BACKGROUND Progesterone (PRO) may confer a survival advantage in traumatic brain injury (TBI) by reducing cerebral edema. We hypothesized that PRO reduces edema by blocking polymorphonuclear (PMN) interactions with endothelium (EC) in the blood-brain barrier (BBB). METHODS CD1 mice received repeated PRO (16 mg/kg intraperitoneally) or vehicle (cyclodextrin) for 36 hours after TBI. Sham animals underwent craniotomy without TBI. The modified Neurological Severity Score graded neurologic recovery. A second craniotomy allowed in vivo observation of pial EC/PMN interactions and vascular macromolecule leakage. Wet/dry ratios assessed cerebral edema. RESULTS Compared with the vehicle, PRO reduced subjective cerebral swelling (2.9 ± .1 vs 1.2 ± .1, P <.001), PMN rolling (95 ± 1.8 vs 57 ± 2.0 cells/100 μm/min, P <.001), total EC/PMN adhesion (2.0 ± .4 vs .8 ± .1 PMN/100 μm, P <.01), and vascular permeability (51.8% ± 4.9% vs 27.1% ± 4.6%, P <.01). TBI groups had similar a Neurological Severity Score and cerebral wet/dry ratios (P > .05). CONCLUSIONS PRO reduces live pericontusional EC/PMN and BBB macromolecular leakage after TBI. Direct PRO effects on the microcirculation warrant further investigation.

BACKGROUND Traumatic brain injury (TBI) confers a high risk of venous thrombosis, but early prevention with heparinoids is often withheld, fearing cerebral hematoma expansion. Yet, studies have shown heparinoids not only to be safe but also to limit brain edema and contusion size after TBI. Human TBI data also suggest faster radiologic and clinical neurologic recovery with earlier heparinoid administration. We hypothesized that enoxaparin (ENX) after TBI blunts in vivo leukocyte (LEU) mobilization to injured brain and cerebral edema, while improving neurologic recovery without increasing the size of the cerebral hemorrhagic contusion. METHODS CD1 male mice underwent either TBI by controlled cortical impact (CCI, 1-mm depth, 6 m/s) or sham craniotomy. ENX (1 mg/kg) or vehicle (VEH, 0.9% saline, 1 mL/kg) was administered at 2, 8, 14, 23, and 32 hours after TBI. At 48 hours, intravital microscopy was used to visualize live LEUs interacting with endothelium and microvascular leakage of fluorescein isothiocyanate–albumin. Neurologic function (Neurological Severity Score, NSS), activated clotting time, hemorrhagic contusion size, as well as brain and lung wet-to-dry ratios were evaluated post mortem. Analysis of variance with Bonferroni correction was used for statistical comparisons between groups. RESULTS Compared with VEH, ENX significantly reduced in vivo LEU rolling on endothelium (72.7 ± 28.3 LEU/100 μm/min vs. 30.6 ± 18.3 LEU/100 μm/min, p = 0.02) and cerebrovascular albumin leakage (34.5% ± 8.1% vs. 23.8% ± 5.5%, p = 0.047). CCI significantly increased ipsilateral cerebral hemisphere edema, but ENX treatment reduced post-CCI edema to near control levels (81.5% ± 1.5% vs. 77.6% ± 0.6%, p < 0.01). Compared with VEH, ENX reduced body weight loss at 24 hours (8.7% ± 1.2% vs. 5.8% ± 1.1%, p < 0.01) and improved NSS at 24 hours (14.5 ± 0.5 vs. 16.2 ± 0.4, p < 0.01) and 48 hours (15.1 ± 0.4 vs. 16.7 ± 0.5, p < 0.01) after injury. There were no significant differences in activated clotting time, hemorrhagic contusion size, and lung water content between the groups. CONCLUSION ENX reduces LEU recruitment to injured brain, diminishing visible microvascular permeability and edema. ENX may also accelerate neurologic recovery without increasing cerebral contusion size. Further study in humans is necessary to determine safety, appropriate dosage, and timing of ENX administration early after TBI.

BACKGROUND Enoxaparin (ENX) has been shown to reduce cerebral edema and improve neurologic recovery after traumatic brain injury (TBI), through blunting of cerebral leukocyte (LEU) recruitment. High mobility group box 1 (HMGB1) protein may induce inflammation through LEU activation. We hypothesized that ENX after TBI reduces LEU-mediated edema through blockade of HMGB1 signaling. METHODS Twenty-three CD1 mice underwent severe TBI by controlled cortical impact and were randomized to one of four groups receiving either monoclonal antibody against HMGB1 (MAb) or isotype (Iso) and either ENX (1 mg/kg) or normal saline (NS): NS + Iso (n = 5), NS + MAb (n = 6), ENX + Iso (n = 6), ENX + MAb (n = 6). ENX or NS was administered 2, 8, 14, 23 and 32 hours after TBI. MAb or Iso (25 μg) was administered 2 hours after TBI. At 48 hours, cerebral intravital microscopy served to visualize live LEU interacting with endothelium and microvascular fluorescein isothiocyanate–albumin leakage. The Neurological Severity Score (NSS) graded neurologic recovery; wet-to-dry ratios determined cerebral/lung edema. Analysis of variance with Bonferroni correction was used for statistical analyses. RESULTS ENX and MAb similarly reduced in vivo pial LEU rolling without demonstrating additive effect. In vivo albumin leakage was greatest in vehicle-treated animals but decreased by 25% with either MAb or ENX but by 50% when both were combined. Controlled cortical impact–induced cerebral wet-to-dry ratios were reduced by MAb or ENX without additive effect. Postinjury lung water was reduced by ENX but not by MAb. Neurologic recovery at 24 hours and 48 hours was similarly improved with ENX, MAb, or both treatments combined. CONCLUSION Mirroring ENX, HMGB1 signaling blockade reduces LEU recruitment, cerebrovascular permeability, and cerebral edema following TBI. ENX further reduced lung edema indicating a multifaceted effect beyond HMGB1 blockade. Further study is needed to determine how ENX may play a role in blunting HMGB1 signaling in brain injury patients.

BACKGROUND Severe traumatic brain injury (TBI) may increase the risk of venous thromboembolic complications; however, early prevention with heparinoids is often withheld for its anticoagulant effect. New evidence suggests low molecular weight heparin reduces cerebral edema and improves neurological recovery after stroke and TBI, through blunting of cerebral leukocyte (LEU) recruitment. It remains unknown if unfractionated heparin (UFH) similarly affects brain inflammation and neurological recovery post-TBI. We hypothesized that UFH after TBI reduces cerebral edema by reducing LEU-mediated inflammation and improves neurological recovery. METHODS CD1 male mice underwent either TBI by controlled cortical impact (CCI) or sham craniotomy. UFH (75 U/kg or 225 U/kg) or vehicle (VEH, 0.9% saline) was administered 2, 11, 20, 27, and 34 hours after TBI. At 48 hours, pial intravital microscopy through a craniotomy was used to visualize live brain LEUs interacting with endothelium and microvascular fluorescein isothiocyanate–albumin leakage. Neurologic function (Garcia Neurological Test, GNT) and body weight loss ratios were evaluated 24 and 48 hours after TBI. Cerebral and lung wet-to-dry ratios were evaluated post mortem. ANOVA with Bonferroni correction was used to determine significance (p < 0.05). RESULTS Compared to positive controls (CCI), both UFH doses reduced post-TBI in vivo LEU rolling on endothelium, concurrent cerebrovascular albumin leakage, and ipsilateral cerebral water content after TBI. Additionally, only low dose UFH (75 U/kg) improved GNT at both 24 and 48 hours after TBI. High dose UFH (225 U/kg) significantly increased body weight loss above sham at 48 hours. Differences in lung water content and blood pressure between groups were not significant. CONCLUSIONS UFH after TBI reduces LEU recruitment, microvascular permeability, and brain edema to injured brain. Lower UFH doses concurrently improve neurological recovery whereas higher UFH may worsen functional recovery. Further study is needed to determine if this is caused by increased bleeding from injured brain with higher UFH doses.

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BACKGROUND Mannitol, hypertonic saline, and progesterone may blunt leukocyte recruitment after traumatic brain injury (TBI). We hypothesized that progesterone reduces pericontusional recruitment of leukocytes to a greater extent than either osmotherapy a day after TBI. METHODS CD1 mice underwent controlled cortical impact and were treated with osmotherapy (mannitol and hypertonic saline) or progesterone. Thirty-two hours after TBI, live pial microscopy was used to evaluate leukocyte–endothelial interactions and immunohistochemistry was used for the detection of pericontusional tissue polymorphonuclear neutrophils. Neurologic recovery was assessed before sacrifice. RESULTS Mannitol resulted in the lowest in vivo leukocyte recruitment compared with progesterone (795 ± 282 vs 1,636 ± 434 LEU/100 μm/minutes, P < .05). Mannitol also displayed lower tissue accumulation of leukocytes as compared with progesterone (5.7 ± 1.7 vs 15.2 ± .1 LEU/mm2, P = .03). However, progesterone resulted in better neurologic recovery than either osmotherapy. CONCLUSIONS Leukocyte recruitment to injured brain is lowest with mannitol administration. How different agents alter progression of secondary brain injury will require further evaluation in humans.

2,3-O desulfated heparin after TBI reduces cerebral LEU recruitment, microvascular permeability and edema. 2,3-O desulfated heparin may also improve acute neurologic recovery leading to improved learning/memory ability weeks after injury.