Prophylactic treatment with CN-105 improves functional outcomes in a murine model of closed head injury.

The treatment of traumatic brain injury (TBI) in military populations is hindered by underreporting and underdiagnosis. Clinical symptoms and outcomes may be mitigated with an effective pre-injury prophylaxis. This study evaluates whether CN-105, a 5-amino acid apolipoprotein E (ApoE) mimetic peptide previously shown to modify the post-traumatic neuroinflammatory response, would maintain its neuroprotective effects if administered prior to closed-head injury in a clinically relevant murine model. CN-105 was synthesized by Polypeptide Inc. (San Diego, CA) and administered to C57-BL/6 mice intravenously (IV) and/or by intraperitoneal (IP) injection at various time points prior to injury while vehicle treated animals received IV and/or IP normal saline. Animals were randomized following injury and behavioral observations were conducted by investigators blinded to treatment. Vestibulomotor function was assessed using an automated Rotarod (Ugo Basile, Comerio, Italy), and hippocampal microglial activation was assessed using F4/80 immunohistochemical staining in treated and untreated mice 7 days post-TBI. Separate, in vivo assessments of the pharmacokinetics was performed in healthy CD-1. IV CN-105 administered prior to head injury improved vestibulomotor function compared to vehicle control-treated animals. CN-105 co-administered by IP and IV dosing 6 h prior to injury also improved vestibulomotor function up to 28 days following injury. Microglia counted in CN-105 treated specimens were significantly fewer (P = 0.03) than in vehicle specimens. CN-105 improves functional outcomes and reduces hippocampal microglial activation when administered prior to injury and could be adapted as a pre-injury prophylaxis for soldiers at high risk for TBI.

Antithrombotic choice in blunt cerebrovascular injuries: Experience at a tertiary trauma center, systematic review, and meta-analysis.

BACKGROUND: Blunt cerebrovascular injuries (BCVIs) may occur following trauma and lead to ischemic stroke if untreated. Antithrombotic therapy decreases this risk; however, the optimal agent has yet to be determined in this population. The aim of this study was to compare the risk-benefit profile of antiplatelet (AP) versus anticoagulant (AC) therapy in rates of ischemic stroke and hemorrhagic complications in BCVI patients. METHODS: We performed a retrospective review of BCVI patients at our tertiary care Trauma hospital from 2010 to 2015, and a systematic review and meta-analysis of the literature. The OVID Medline, Embase, Web of Science, and Cochrane Library databases were searched from inception to September 16, 2019. References of included publications were searched manually for other relevant articles. The search was limited to articles in humans, in patients 18 years or older, and in English. Studies that reported treatment-stratified clinical outcomes following AP or AC treatment in BCVI patients were included. Exclusion criteria included case reports, case series with n < 5, review articles, conference abstracts, animal studies, and non-peer-reviewed publications. Data were extracted from each study independently by two reviewers, including study design, country of origin, sex and age of patients, Injury Severity Score, Biffl grade, type of treatment, ischemic stroke rate, and hemorrhage rate. Pooled estimates using odds ratio (OR) were combined using a random-effects model using a Mantel-Hanzel weighting. The main outcome of interest was rate of ischemic stroke due to BCVI, and the secondary outcome was hemorrhage rate based on AC or AP treatment. RESULTS: In total, there were 2044 BCVI patients, as reported in the 22 studies in combination with our institutional data. The stroke rate was not significantly different between the two treatment groups (OR, 1.27; 95% confidence interval, 0.40-3.99); however, the hemorrhage rate was decreased in AP versus AC treated groups (OR, 0.38; 95% confidence interval, 0.15-1.00). CONCLUSION: Based on this meta-analysis, both AC and AP seem similarly effective in preventing ischemic stroke, but AP is better tolerated in the trauma population. This suggests that AP therapy may be preferred, but this should be further assessed with prospective randomized trials. LEVEL OF EVIDENCE: Review article, level II.

Interactions among Genetic Background, Anesthetic Agent, and Oxygen Concentration Shape Blunt Traumatic Brain Injury Outcomes in Drosophila melanogaster.

Following traumatic brain injury (TBI), the time window during which secondary injuries develop provides a window for therapeutic interventions. During this time, many TBI victims undergo exposure to hyperoxia and anesthetics. We investigated the effects of genetic background on the interaction of oxygen and volatile general anesthetics with brain pathophysiology after closed-head TBI in the fruit fly Drosophila melanogaster. To test whether sevoflurane shares genetic risk factors for mortality with isoflurane and whether locomotion is affected similarly to mortality, we used a device that generates acceleration-deceleration forces to induce TBI in ten inbred fly lines. After TBI, we exposed flies to hyperoxia alone or in combination with isoflurane or sevoflurane and quantified mortality and locomotion 24 and 48 h after TBI. Modulation of TBI-induced mortality and locomotor impairment by hyperoxia with or without anesthetics varied among fly strains and among combinations of agents. Resistance to increased mortality from hyperoxic isoflurane predicted resistance to increased mortality from hyperoxic sevoflurane but did not predict the degree of locomotion impairment under any condition. These findings are important because they demonstrate that, in the context of TBI, genetic background determines the latent toxic potentials of oxygen and anesthetics.

New ischemic lesions on brain magnetic resonance imaging in patients with blunt traumatic cerebrovascular injury.

BACKGROUND: Patients with blunt cerebrovascular injuries are at risk of thromboembolic stroke. Although primary prevention with antithrombotic therapy is widely used in this setting, its effectiveness is not well defined and requires further investigation. The aim of this study was to evaluate the utility of magnetic resonance imaging (MRI)-detected ischemic brain lesions as a possible future outcome for randomized clinical trials in this patient population. METHODS: This prospective observational study included 20 adult blunt trauma patients admitted to a level I trauma center with a screening neck CTA showing extracranial carotid or vertebral artery injury. All subjects lacked initial evidence of an ischemic stroke and were managed with antithrombotic therapy and observation and then underwent brain MRI within 30 days of the injury to assess for ischemic lesions. The MRI scans included diffusion, susceptibility, and Fluid-attenuated Inversion Recovery (FLAIR) sequences, and were reviewed by two neuroradiologists blinded to the computed tomography angiography (CTA) findings. RESULTS: Eleven CTAs were done in the emergency department upon admission. There were 12 carotid artery dissections and 11 unilateral or bilateral vertebral artery injuries. Median interval between injury and MRI scan was 4 days (range, 0.1-14; interquartile range, 3-7 days). Diffusion-weighted imaging evidence of new ischemic lesions was present in 10 (43%) of 23 of the injured artery territories. In those injuries with ischemic lesions, the median number was 8 (range, 2-25; interquartile range, 5-8). None of the lesions were symptomatic. Blunt cerebrovascular injury was associated with a higher mean ischemic lesion count (mean count of 3.17 vs. 0.14, p < 0.0001), with the association remaining after adjusting for injury severity score (p < 0.0001). CONCLUSION: In asymptomatic blunt trauma patients with CTA evidence of extracranial cerebrovascular injury and treated with antithrombotic therapy, nearly half of arterial injuries are associated with ischemic lesions on MRI. LEVEL OF EVIDENCE: Therapeutic/care management, level IV.

Cerebrolysin Reduces Astrogliosis and Axonal Injury and Enhances Neurogenesis in Rats After Closed Head Injury.

BACKGROUND: Cerebrolysin is a neuropeptide preparation with neuroprotective and neurotrophic properties. Our previous study demonstrates that cerebrolysin significantly improves functional recovery in rats after mild traumatic brain injury (mTBI). OBJECTIVE: To determine histological outcomes associated with therapeutic effects of cerebrolysin on functional recovery after TBI. METHODS: In this prospective, randomized, blinded, and placebo-controlled study, adult Wistar rats with mild TBI induced by a closed head impact were randomly assigned to one of the cerebrolysin dose groups (0.8, 2.5, 7.5 mL/kg) or placebo, which were administered 4 hours after TBI and then daily for 10 consecutive days. Functional tests assessed cognitive, behavioral, motor, and neurological performance. Study end point was day 90 after TBI. Brains were processed for histological tissue analyses of astrogliosis, axonal injury, and neurogenesis. RESULTS: Compared with placebo, cerebrolysin significantly reduced amyloid precursor protein accumulation, astrogliosis, and axonal damage in various brain regions and increased the number of neuroblasts and neurogenesis in the dentate gyrus. There was a significant dose effect of cerebrolysin on functional outcomes at 3 months after injury compared with saline treatment. Cerebrolysin at a dose of ⩾0.8 mL/kg significantly improved cognitive function, whereas at a dose of ⩾2.5 mL/kg, cerebrolysin also significantly improved sensorimotor function at various time points. There were significant correlations between multiple histological and functional outcomes 90 days after mTBI. CONCLUSIONS: Our findings demonstrate that cerebrolysin reduces astrogliosis and axonal injury and promotes neurogenesis, which may contribute to improved functional recovery in rats with mTBI.

Minocycline plus N-acetylcysteine protect oligodendrocytes when first dosed 12 hours after closed head injury in mice.

The mouse closed head injury (CHI) model of traumatic brain injury (TBI) produces widespread demyelination. Myelin content is restored by minocycline (MINO) plus n-acetylcysteine (NAC) or MINO alone when first dosed at 12 h after CHI. In a rat controlled cortical impact model of TBl, a first dose of MINO plus NAC one h after injury protects resident oligodendrocytes that induce remyelination. In contrast, MINO less effectively protects oligodendrocytes and remyelination is mediated by oligodendrocyte precursor cell proliferation and differentiation. MINO plus NAC or MINO alone is hypothesized to work similarly in the CHI model as in the controlled cortical impact model even when first dosed at 12-h post-CHI. We tested this hypothesis by examining the time course of the changes in the oligodendrocyte antigenic markers CC1, 2',3'-Cyclic-nucleotide 3'-phosphodiesterase and phospholipid protein between 2 and 14 days post-CHI in mice treated with saline, NAC, MINO or MINO plus NAC. CHI produced a long-lasting loss of these markers that was not altered by NAC treatment. In contrast, oligodendrocyte marker expression was maintained by MINO plus NAC between 2 and 14 days post-injury. MINO alone did not prevent the early loss of oligodendrocyte markers, but marker expression significantly increased by 14-days post-injury. These data suggest that MINO plus NAC or MINO alone when first dosed 12 h after CHI increase myelin content using similar mechanisms seen when first dosed 1 h after closed head injury. These data also suggest that drugs protect oligodendrocytes with a clinically useful therapeutic time window.

Head injury on Warfarin: likelihood of delayed intracranial bleeding in patients with negative initial head CT.

OBJECTIVE: To determine the likelihood that head injured patients on Warfarin with a negative initial head CT will have a positive repeat head CT. A retrospective chart review of our institution's trauma registry was performed for all patients admitted for blunt head trauma and on Warfarin anti-coagulation from January 2009 to April 2014. Inclusion criteria included patients over 18 years of age with initial GCS ≥ 13, INR greater than 1.5 and negative initial head CT. Initial CT findings, repeat CT findings and INR were recorded. Interventions performed on patients with a delayed bleed were also investigated. RESULTS: 394 patients met the study inclusion criteria. 121 (31%) of these patients did not receive a second CT while 273 patients (69%) underwent a second CT. The mean INR was 2.74. Six patients developed a delayed bleed, of which two were clinically significant. No patients had any neurosurgical intervention. Our results demonstrate a low rate of delayed bleeding. The utility of repeat head CT in the neurologically stable patient is thus questioned. Patients who have an abnormal baseline neurological status and those with INR >3 may represent a subgroup of patients in whom repeat head CT should be performed.

Differential effects of minocycline on microglial activation and neurodegeneration following closed head injury in the neonate rat.

The role of microglia in the pathophysiology of injury to the developing brain has been extensively studied. In children under the age of 4 who have sustained a traumatic brain injury (TBI), markers of microglial/macrophage activation were increased in the cerebrospinal fluid and were associated with worse neurologic outcome. Minocycline is an antibiotic that decreases microglial/macrophage activation following hypoxic-ischemia in neonatal rodents and TBI in adult rodents thereby reducing neurodegeneration and behavioral deficits. In study 1, 11-day-old rats received an impact to the intact skull and were treated for 3days with minocycline. Immediately following termination of minocycline administration, microglial reactivity was reduced in the cortex and hippocampus (p<0.001) and was accompanied by an increase in the number of fluoro-Jade B profiles (p<0.001) suggestive of a reduced clearance of degenerating cells; however, this effect was not sustained at 7days post-injury. Although microglial reactivity was reduced in the white matter tracts (p<0.001), minocycline treatment did not reduce axonal injury or degeneration. In the thalamus, minocycline treatment did not affect microglial reactivity, axonal injury and degeneration, and neurodegeneration. Injury-induced spatial learning and memory deficits were also not affected by minocycline. In study 2, to test whether extended dosing of minocycline may be necessary to reduce the ongoing pathologic alterations, a separate group of animals received minocycline for 9days. Immediately following termination of treatment, microglial reactivity and neurodegeneration in all regions examined were exacerbated in minocycline-treated brain-injured animals compared to brain-injured animals that received vehicle (p<0.001), an effect that was only sustained in the cortex and hippocampus up to 15days post-injury (p<0.001). Whereas injury-induced spatial learning deficits remained unaffected by minocycline treatment, memory deficits appeared to be significantly worse (p<0.05). Sex had minimal effects on either injury-induced alterations or the efficacy of minocycline treatment. Collectively, these data demonstrate the differential effects of minocycline in the immature brain following impact trauma and suggest that minocycline may not be an effective therapeutic strategy for TBI in the immature brain.

Site-targeted complement inhibition by a complement receptor 2-conjugated inhibitor (mTT30) ameliorates post-injury neuropathology in mouse brains.

Intracerebral complement activation after severe traumatic brain injury (TBI) leads to a cascade of neuroinflammatory pathological sequelae that propagate host-mediated secondary brain injury and adverse outcomes. There are currently no specific pharmacological agents on the market to prevent or mitigate the development of secondary cerebral insults after TBI. A novel chimeric CR2-fH compound (mTT30) provides targeted inhibition of the alternative complement pathway at the site of tissue injury. This experimental study was designed to test the neuroprotective effects of mTT30 in a mouse model of closed head injury. The administration of 500 µg mTT30 i.v. at 1 h, 4 h and 24 h after head injury attenuated complement C3 deposition in injured brains, reduced the extent of neuronal cell death, and decreased post-injury microglial activation, compared to vehicle-injected placebo controls. These data imply that site-targeted alternative pathway complement inhibition may represent a new promising therapeutic avenue for the future management of severe TBI.

Neuroprotective effect of carnosine and cyclosporine-A against inflammation, apoptosis, and oxidative brain damage after closed head injury in immature rats.

CONTEXT: Traumatic brain injury in the pediatric population can have a great economic and emotional impact on both the child's family and society. OBJECTIVE: The present study aimed to compare the effects of carnosine (CAR) and/or cyclosporine A (CyA) on oxidative brain damage after closed head injury (CHI) in immature rats. MATERIALS AND METHODS: Thirty-day-old rat pups were divided into five groups: non-traumatic control group, trauma group underwent CHI, trauma group injected with CAR (200 mg/kg, i.p.) following CHI for 7 d, trauma group injected with CyA (20 mg/kg, i.p.) given 15 min and 24 h after CHI, and trauma group treated with CAR and CyA. At the end of the treatment, rats were sacrificed; blood and brains were collected for assessing different biochemical parameters. RESULTS: Trauma significantly increased brain level of malondialdehyde, nitric oxide, glucose, calcium, inflammatory mediators. Brain DNA damage was confirmed by comet assay and the significant increase in brain caspase-3 activity. Moreover, the serum level of Fas ligand in traumatized animals was significantly elevated. Concomitant decrease in brain-reduced glutathione (GSH) and calcium-adenosine triphosphatase activity was observed in the traumatized-untreated group. Treatment of traumatized animals with CAR and/or CyA ameliorated all the biochemical changes induced by CHI with marked protective effect in the combination group. DISCUSSION AND CONCLUSION: CAR and CyA exerted a synergistic neuroprotective effect against CHI through blocking the induction of lipid peroxidation, reducing inflammatory, and oxidative stress biomarkers, preserving brain GSH content, and reducing the alterations in brain apoptotic biomarkers in traumatized animals.

Neuroprotective Effects of Erythropoietin in Patients with Severe Closed Brain Injury.

AIM: Our research was focused on the neuroprotective function of erythropoietin (Epo) in patients with severe closed traumatic brain injury (TBI). MATERIAL AND METHODS: Our model examined the influence of the outcome and neurological recovery in 42 adults with TBI who were admitted to ICU within 6 hours of their injury and were recruited into a randomized controlled study of two groups; only the patients of the intervention group received 10,000 i.u. of Epo for 7 consecutive days. A prognostic model based on CRASH II injury model and outcome was measured by survival and Glasgow Outcome Scale-Extended version (GOS-E) score at 6 months post-injury. RESULTS: Six patients (18.7%) died during the first two weeks; 4 of the control group and 2 of the intervention group. A mortality rate of 22.2% and 8.3% for the control and intervention group respectively was observed. A lower rate of good outcome (GOS-E score > 4) at 6 months was mentioned among patients of the control group. CONCLUSION: The study provides evidence of lower mortality and better neurological outcome for the patients who received Epo increasing the possibility that Epo therapy could be used in clinical practice, limiting neuronal damage induced by TBI.

Taurine attenuates hippocampal and corpus callosum damage, and enhances neurological recovery after closed head injury in rats.

The protective effects of taurine against closed head injury (CHI) have been reported. This study was designed to investigate whether taurine reduced white matter damage and hippocampal neuronal death through suppressing calpain activation after CHI in rats. Taurine (50 mg/kg) was administered intravenously 30 min and 4 h again after CHI. It was found that taurine lessened the corpus callosum damage, attenuated the neuronal cell death in hippocampal CA1 and CA3 subfields and improved the neurological functions 7 days after CHI. Moreover, it suppressed the over-activation of calpain, enhanced the levels of calpastatin, and reduced the degradation of neurofilament heavy protein, myelin basic protein and αII-spectrin in traumatic tissue 24 h after CHI. These data confirm the protective effects of taurine against gray and white matter damage due to CHI, and suggest that down-regulating calpain activation could be one of the protective mechanisms of taurine against CHI.

Protective effects of taurine against closed head injury in rats.

Taurine, an abundant amino acid in the nervous system, is reported to reduce ischemic brain injury in a dose-dependent manner. This study was designed to investigate whether taurine protected the brain against closed head injury (CHI) in rats. Taurine was administered intravenously 30 min after CHI. It was found that taurine lessened body-weight loss and improved neurological functions at 7 days after CHI. Moreover, it lowered brain edema and blood-brain barrier permeability, enhanced activity of superoxide dismutase and the level of glutathione, and reduced levels of malondialdehyde and lactic acid in traumatic tissue 24 h after CHI. In addition, it attenuated neuronal cell death in hippocampal CA1 and CA3 subfields 7 days after CHI. All of these effects were dose dependent. These data demonstrated the dose-dependent protection of taurine against experimental CHI and suggest that taurine treatment might be beneficial in reducing trauma-induced oxidative damage to the brain, thus showing the potential for clinical implications.

Patients with blunt head trauma on anticoagulation and antiplatelet medications: can they be safely discharged after a normal initial cranial computed tomography scan?

The literature reports delayed intracranial hemorrhage (ICH) after blunt trauma in patients taking preinjury anticoagulant and antiplatelet (AC/AP) medications. We sought to evaluate the incidence of delayed ICH at our institution and hypothesize that patients taking AC/AP medications who are found to have a negative first computed tomography (CT) scan will not require a second CT scan. A total of 303 patients were retrospectively reviewed. Age, gender, mechanism of injury, international normalized ratio (INR), initial and secondary cranial CT findings, and outcomes were recorded. One hundred sixty-eight (55.4%) were found to be taking AP/AC medications. Ninety-six (57%) were male and 72 (43%) female. Aspirin use was 42.8 per cent (72 of 168), clopidogrel next (39 of 168 [23.0%]), and warfarin least (18 of 168 [10.7%]). One hundred sixty-six (98.8%) presented with significant findings on the first CT scan. Fourteen (87.5%) of the 16 patients with an INR 2.0 or higher presented with an ICH on the first CT. Ninety percent of patients with an INR 1.5 or higher presented with positive findings on the first CT scan. One hundred per cent of patients with an INR 3.0 or higher presented with an ICH on the first CT scan. The incidence of a delayed ICH was two of 168 (1.19%). Of those two patients with a delayed ICH, 100 per cent were taking warfarin and had an INR greater than 2.0. The incidence of delayed ICH was 1.19 per cent. The protocol requiring a second CT scan for all patients on AC/AP medications after a negative first CT scan should be questioned. For patients with blunt head trauma taking warfarin or a warfarin-aspirin combination, a repeat cranial CT scan after a negative initial CT is acceptable. For patients taking clopidogrel, a period of observation may be warranted.

More harm than good: antiseizure prophylaxis after traumatic brain injury does not decrease seizure rates but may inhibit functional recovery.

BACKGROUND: The purposes of this study were to examine the current Brain Trauma Foundation recommendation for antiseizure prophylaxis with phenytoin during the first 7 days after traumatic brain injury (TBI) in preventing seizures and to determine if this medication affects functional recovery at discharge. METHODS: The records of adult (age ≥ 18 years) patients with blunt severe TBI who remained in the hospital at least 7 days after injury were retrospectively reviewed from January 2008 to January 2010. Clinical seizure rates during the first 7 days after injury and functional outcome at discharge were compared for the two groups based on antiseizure prophylaxis, no prophylaxis (NP) versus phenytoin prophylaxis (PP). Statistical analysis was performed using χ2. RESULTS: A total of 93 adult patients who met the previously mentioned criteria were identified (43 [46%] NP group vs. 50 [54%] PP group). The two groups were well matched. Contrary to expectation, more seizures occurred in the PP group as compared with the NP group; however, this did not reach significance (PP vs. NP, 2 [4%] vs. 1 [2.3%], p = 1). There was no significant difference in the two groups (PP vs. NP) as far as disposition are concerned, mortality caused by head injury (4 [8%] vs. 3 [7%], p = 1), discharge home (16 [32%] vs. 17 [40%], p = 0.7), and discharge to rehabilitation (30 [60%] vs. 23 [53%], p = 0.9). However, with PP, there was a significantly longer hospital stay (PP vs. NP, 36 vs. 25 days, p = 0.04) and significantly worse functional outcome at discharge based on Glasgow Outcome Scale (GOS) score (PP vs. NP, 2.9 vs. 3.4, p < 0.01) and modified Rankin Scale score (2.3 ± 1.7 vs. 3.1 ± 1.5, p = 0.02). CONCLUSION: PP may not decrease early posttraumatic seizure and may suppress functional outcome after blunt TBI. These results need to be verified with randomized studies before recommending changes in clinical practice and do not apply to penetrating trauma. LEVEL OF EVIDENCE: Therapeutic study, level IV; epidemiologic study, level III.

Safety and efficacy of pharmacologic thromboprophylaxis following blunt head injury: a systematic review.

BACKGROUND: Patients with blunt head injury are at high risk of venous thromboembolism. However, pharmacologic thromboprophylaxis (PTP) may cause progression of intracranial hemorrhage, and clinicians must often weigh up the risks and benefits. This review aimed to determine whether adding PTP to mechanical prophylaxis confers net benefit or harm and the optimal timing, dose, and agent for PTP in patients with blunt head injury. METHODS: We searched MEDLINE, EMBASE, The Cochrane Library Central Register of Controlled Trials (CENTRAL), and www.clinicaltrials.gov on April 24, 2013, to identify controlled studies and ongoing trials that assessed the efficacy or safety of thromboprophylaxis interventions in the early management of head-injured patients. Studies were classified based on types of interventions and comparisons, and the quality of included studies was assessed using Cochrane risk-of-bias tool and the Newcastle-Ottawa Quality Assessment Scale. We intended to undertake a meta-analysis if studies were sufficiently similar. RESULTS: Sixteen studies met the inclusion criteria, including four randomized controlled trials. At least two randomized controlled trials were at high risk of bias owing to inadequate randomization and concealment of allocation, and observational studies were potentially confounded by substantial differences between comparison groups. Heterogeneity of included studies precluded meta-analysis. Results were mixed, with some studies supporting and others refuting addition of PTP to mechanical interventions. Little evidence was available about dose or choice of agent. The safety and efficacy of early PTP in patients without early progression of hemorrhage is unclear. CONCLUSION: There is currently insufficient evidence to guide thromboprophylaxis in patients with blunt head injury. Standardized definitions and outcome measurements would facilitate comparison of outcomes across future studies. Studies in mixed populations should report head-injured specific subgroup data. Future randomized controlled trials should investigate the efficacy and safety of early pharmacologic prophylaxis in addition to mechanical intervention. LEVEL OF EVIDENCE: Systematic review, level IV.

[Protective effects of carnosine against closed head injury in mice].

OBJECTIVE: To investigate the protective effects of carnosine against experimental closed head injury (CHI) in mice. METHODS: The CHI model was established by free-falling weight-drop. Carnosine (250 mg/kg or 500 mg/kg) was administered intraperitoneally 30 min before brain trauma, then q.d for 7 d; while normal saline was administrated for control group. The neurological defect was evaluated by neurological severity score (NSS) within 7 d; the survival rate and the histological alternations were observed. RESULTS: Carnosine prevented the body weight loss of mice at dose of 500 mg/kg; significantly increased the survival rate, and reduced the neurological defect and histological damage at dose of 250 and 500 mg/kg. CONCLUSION: Carnosine can attenuate closed head injury in mice.

Improvement in functional recovery with administration of Cerebrolysin after experimental closed head injury.

OBJECT: Cerebrolysin is a unique peptide preparation that mimics the action of neurotrophic factors. This study was designed to investigate the effects of acute treatment of experimental closed head injury (CHI) in rats with Cerebrolysin on neurological function. METHODS: Adult male Wistar rats (n = 60) were subjected to impact acceleration-induced CHI. Closed head injured rats received intraperitoneal injection of saline (n = 30) or Cerebrolysin (2.5 ml/kg, n = 30) starting 1 hour postinjury and administered once daily until they were killed (2 or 14 days after CHI). To evaluate functional outcome, the modified neurological severity score (mNSS), foot fault, adhesive removal, and Morris water maze (MWM) tests were performed. Animals were killed on Day 14 (n = 20) after injury, and their brains were removed and processed for measurement of neuronal cells, axonal damage, apoptosis, and neuroblasts. The remaining rats (n = 40) were killed 2 days postinjury to evaluate cerebral microvascular patency by fluorescein isothiocyanate (FITC)-dextran perfusion (n = 16) and to measure the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) by using real-time reverse transcriptase-polymerase chain reaction (RT-PCR, n = 8) and by immunohistochemical analysis (n = 16). RESULTS: At 14 days post-CHI, the Cerebrolysin treatment group exhibited significant improvements in functional outcomes (the adhesive removal, mNSS, foot-fault, and MWM tests), and significantly more neurons and neuroblasts were present in the dentate gyrus (DG) (p < 0.05) compared with the saline-treated group (p < 0.05). At 2 days post-CHI, the Cerebrolysin group exhibited a significantly higher percentage of phosphorylated neurofilament H (pNF-H)-positive staining area in the striatum (p < 0.05), a significant increase in the percentage of FITC-dextran perfused vessels in the brain cortex (p < 0.05), a significant increase in the number of VEGF-positive cells (p < 0.05), and a significant reduction in the MMP-9 staining area (p < 0.05) compared with the saline-treated group. There was no significant difference in mRNA levels of MMP-9 and VEGF in the hippocampus and cortex 48 hours postinjury between Cerebrolysin- and saline-treated rats that sustained CHI. CONCLUSIONS: Acute Cerebrolysin treatment improves functional recovery in rats after CHI. Cerebrolysin is neuroprotective for CHI (increased neurons in the dentate gyrus and the CA3 regions of the hippocampus and increased neuroblasts in the dentate gyrus) and may preserve axonal integrity in the striatum (significantly increased percentage of pNF-H-positive tissue in the striatum). Reduction of MMP-9 and elevation of VEGF likely contribute to enhancement of vascular patency and integrity as well as neuronal survival induced by Cerebrolysin. These promising results suggest that Cerebrolysin may be a useful treatment in improving the recovery of patients with CHI.