title: Pharmacologic modulation of cerebral metabolic derangement and excitotoxicity in a porcine model of traumatic brain injury and hemorrhagic shock.
abstract: BACKGROUND
  Cerebral metabolic derangement and excitotoxicity play critical roles in the evolution of traumatic brain injury (TBI). We have shown previously that treatment with large doses of valproic acid (VPA) decreases the size of brain lesion. The goal of this experiment was to determine whether this effect was owing to metabolic modulation.
  
  
  METHODS
  Yorkshire swine (n = 9) underwent a protocol of computer-controlled TBI and 40% hemorrhage and were resuscitated randomly with either fresh frozen plasma equal to the volume of shed blood (FFP; n = 4) or VPA (300 mg/kg) and FFP (FFP+VPA; n = 5). Hemodynamics, brain oxygenation, and blood glucose were monitored continuously for 6 hours after resuscitation. Cerebral microdialysis was used to measure glucose, lactate, pyruvate, glutamate, and glycerol levels at baseline, 1 and 2 hours post-shock, post-resuscitation (PR), and at 2, 4, and 6 hours PR. Brain samples from the injured side were then separated into mitochondrial and cytosolic fractions, and activity of pyruvate dehydrogenase complex (PDH) was measured using a dipstick assay kit.
  
  
  RESULTS
  At baseline, there was no difference in brain lactate, pyruvate, glycerol, and glutamate concentrations between the groups. At all time points, there were no differences between the groups in brain oxygenation, cerebral perfusion pressure, or blood and brain glucose concentrations. After VPA infusion (PR time point), however, there was sustained decrease in lactate (0.91 ± 0.47 vs 2.54 ± 0.59 mmol/L; P < .01) and pyruvate (12.80 ± 4.89 vs 46.25 ± 9.22; P < .001) concentrations compared with the FFP alone group, implying superior glucose utilization for ATP production. There was also a decrease in concentrations of glutamate (6.64 ± 3.68 vs 42.25 ± 27.07 mmol/L; P = .02) and glycerol (19.20 ± 6.76 vs 69.75 ± 30.07 mmol/L; P = .01), in the FFP+VPA group, signifying lesser degree of excitotoxicity and brain damage, respectively. Brain PDH activity was greater in the mitochondrial fractions (5,984 ± 504 adjusted volume intensity [INT] × mm(2) vs 4,332 ± 1,055 INT × mm(2); P = .04) and lower in cytosolic fractions in the FFP+VPA group (1,597 ± 1,395 vs 4,026 ± 1,067 INT × mm(2); P = .03), indicating better mitochondrial membrane function and enhanced mitochondrial PDH retention.
  
  
  CONCLUSIONS
  VPA treatment attenuates perturbation of post-traumatic cerebral metabolism by mitigating mitochondrial dysfunction, and decreases glutamate-mediated excitotoxic damage. These properties could explain its effectiveness in decreasing lesion size and post-traumatic cerebral edema.
authors.affiliation: Division of Trauma, Emergency Surgery and Surgical Critical Care, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA.
authors.forename: John O
authors.initials: JO
authors.lastname: Hwabejire
authors.forename: Guang
authors.initials: G
authors.lastname: Jin
authors.forename: Ayesha M
authors.initials: AM
authors.lastname: Imam
authors.forename: Michael
authors.initials: M
authors.lastname: Duggan
authors.forename: Martin
authors.initials: M
authors.lastname: Sillesen
authors.forename: Danielle
authors.initials: D
authors.lastname: Deperalta
authors.forename: Cecilie H
authors.initials: CH
authors.lastname: Jepsen
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lu
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Li
authors.forename: Marc A
authors.initials: MA
authors.lastname: deMoya
authors.forename: Hasan B
authors.initials: HB
authors.lastname: Alam
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002560:Cerebrovascular Circulation; D004195:Disease Models, Animal; D005260:Female; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D017551:Microdialysis; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000378:metabolism; D013552:Swine; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D018696:Neuroprotective Agents; D011768:Pyruvate Dehydrogenase Complex; D014635:Valproic Acid; D000255:Adenosine Triphosphate; D002118:Calcium