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Suite 8215N, Los Angeles, CA 90048; email: eric.ley@cshs.org. DOI: 10.1097/TA.0b013e31825a769b Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.