The in vivo effect of propranolol on cerebral perfusion and hypoxia after traumatic brain injury.
BACKGROUND
Recent epidemiologic evidence has identified beta-blockade as independently associated with improved survival in patients with isolated traumatic brain injury (TBI). Reduced sympathetic discharge and catecholamine release may improve circulation in the injured areas and influence delayed demise. The purpose of this study was to investigate the cerebral effect of beta-blockade in a murine TBI model using immunohistochemical and microPET analysis.


METHODS
Balb/c mice underwent TBI as in a previously described model and were randomized to receive treatment with propranolol or placebo in a blinded fashion. Immunofluorescent images were obtained for vessel density (CD31), vessel perfusion (Ricinus communis agglutinin [RCA]-lectin), and cerebral hypoxia (hypoxyprobe-1) and compared by digital quantification. Perfusion measurements were acquired using positron emission tomography microPET scans with [64Cu]-pyruvaldehyde bis(N4-methylthiosemicarbazone) ([64Cu]-PTSM) and converted into standardized uptake values (SUV) for analysis.


RESULTS
On immunohistochemical analysis, the normal mouse cerebral perfusion was a quantitated mean of 325 +/- 20, the cerebral perfusion after TBI and treatment with placebo was 113 +/- 25, and the cerebral perfusion after TBI treated with propranolol was 172 +/- 23. Immunohistochemical analysis demonstrated treatment with propranolol improved cerebral perfusion by 152% (p value <0.01) and reduced cerebral hypoxia by 24.2% (p value <0.01) compared with treatment with placebo. MicroPET imaging of the normal mouse brain after injection with placebo measured a SUV of 0.7075 +/- 0.02; the normal mouse brain after treatment with propranolol measured a SUV of 0.400 +/- 0.02. After TBI and treatment with placebo, the SUV reduced to 0.395 +/- 0.01; after treatment with propranolol the SUV measured 0.515 +/- 0.04. MicroPET imaging demonstrated propranolol improved cerebral perfusion after TBI to 130% of placebo (p value <0.01).


CONCLUSIONS
Propranolol in vivo increased cerebral perfusion and decreased cerebral hypoxia. This research demonstrates beta-blockade may prevent additional brain damage after traumatic insult and should be the focus of future clinical trials.
Ley
Eric J
EJ
Department of Surgery, Division of Trauma and Critical Care, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Scehnet
Jeff
J
Park
Ryan
R
Schroff
Stu
S
Dagliyan
Grant
G
Conti
Peter S
PS
Margulies
Daniel R
DR
Salim
Ali
A
D000704:Analysis of Variance; D000818:Animals; D001930:Brain Injuries / Q000000981:diagnostic imaging / Q000188:drug therapy*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D000860:Hypoxia / Q000000981:diagnostic imaging / Q000188:drug therapy*; D007150:Immunohistochemistry; D016014:Linear Models; D051379:Mice; D008807:Mice, Inbred BALB C; D009942:Organometallic Compounds; D011433:Propranolol / Q000494:pharmacology*; D019275:Radiopharmaceuticals; D011897:Random Allocation; D018709:Statistics, Nonparametric; D013882:Thiosemicarbazones; D014055:Tomography, Emission-Computed
D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D013882:Thiosemicarbazones; C052629:copper pyruvaldehyde bis(N(4)-methylthiosemicarbazone) complex; D011433:Propranolol