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1.
J Trauma Acute Care Surg ; 90(2): 274-280, 2021 02 01.
Article in English | MEDLINE | ID: mdl-33093292

ABSTRACT

BACKGROUND: Acute traumatic coagulopathy often accompanies traumatic brain injury (TBI) and may impair cognitive recovery. Antithrombin III (AT-III) reduces the hypercoagulability of TBI. Antithrombin III and heparinoids such as enoxaparin (ENX) demonstrate potent anti-inflammatory activity, reducing organ injury and modulating leukocyte (LEU) activation, independent of their anticoagulant effect. It is unknown what impact AT-III exerts on cerebral LEU activation and blood-brain barrier (BBB) permeability after TBI. We hypothesized that AT-III reduces live microcirculatory LEU-endothelial cell (EC) interactions and leakage at the BBB following TBI. METHODS: CD1 mice (n = 71) underwent either severe TBI (controlled cortical impact (CCI), 6-m/s velocity, 1-mm depth, and 4-mm diameter) or sham craniotomy and then received either AT-III (250 IU/kg), ENX (1.5 mg/kg), or vehicle (saline) every 24 hours. Forty-eight hours post-TBI, cerebral intravital microscopy visualized in vivo penumbral microvascular LEU-EC interactions and microvascular leakage to assess BBB inflammation/permeability. Body weight loss and the Garcia neurological test (motor, sensory, reflex, balance) served as surrogates of clinical recovery. RESULTS: Both AT-III and ENX similarly reduced in vivo penumbral LEU rolling and adhesion (p < 0.05). Antithrombin III also reduced live BBB leakage (p < 0.05). Antithrombin III animals demonstrated the least 48-hour body weight loss (8.4 ± 1%) versus controlled cortical impact and vehicle (11.4 ± 0.5%, p < 0.01). Garcia neurological test scores were similar among groups. CONCLUSION: Antithrombin III reduces post-TBI penumbral LEU-EC interactions in the BBB leading to reduced neuromicrovascular permeability. Antithrombin III further reduced body weight loss compared with no therapy. Further study is needed to determine if these AT-III effects on neuroinflammation affect longer-term neurocognitive recovery after TBI.


Subject(s)
Antithrombin III/pharmacology , Blood-Brain Barrier/drug effects , Brain Hemorrhage, Traumatic/drug therapy , Leukocytes/drug effects , Animals , Brain Hemorrhage, Traumatic/blood , Cell Migration Assays, Leukocyte , Disease Models, Animal , Enoxaparin/pharmacology , Leukocyte Rolling/drug effects , Male , Mice
2.
J Neurotrauma ; 38(5): 604-615, 2021 03.
Article in English | MEDLINE | ID: mdl-33191851

ABSTRACT

Hemorrhage volume is an important variable in emergently assessing traumatic brain injury (TBI). The most widely used method for rapid volume estimation is ABC/2, a simple algorithm that approximates lesion geometry as perfectly ellipsoid. The relative prognostic value of volume measurement based on more precise hematoma topology remains unknown. In this study, we compare volume measurements obtained using ABC/2 versus computer-assisted volumetry (CAV) for both intra- and extra-axial traumatic hemorrhages, and then quantify the association of measurements using both methods with patient outcome following moderate to severe TBI. A total of 517 computer tomography (CT) scans acquired during the Progesterone for Traumatic Brain Injury Experimental Clinical Treatment Phase-III (ProTECTIII) multi-center trial were retrospectively reviewed. Lesion volumes were measured using ABC/2 and CAV. Agreement between methods was tested using Bland-Altman analysis. Relationship of volume measurements with 6-month mortality, Extended Glasgow Outcome Scale (GOS-E), and Disability Rating Scale (DRS) were assessed using linear regression and area under the curve (AUC) analysis. In subdural hematoma (SDH) >50cm3, ABC/2 and CAV produce significantly different volume measurements (p < 0.0001), although the difference was not significant for smaller SDH or intra-axial lesions. The disparity between ABC/2 and CAV measurements varied significantly with hematoma size for both intra- and extra-axial lesions (p < 0.0001). Across all lesions, volume was significantly associated with outcome using either method (p < 0.001), but CAV measurement was a significantly better predictor of outcome than ABC/2 estimation for SDH. Among large traumatic SDH, ABC/2 significantly overestimates lesion volume compared with measurement based on precise bleed topology. CAV also offers significantly better prediction of patient functional outcofme and mortality.


Subject(s)
Brain Hemorrhage, Traumatic/diagnostic imaging , Brain Hemorrhage, Traumatic/mortality , Data Analysis , Image Processing, Computer-Assisted/methods , Progesterone , Tomography, X-Ray Computed/methods , Brain Hemorrhage, Traumatic/drug therapy , Brain Injuries, Traumatic/diagnostic imaging , Brain Injuries, Traumatic/mortality , Female , Humans , Male , Mortality/trends , Progesterone/therapeutic use , Prognosis , Prospective Studies , Single-Blind Method , Treatment Outcome
3.
J Stroke Cerebrovasc Dis ; 30(1): 105436, 2021 Jan.
Article in English | MEDLINE | ID: mdl-33171426

ABSTRACT

BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic agent, which has shown an effect on reducing blood loss in many diseases. Many studies focus on the effect of TXA on cerebral hemorrhage, however, whether TXA can inhibit hematoma expansion is still controversial. Our meta-analysis performed a quantitative analysis to evaluate the efficacy of TXA for the hematoma expansion in spontaneous and traumatic intracranial hematoma. METHOD: Pubmed (MEDLINE), Embase, and Cochrane Library were searched from January 2001 to May 2020 for randomized controlled trials (RCTs). RESULT: We pooled 3102 patients from 7 RCTs to evaluate the efficacy of TXA for hematoma expansion. Hematoma expansion (HE) rate and hematoma volume (HV) change from baseline were used to analyze. We found that TXA led to a significant reduction in HE rate (P = 0.002) and HV change (P = 0.03) compared with the placebo. Patients with moderate or serious hypertension benefit more from TXA. (HE rate: P = 0.02, HV change: P = 0.04) TXA tends to have a better efficacy on HV change in intracerebral hemorrhage (ICH). (P = 0.06) CONCLUSIONS: TXA showed good efficacy for hematoma expansion in spontaneous and traumatic intracranial hemorrhage. Patients with moderate/severe hypertension and ICH may be more suitable for TXA administration in inhibiting hematoma expansion .


Subject(s)
Antifibrinolytic Agents/therapeutic use , Brain Hemorrhage, Traumatic/drug therapy , Cerebral Hemorrhage/drug therapy , Hematoma/drug therapy , Tranexamic Acid/therapeutic use , Antifibrinolytic Agents/adverse effects , Brain Hemorrhage, Traumatic/diagnostic imaging , Brain Hemorrhage, Traumatic/mortality , Cerebral Hemorrhage/diagnostic imaging , Cerebral Hemorrhage/mortality , Disease Progression , Hematoma/diagnostic imaging , Hematoma/mortality , Humans , Randomized Controlled Trials as Topic , Tranexamic Acid/adverse effects , Treatment Outcome
4.
J Pak Med Assoc ; 70(Suppl 1)(2): S49-S52, 2020 Feb.
Article in English | MEDLINE | ID: mdl-31981336

ABSTRACT

The guidelines for management of traumatic brain injury (TBI) are based largely on measures to maintain an optimum internal milieu for prevention of secondary brain injury and enhancing recovery. One of the most common reasons for worsening outcomes following TBI is expanding intracranial haematoma which is compounded by the fibrinolytic physiology that follows TBI. Tranexamic acid (TXA) has a time tested role in preventing poor outcomes linked to excessive haemorrhage in trauma patients. Historically, patients with isolated head trauma were excluded from TXA use due to a theoretical increased risk of thrombosis. Recent evidence that redefines the beneficial role of early TXA administration in preventing mortality amongst patients with TBI is now at hand and offers a real prospect of a pharmacological intervention that would be adopted as a recommendation based on Class l evidence.


Subject(s)
Antifibrinolytic Agents/therapeutic use , Brain Hemorrhage, Traumatic/prevention & control , Brain Injuries, Traumatic/drug therapy , Tranexamic Acid/therapeutic use , Brain Contusion/drug therapy , Brain Hemorrhage, Traumatic/drug therapy , Disease Progression , Early Medical Intervention , Humans , Prognosis
7.
Sci Rep ; 6: 33577, 2016 09 19.
Article in English | MEDLINE | ID: mdl-27641617

ABSTRACT

Transient receptor potential channel 1/4 (TRPC1/4) are considered to be related to subarachnoid hemorrhage (SAH)-induced cerebral vasospasm. In this study, a SAH rat model was employed to study the roles of TRPC1/4 in the early brain injury (EBI) after SAH. Primary cultured hippocampal neurons were exposed to oxyhemoglobin to mimic SAH in vitro. The protein levels of TRPC1/4 increased and peaked at 5 days after SAH in rats. Inhibition of TRPC1/4 by SKF96365 aggravated SAH-induced EBI, such as cortical cell death (by TUNEL staining) and degenerating (by FJB staining). In addition, TRPC1/4 overexpression could increase calcineurin activity, while increased calcineurin activity could promote the dephosphorylation of N-methyl-D-aspartate receptor (NMDAR). Calcineurin antagonist FK506 could weaken the neuroprotection and the dephosphorylation of NMDAR induced by TRPC1/4 overexpression. Contrarily, calcineurin agonist chlorogenic acid inhibited SAH-induced EBI, even when siRNA intervention of TRPC1/4 was performed. Moreover, calcineurin also could lead to the nuclear transfer of nuclear factor of activated T cells (NFAT), which is a transcription factor promoting the expressions of TRPC1/4. TRPC1/4 could inhibit SAH-induced EBI by supressing the phosphorylation of NMDAR via calcineurin. TRPC1/4-induced calcineurin activation also could promote the nuclear transfer of NFAT, suggesting a positive feedback regulation of TRPC1/4 expressions.


Subject(s)
Brain Hemorrhage, Traumatic/metabolism , Calcineurin/metabolism , NFATC Transcription Factors/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , TRPC Cation Channels/metabolism , Active Transport, Cell Nucleus , Animals , Biomarkers , Brain Hemorrhage, Traumatic/drug therapy , Brain Hemorrhage, Traumatic/pathology , Cell Death/drug effects , Models, Biological , Neurons/drug effects , Neurons/metabolism , Oxyhemoglobins/metabolism , Oxyhemoglobins/pharmacology , Phosphorylation , Rats , Subarachnoid Hemorrhage , TRPC Cation Channels/antagonists & inhibitors
8.
Neuroscience ; 284: 912-919, 2015 Jan 22.
Article in English | MEDLINE | ID: mdl-25446362

ABSTRACT

The 70-kDa heat shock protein (HSP70) is known to protect the brain from injury through multiple mechanisms. We investigated the effect of pharmacological HSP70 induction in experimental traumatic brain injury (TBI). 3-month-old male C57/B6 mice were given 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) intraperitoneally (IP, 2 mg/kg) or intracerebroventricularly (ICV, 1 µg/kg) to determine whether HSP70 could be induced in the brain. Mice were subjected to TBI via cortical controlled impact, and were treated with 17-AAG (or vehicle) IP according to one of two treatment regimens: (1) 2 mg/kg at the time of injury, (2) a total of three doses (4 mg/kg) at 2 and 1d prior to TBI and again at the time of injury. Brains were assessed for HSP70 induction, hemorrhage volume at 3 d, and lesion size at 14 d post-injury. Immunohistochemistry showed that both IP and ICV administration of 17-AAG increased HSP70 expression primarily in microglia and in a few neurons by 24 h but not in astrocytes. 17-AAG induced HSP70 in injured brain tissue as early as 6 h, peaking at 48 h and largely subsiding by 72 h after IP injection. Both treatment groups showed decreased hemorrhage volume relative to untreated mice as well as improved neurobehavioral outcomes. These observations indicate that pharmacologic HSP70 induction may prove to be a promising treatment for TBI.


Subject(s)
Benzoquinones/administration & dosage , Brain Injuries/drug therapy , Brain/drug effects , HSP70 Heat-Shock Proteins/metabolism , Lactams, Macrocyclic/administration & dosage , Neuroprotective Agents/administration & dosage , Animals , Astrocytes/drug effects , Astrocytes/metabolism , Astrocytes/pathology , Brain/metabolism , Brain/pathology , Brain Hemorrhage, Traumatic/drug therapy , Brain Hemorrhage, Traumatic/metabolism , Brain Hemorrhage, Traumatic/pathology , Brain Injuries/metabolism , Brain Injuries/pathology , Disease Models, Animal , Male , Mice, Inbred C57BL , Microglia/drug effects , Microglia/metabolism , Microglia/pathology , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Time Factors , Treatment Outcome
9.
J Neurol Surg A Cent Eur Neurosurg ; 73(2): 89-92, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22467482

ABSTRACT

BACKGROUND: The choice of the ideal hemostatic agent for intraoperative cerebral bleeding is under continuous debate. Our aim was to assess the influence of such materials on bleeding time in hemorrhagic cerebral contusions. We compared oxidized regenerated cellulose in fibrillar form (ORC) to microfibrillar collagen fleece (CF) in an experimental study. METHODS: N=50 Sprague Dawley rats underwent a bilateral craniectomy. 3 separate standardized superficial cortical impacts were inflicted using a high-speed drill. Immediately after lesion placement, each of the 3 lesions was covered with (a) nothing (control), (b) ORC, or (c) CF. We observed the 3 lesions with a surgical microscope. The bleeding times were recorded for each cerebral lesion and compared using ANOVA test. RESULTS: All traumatic lesions produced significant bleeding. The statistical analysis showed a clear reduction in bleeding time for groups treated with either ORC or CF compared to the control group. Lesions covered with ORC and CF showed no significant difference with regard to bleeding time. CONCLUSIONS: ORC and CF significantly reduce blood loss from hemorrhagic contusions. Our data suggest that they effectively reduce bleeding time. We advocate the use of hemostatic material for limiting bleeding from superficial cortical lesions.


Subject(s)
Brain Hemorrhage, Traumatic/drug therapy , Cellulose, Oxidized/pharmacology , Coagulants/pharmacology , Collagen/pharmacology , Hemostatic Techniques/trends , Animals , Bleeding Time , Brain Hemorrhage, Traumatic/pathology , Brain Hemorrhage, Traumatic/physiopathology , Brain Injuries/complications , Brain Injuries/physiopathology , Cellulose, Oxidized/chemistry , Coagulants/chemistry , Collagen/chemistry , Disease Models, Animal , Male , Rats , Rats, Sprague-Dawley , Treatment Outcome
10.
J Trauma Acute Care Surg ; 72(1): 136-42, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22027883

ABSTRACT

BACKGROUND: The leading causes of death for trauma patients in civilian and combat settings are traumatic brain injury and uncontrolled hemorrhage, respectively. This study examines the hemostatic activity of an ideal amphipathic peptide (IAP) attached to a biocompatible surface. METHODS: Procoagulant properties of IAP attached to a surface were first tested, in vitro, using factor Xa and thrombin generation assays and thromboelastography. Rabbits and swine were used for in vivo studies. Injuries were performed using scalpel blade 11, and free bleeding was allowed for five seconds. While bleeding, IAP coupled to a hydrogel or QuikClot were applied to the wound and the time was recorded until bleeding stopped. RESULTS: Results show that when IAP is attached to a surface, both factor IXa and factor Xa activities are promoted. Thromboelastography shows that surface-attached IAP results in earlier onset and stronger clot formation. In rabbits, the incorporation of IAP onto a biocompatible hydrogel reduces bleeding times by 40% (p < 0.03). In pigs, bleeding times are reduced 30% to 50% (p < 0.02) by surface-coupled IAP. Finally, using a rabbit liver laceration model, the properties of surface-coupled IAP are less damaging when compared with QuikClot, a currently used material in external hemorrhagic injuries. CONCLUSIONS: This study provides a relevant proof of concept for the development of IAP coupled to a biocompatible surface as a hemostatic agent, that is potentially safer than the commercially available QuikClot.


Subject(s)
Bandages, Hydrocolloid , Brain Hemorrhage, Traumatic/drug therapy , Hemostatics/therapeutic use , Peptides/therapeutic use , Animals , Ear, External/injuries , Factor Xa/analysis , Femoral Artery/injuries , Hemostatics/administration & dosage , Liver/injuries , Male , Peptides/administration & dosage , Rabbits , Swine , Thrombelastography , Thrombin/analysis
11.
Mol Med ; 18: 186-93, 2012 Mar 27.
Article in English | MEDLINE | ID: mdl-22160303

ABSTRACT

Traumatic brain injury (TBI) and hemorrhagic shock often occur concomitantly due to multiple injuries. Gastrointestinal dysfunction occurs frequently in patients with TBI. However, whether alterations in the gastrointestinal system are involved in modulating neuronal damage and recovery after TBI is largely neglected. Ghrelin is a "gut-brain" hormone with multiple functions including antiinflammation and antiapoptosis. The purpose of this study was to determine whether ghrelin attenuates brain injury in a rat model of TBI and uncontrolled hemorrhage (UH). To study this, brain injury was induced by dropping a 450-g weight from 1.5 m onto a steel helmet attached to the skull of male adult rats. Immediately after TBI, a midline laparotomy was performed and both lumbar veins were isolated and severed at the junction with the vena cava. At 45 min after TBI/UH, ghrelin (4, 8 or 16 nmol/rat) or 1 mL normal saline (vehicle) was intravenously administered. Brain levels of TNF-α and IL-6, and cleaved PARP-1 levels in the cortex were measured at 4 h after TBI/UH. Beam balance test, forelimb placing test and hindlimb placing test were used to assess sensorimotor and reflex function. In additional groups of animals, ghrelin (16 nmol/rat) or vehicle was subcutaneously (s.c.) administered daily for 10 d after TBI/UH. The animals were monitored for 28 d to record body weight changes, neurological severity scale and survival. Our results showed that ghrelin downregulated brain levels of TNF-α and IL-6, reduced cortical levels of cleaved PARP-1, improved sensorimotor and reflex functions, and decreased mortality after TBI/UH. Thus, ghrelin has a great potential to be further developed as an effective resuscitation approach for the trauma victims with brain injury and severe blood loss.


Subject(s)
Brain Hemorrhage, Traumatic/drug therapy , Brain Injuries/drug therapy , Ghrelin/therapeutic use , Shock, Hemorrhagic/drug therapy , Animals , Blotting, Western , Immunohistochemistry , Interleukin-6/metabolism , Male , Poly (ADP-Ribose) Polymerase-1 , Poly(ADP-ribose) Polymerases/metabolism , Rats , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/metabolism
12.
J Neurotrauma ; 25(2): 130-9, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18260796

ABSTRACT

This study was undertaken to evaluate the effect of simvastatin, a cholesterol-lowering agent, on the Akt-mediated signaling pathway and neurogenesis in the dentate gyrus (DG) of the hippocampus in rats after traumatic brain injury (TBI). Adult male Wistar rats were divided into three groups: (1) sham group (n = 8); (2) saline control group (n = 40); and (3) simvastatin-treated group (n = 40). Controlled cortical impact (CCI) injury was performed over the left parietal lobe. Simvastatin was administered orally at a dose of 1 mg/kg starting at day 1 after TBI and then daily for 14 days. Bromodeoxyuridine (BrdU) was injected intraperitoneally into rats. A modified Morris Water Maze (WM) task was performed between 31 and 35 days after treatment to test spatial memory (n = 8/group). Animals were sacrificed at 1, 3, 7, 14, and 35 days after treatment (n = 8/group/time point). Western blot was utilized to investigate the changes in the Akt-mediated signaling pathway. Enzyme-linked immunosorbent assay (ELISA) analyses were employed to measure vascular endothelial growth factor (VEGF) and brain-derived neurotrophin factor (BDNF) expression. Immunohistochemical and fluorescent staining were performed to detect the BrdU- and neuronal nuclei (NeuN)/BrdU-positive cells. Our data show that simvastatin treatment increases phosphorylation of v-akt murine thymoma viral oncogene homolog (Akt), glycogen synthase kinase-3beta (GSK-3beta), and cAMP response element-binding proteins (CREB); elevates the expression of BDNF and VEGF in the DG; increases cell proliferation and differentiation in the DG; and enhances the recovery of spatial learning. These data suggest that the neurorestorative effect of simvastatin may be mediated through activation of the Akt-mediated signaling pathway, subsequently upregulating expression of growth factors and inducing neurogenesis in the DG of the hippocampus, thereby leading to restoration of cognitive function after TBI in rats.


Subject(s)
Brain Hemorrhage, Traumatic/drug therapy , Brain-Derived Neurotrophic Factor/biosynthesis , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Oncogene Protein v-akt/physiology , Phosphatidylinositol 3-Kinases/physiology , Signal Transduction/physiology , Simvastatin/pharmacology , Vascular Endothelial Growth Factor A/biosynthesis , Animals , Antimetabolites , Blotting, Western , Brain Hemorrhage, Traumatic/pathology , Brain Hemorrhage, Traumatic/physiopathology , Bromodeoxyuridine , Cell Proliferation/drug effects , Cyclic AMP Response Element-Binding Protein/biosynthesis , Glycogen Synthase Kinase 3/biosynthesis , Immunohistochemistry , Male , Maze Learning/drug effects , Maze Learning/physiology , Memory/drug effects , Memory/physiology , Neurons/drug effects , Neurons/physiology , Rats , Rats, Wistar , Up-Regulation/drug effects
13.
J Clin Anesth ; 18(7): 545-51, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17126787

ABSTRACT

We report three patients with severe traumatic brain injury, both open and closed, who were treated with recombinant activated factor VII. This treatment was given in a desperate, last-ditch effort to save the life of patient 1, as a preventive or early treatment of a developing hematoma in patient 2, and as treatment of a threatening hematoma in patient 3. One of the three patients survived. During the past few years we have broadened the indications for recombinant activated factor VII and started using it as a preventive measure rather than as a "last line of defense." However, the potential complications of disseminated intravascular coagulation and thrombotic events, as well as the cost-effectiveness in view of the available evidence-based medicine, should be considered.


Subject(s)
Brain Hemorrhage, Traumatic/drug therapy , Factor VII/administration & dosage , Hematoma, Subdural/drug therapy , Hematoma, Subdural/prevention & control , Adult , Aged , Brain Hemorrhage, Traumatic/diagnostic imaging , Brain Hemorrhage, Traumatic/economics , Child , Disseminated Intravascular Coagulation/chemically induced , Disseminated Intravascular Coagulation/economics , Factor VII/adverse effects , Factor VII/economics , Factor VIIa , Hematoma, Subdural/economics , Humans , Male , Radiography , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Recombinant Proteins/economics , Thrombosis/chemically induced , Thrombosis/economics
14.
J Cereb Blood Flow Metab ; 26(11): 1407-18, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16538231

ABSTRACT

In the present study, we investigate the hypothesis that mitochondrial oxidative damage and dysfunction precede the onset of neuronal loss after controlled cortical impact traumatic brain injury (TBI) in mice. Accordingly, we evaluated the time course of post-traumatic mitochondrial dysfunction in the injured cortex and hippocampus at 30 mins, 1, 3, 6, 12, 24, 48, and 72 h after severe TBI. A significant decrease in the coupling of the electron transport system with oxidative phosphorylation was observed as early as 30 mins after injury, followed by a recovery to baseline at 1 h after injury. A statistically significant (P<0.0001) decline in the respiratory control ratio was noted at 3 h, which persisted at all subsequent time-points up to 72 h after injury in both cortical and hippocampal mitochondria. Structural damage seen in purified cortical mitochondria included severely swollen mitochondria, a disruption of the cristae and rupture of outer membranes, indicative of mitochondrial permeability transition. Consistent with this finding, cortical mitochondrial calcium-buffering capacity was severely compromised by 3 h after injury, and accompanied by significant increases in mitochondrial protein oxidation and lipid peroxidation. A possible causative role for reactive nitrogen species was suggested by the rapid increase in cortical mitochondrial 3-nitrotyrosine levels shown as early as 30 mins after injury. These findings indicate that post-traumatic oxidative lipid and protein damage, mediated in part by peroxynitrite, occurs in mitochondria with concomitant ultrastructural damage and impairment of mitochondrial bioenergetics. The data also indicate that compounds which specifically scavenge peroxynitrite (ONOO(-)) or ONOO(-)-derived radicals (e.g. ONOO(-)+H(+) --> ONOOH --> (*)NO(2)+(*)OH) may be particularly effective for the treatment of TBI, although the therapeutic window for this neuroprotective approach might only be 3 h.


Subject(s)
Brain Hemorrhage, Traumatic/drug therapy , Brain Hemorrhage, Traumatic/pathology , Mitochondria/pathology , Neuroprotective Agents/therapeutic use , Oxidative Stress/drug effects , Animals , Blotting, Northern , Brain Hemorrhage, Traumatic/metabolism , Calpain/physiology , Cytoskeleton/pathology , Male , Membrane Lipids/metabolism , Membrane Proteins/metabolism , Mice , Microscopy, Electron , Mitochondria/metabolism , Nerve Degeneration , Oxygen Consumption/physiology , Peroxynitrous Acid/metabolism , Reactive Oxygen Species , Tyrosine/analogs & derivatives , Tyrosine/metabolism
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