Angiotensin Receptor Type 2 Activation Induces Neuroprotection and Neurogenesis After Traumatic Brain Injury

Angiotensin II receptor type 2 (AT₂) agonists have been shown to limit brain ischemic insult and to improve its outcome. The activation of AT₂ was also linked to induced neuronal proliferation and differentiation in vitro. In this study, we examined the therapeutic potential of AT₂ activation following traumatic brain injury (TBI) in mice, a brain pathology that displays ischemia-like secondary damages. The AT₂ agonist CGP42112A was continuously infused immediately after closed head injury (CHI) for 3 days. We have followed the functional recovery of the injured mice for 35 days post-CHI, and evaluated cognitive function, lesion volume, molecular signaling, and neurogenesis at different time points after the impact. We found dose-dependent improvement in functional recovery and cognitive performance after CGP42112A treatment that was accompanied by reduced lesion volume and induced neurogenesis in the neurogenic niches of the brain and also in the injury region. At the cellular/molecular level, CGP42112A induced early activation of neuroprotective kinases protein kinase B (Akt) and extracellular-regulated kinases ½ (ERK½), and the neurotrophins nerve growth factor and brain-derived neurotrophic factor; all were blocked by treatment with the AT₂ antagonist PD123319. Our results suggest that AT₂ activation after TBI promotes neuroprotection and neurogenesis, and may be a novel approach for the development of new drugs to treat victims of TBI.     

Chemokine CCL2 Induces Apoptosis in Cortex Following Traumatic Brain Injury

The chemokine C-C motif ligand 2 (CCL2) is an important mediator of neuroinflammation. Released in response to acute injury, ischemia, and neurodegenerative disease, CCL2 binds primarily to the G-protein-coupled chemokine C-C motif receptor 2 (CCR2) to recruit inflammatory cells to sites of tissue damage. Inflammation is thought to have both beneficial and deleterious consequences following traumatic brain injury (TBI), so we investigated CCL2–CCR2 signaling during the post-TBI period to assess possible neurodegenerative and protective actions. Local TBI in adult rat cortex was induced by Feeney’s weight-drop method, and the expression of CCL2 and CCR2 in the tissue around the contusion site was measured by real-time quantitative PCR. Both CCL2 and CCR2 mRNA levels were increased markedly for at least 10 days after injury, peaking on day 3. The CCL2 protein was mainly co-localized with the astroglial marker glial fibrillary acidic protein and CCR2 protein with the neuronal nuclear marker NeuN as revealed by double immunofluorescence staining. A selective CCR2 antagonist, RS504393, reduced TUNEL staining, a marker of apoptosis, and improved performance in the Morris water maze 3 days post-TBI, suggesting that CCL2–CCR2 signaling has deleterious effects on neuronal survival and learning. Targeting the CCL2–CCR2 pathway may provide a novel therapeutic approach for the treatment of TBI.     

脑创伤后bcl—2蛋白的神经保护作用

目的 探讨液压脑损伤后凋亡抑制基因bcl—2的变化规律及bcl—2基因在创伤性脑损伤后细胞凋亡中的作用。方法 应用免疫组化观察大鼠中型液压脑损伤伤前及伤后6h、12h、1d、3d、7dbcl—2蛋白表达情况,应用TUNEIL和电镜观察伤后细胞死亡的形态。结果 免疫反应阳性细胞主要位于伤侧大脑半球皮质、皮层下白质、海马CAl、CA3及齿状回的神经元和神经胶质细胞,以海马CA3区最为显。在高倍镜下,表达Bcl—2蛋白的神经细胞胞核形态正常,很少见到凋亡或坏死的形态特征。伤后早期(6h),打击侧海马CA3区Bcl—2蛋白表达显下降;Bcl—2早期改变出现在伤后6h,比细胞凋亡提前表现;伤后l—3h,Bcl—2的表达下降相对缓慢。结论 bcl—2蛋白在抑制脑创伤后细胞凋亡中起重要作用,bcl—2可能是一种可诱导的神经保护因子。     

Scriptaid, a Novel Histone Deacetylase Inhibitor, Protects Against Traumatic Brain Injury via Modulation of PTEN and AKT Pathway

Traumatic brain injury (TBI) is a leading cause of motor and cognitive deficits in young adults for which there is no effective therapy. The present study characterizes the protective effect of a new histone deacetylase inhibitor, Scriptaid (Sigma-Aldrich Corporation, St. Louis, MO), against injury from controlled cortical impact (CCI). Scriptaid elicited a dose-dependent decrease in lesion size at 1.5 to 5.5 mg/kg and a concomitant attenuation in motor and cognitive deficits when delivered 30 minutes postinjury in a model of moderate TBI. Comparable protection was achieved even when treatment was delayed to 12 h postinjury. Furthermore, the protection of motor and cognitive functions was long lasting, as similar improvements were detected 35 days postinjury. The efficacy of Scriptaid (Sigma-Aldrich Corporation) was manifested as an increase in surviving neurons, as well as the number/length of their processes within the CA3 region of the hippocampus and the pericontusional cortex. Consistent with other histone deacetylase inhibitors, Scriptaid treatment prevented the decrease in phospho-AKT (p-AKT) and phosphorylated phosphatase and tensin homolog deleted on chromosome 10 (p-PTEN) induced by TBI in cortical and CA3 hippocampal neurons. Notably, the p-AKT inhibitor LY294002 attenuated the impact of Scriptaid, providing mechanistic evidence that Scriptaid functions partly by modulating the prosurvival AKT signaling pathway. As Scriptaid offers long-lasting neuronal and behavioral protection, even when delivered 12 h after controlled cortical impact, it is an excellent new candidate for the effective clinical treatment of TBI.     

The Novel Free Radical Scavenger, Edaravone, Increases Neural Stem Cell Number Around the Area of Damage Following Rat Traumatic Brain Injury

Edaravone is a novel free radical scavenger that is clinically employed in patients with acute cerebral infarction, but has not previously been used to treat traumatic brain injury (TBI). In this study, we investigated the effect of edaravone administration on rat TBI. In particular, we used immunohistochemistry to monitor neural stem cell (NSC) proliferation around the area damaged by TBI. Two separate groups of rats were administered saline or edaravone (3 mg/kg) after TBI and then killed chronologically. We also used ex vivo techniques to isolate NSCs from the damaged region and observed nestin-positive cells at 1, 3, and 7 days following TBI in both saline- and edaravone-treated groups. At 3 days following TBI in both groups, there were many large cells that morphologically resembled astrocytes. At 1 and 7 days following TBI in the saline group, there were a few small nestin-positive cells. However, in the edaravone group, there were many large nestin-positive cells at 7 days following TBI. At 3 and 7 days following TBI, the number of nestin-positive cells in the edaravone group increased significantly compared with the saline group. There were many single-stranded DNA-, 8-hydroxy-2′-deoxyguanosine-, and 4-hydroxy-2-nonenal-positive cells in the saline group following TBI, but only a few such cells in the edaravone group following TBI. Furthermore, almost all ssDNA-positive cells in the saline group co-localized with Hu, nestin, and glial fibrillary acidic protein (GFAP) staining, but not in the edaravone group. In the ex vivo study, spheres could only be isolated from injured brain tissue in the saline group at 3 days following TBI. However, in the edaravone group, spheres could be isolated from injured brain tissue at both 3 and 7 days following TBI. The number of spheres isolated from injured brain tissue in the edaravone group showed a significant increase compared with the saline group. The spheres isolated from both saline and edaravone groups were immunopositive for nestin, but not Tuj1 or vimentin. Moreover, the spheres differentiated into Tuj1-, GFAP-, and O4-positive cells after 4 days in culture without bFGF. This result indicated that the spheres were neurospheres composed of NSCs that could differentiate into neurons and glia. Edaravone administration inhibited production of free radicals known to induce neuronal degeneration and cell death after brain injury, and protected nestin-positive cells, including NSCs, with the potential to differentiate into neurons and glia around the area damaged by TBI.     

Progesterone Provides the Pleiotropic Neuroprotective Effect on Traumatic Brain Injury Through the Nrf2/ARE Signaling Pathway

Objective

This study was to investigate the role of Nrf2/ARE signaling pathway in the pleiotropic neuroprotective effect of progesterone (PROG) on traumatic brain injury (TBI).

Methods

The Nrf2-knockout (Nrf2?/?) and C57 mice were respectively subjected to a lateral cortical impact injury caused by a free-falling object and randomly divided into three groups: sham-operated, trauma, and trauma + PROG treatment group. The PROG treatment group was given PROG (32 mg/kg of body weight, intraperitoneal injection) immediately after injury. For all groups, a series of brain samples were obtained after trauma at 24 and 72 h, respectively. The cerebral edema was evaluated; the expression of IL-1β, IL-6, and TNF-α was measured using ELISA array, and the apoptosis index was detected by TUNEL. Flow cytometry was used to detect the intracellular calcium concentration.

Results

The water content, the apoptosis index, the levels of inflammatory cytokine, and the intracellular calcium ion were significantly decreased with the PROG treatment in C57 mice with TBI model. However, the effect of PROG on TBI was not found in the Nrf2?/? mouse model of TBI.

Conclusions

PROG reduced cerebral edema, apoptosis, inflammatory reaction, and intracellular calcium ion overload effects after TBI. These beneficial effects were not seen in the Nrf2?/? mouse model of TBI. The results from this study suggested that the Nrf2/ARE signal pathway may be involved in the pleiotropic neuroprotective effect of PROG on TBI.

     

Beneficial Effect of Erythropoietin Short Peptide on Acute Traumatic Brain Injury

There is currently no effective medical treatment for traumatic brain injury (TBI). Beyond the immediate physical damage caused by the initial impact, additional damage evolves due to the inflammatory response that follows brain injury. Here we show that therapy with JM4, a low molecular weight 19-amino acid nonhematopoietic erythropoietin (EPO) peptidyl fragment, containing amino acids 28–46 derived from the first loop of EPO, markedly reduces acute brain injury. Mice underwent controlled cortical injury and received either whole molecule EPO, JM4, or sham-treatment with phosphate-buffered saline. Animals treated with JM4 peptide exhibited a large decrease in number of dead neural cells and a marked reduction in lesion size at both 3 and 8 days postinjury. Therapy with JM4 also led to improved functional recovery and we observed a treatment window for JM4 peptide that remained open for at least 9 h postinjury. The full-length EPO molecule was divided into a series of 6 contiguous peptide segments; the JM4-containing segment and the adjoining downstream region contained the bulk of the death attenuating effects seen with intact EPO molecule following TBI. These findings indicate that the JM4 molecule substantially blocks cell death and brain injury following acute brain trauma and, as such, presents an excellent opportunity to explore the therapeutic potential of a small-peptide EPO derivative in the medical treatment of TBI.     

Secondary Peaks of S100B in Serum Relate to Subsequent Radiological Pathology in Traumatic Brain Injury

Introduction

Patients suffering from severe traumatic brain injury (TBI) often develop secondary brain lesions that may worsen outcome. S100B, a biomarker of brain damage, has been shown to increase in response to secondary cerebral deterioration. The aim of this study was to analyze the occurrence of secondary increases in serum levels of S100B and their relation to potential subsequent radiological pathology present on CT/MRI-scans.

Methods

Retrospective study from a trauma level 1 hospital, neuro-intensive care unit. 250 patients suffering from TBI were included. Inclusion required a minimum of two radiological examinations and at least three serum samples of S100B, with at least one >48 h after trauma.

Results

Secondary pathological findings on CT/MRI, present in 39 % (n = 98) of the patients, were highly correlated to secondary increases of ≥0.05 μg/L S100B (P < 0.0001, pseudo-R ² 0.532). Significance remained also after adjusting for known important TBI predictors. In addition, secondary radiological findings were significantly correlated to outcome (Glasgow Outcome Score, GOS) in uni-(P < 0.0001, pseudo-R ² 0.111) and multivariate analysis. The sensitivity and specificity of detecting later secondary radiological findings was investigated at three S100B cut-off levels: 0.05, 0.1, and 0.5 μg/L. A secondary increase of ≥0.05 μg/L had higher sensitivity (80 %) but lower specificity (89 %), compared with a secondary increase of ≥0.5 μg/L (16 % sensitivity, 98 % specificity), to detect secondary radiological findings.

Conclusions

Secondary increases in serum levels of S100B, even as low as ≥0.05 μg/L, beyond 48 h after TBI are strongly correlated to the development of clinically significant secondary radiological findings.     

The Prognostic Value of Brain Extracellular Fluid Nitric Oxide Metabolites After Traumatic Brain Injury

Background

Nitric oxide (NO) is a compound with both protective and damaging effects on neurons. Quantification of NO metabolites in humans is limited by sample contamination with blood. In vivo cerebral microdialysis may offer an alternative approach as sampling of extracellular fluid (ECF) adjacent to neurons becomes possible. We investigate the prognostic value of brain ECF NO metabolites in patients with traumatic brain injury (TBI).

Methods

A prospective case cohort of 195 ECF samples collected from 11 cases over 4 days following TBI was collected. Nitrate and nitrite concentrations ([NO _x ]) were quantified using a vanadium-based colorimetric assay.

Results

Early ECF [NO _x ] (<48 h post TBI) were significantly higher in non-survivors (median 59.2 μmol/l, n = 7) compared to survivors (23.3 μmol/l, n = 4) (P = 0.04). Late (48–96 h) ECF [NO _x ] remained higher in non-survivors (47.9 μmol/l) compared to survivors (23.0 μmol/l) but this was not significant (P = 0.29). Receiver operator characteristic analysis shows an optimized cutoff level for ECF [NO _x ] of 26.5 μmol/l measured <48 h post TBI for predicting non-survival (sensitivity 100%, specificity 75%).

Conclusion

Early ECF NO _x concentrations are of prognostic value after TBI. ECF NO _x may be a useful biomarker for treatment trials targeted at nitric oxide metabolism.     

Neuroprotection Trials in Traumatic Brain Injury

Traumatic brain injury (TBI) is a significant cause of mortality and morbidity worldwide. Current treatment of acute TBI includes surgical intervention when needed, followed by supportive critical care such as optimizing cerebral perfusion, preventing pyrexia, and treating raised intracranial pressure. While effective in managing the primary injury to the brain and skull, these treatment modalities do not address the complex secondary cascades that occur at a cellular level following initial injury and greatly affect the ultimate neurologic outcome. These secondary processes involve changes in ionic flux, disruption of cellular function, derangement of blood flow and the blood-brain barrier, and elevated levels of free radicals. Over the past few decades, numerous pharmacologic agents and modalities have been investigated in an attempt to interrupt these secondary processes. No neuroprotective agents currently exist that have been proven to improve neurologic outcome following TBI. However, these trials have contributed significantly to the understanding of the clinical sequelae of TBI and to improvements in the quality of care for TBI. With the experience and insights that have been accrued with the trials to date, we will be able to optimize future trial designs and refine established neurologic endpoints to better identify new therapeutic agents and further improve neurologic outcomes from this often devastating condition.     

Induced Normothermia Attenuates Intracranial Hypertension and Reduces Fever Burden after Severe Traumatic Brain Injury

Introduction

Hyperthermia following a severe traumatic brain injury (TBI) is common, potentiates secondary injury, and worsens neurological outcome. Conventional fever treatment is often ineffective. An induced normothermia protocol, utilizing intravascular cooling, was used to assess the impact on fever incidence and intracranial pressure (ICP) in patients with severe TBI.

Methods

A comparative cohort study of 21 adult patients with severe TBI (GCS ≤ 8) treated with induced normothermia [36–36.5°C rectal probe setting; intravascular cooling catheter (CoolLine^®, Alsius Corporation, Irvine, CA)] were matched by age, gender, and severity of injury to 21 historical control severe TBI patients treated with conventional fever control methods. ICP was measured via an external ventricular catheter and time duration for ICP > 25 mmHg was calculated for the initial 72-h monitoring period. Non-parametric rank tests were performed.

Results

Mean (±SD) or median [range] demographics did not differ between groups [total N = 42 (6 female, 36 male, age 36.4 ± 14.8 years and initial GCS 7 [3–8], median and range]. Fever burden in the first 3 days (time >38°C) in the induced normothermia versus control group was significantly less at 1.6% versus 10.6%, respectively (P = 0.03). Mean ICP for patients with induced normothermia versus control was 12.74 ± 4.0 and 16.37 ± 6.9 mmHg, respectively. Furthermore, percentage of time with ICP > 25 mmHg was significantly less in the induced normothermia group (P = 0.03).

Conclusion

Induced normothermia (fever prophylaxis via intravascular cooling catheter) is effective in reducing fever burden and may offer a means to attenuate secondary injury, as evidenced by a reduction in the intracranial hypertension burden.     

Inhibition of Inducible Nitric Oxide Synthase Attenuates Deficits in Synaptic Plasticity and Brain Functions Following Traumatic Brain Injury

Traumatic brain injury (TBI), resulting from external force on the head, usually leads to long-term deficits in motor and cognitive functions. Inducible nitric oxide synthase (iNOS)-mediated excessive inflammation could exacerbate brain damage after TBI. The present study therefore investigated the potential neuroprotective effects of iNOS inhibition after TBI. Male C57BL/6J mice were subjected to controlled cortical impact injury and then treated with high selective iNOS inhibitor 1400W. Expression of iNOS mRNA was determined by quantitative RT-PCR. Western blotting was carried out to determine iNOS protein levels. Motor and cognitive functions, and long-term potentiation (LTP) in the medial prefrontal cortex (mPFC) and hippocampus were examined. Expression of iNOS was induced after TBI in a temporal manner. Treatment with 1400W after TBI improved motor and cognitive functions. TBI mice showed deficits in LTP in both the mPFC and hippocampus, and treatment with 1400W could rescue this impairment. Inhibition of iNOS attenuated deficits in synaptic plasticity and brain functions after TBI. The neuroprotective effect of iNOS inhibition on cognitive function might be via rescuing the TBI-induced LTP impairment.     

Cerebrospinal Fluid NLRP3 is Increased After Severe Traumatic Brain Injury in Infants and Children

Background

Inflammasome-mediated neuroinflammation may cause secondary injury following traumatic brain injury (TBI) in children. The pattern recognition receptors NACHT domain-, Leucine-rich repeat-, and PYD-containing Protein 1 (NLRP1) and NLRP3 are essential components of their respective inflammasome complexes. We sought to investigate whether NLRP1 and/or NLRP3 abundance is altered in children with severe TBI.

Methods

Cerebrospinal fluid (CSF) from children (n = 34) with severe TBI (Glasgow coma scale score [GCS] ≤8) who had externalized ventricular drains (EVD) placed for routine care was evaluated for NLRP1 and NLRP3 at 0–24, 25–48, 49–72, and >72 h post-TBI and was compared to infection-free controls that underwent lumbar puncture to rule out CNS infection (n = 8). Patient age, sex, initial GCS, mechanism of injury, treatment with therapeutic hypothermia, and 6-month Glasgow outcome score were collected.

Results

CSF NLRP1 was undetectable in controls and detected in 2 TBI patients at only <24 h post-TBI. CSF NLRP3 levels were increased in TBI patients compared with controls at all time points, p < 0.001. TBI patients ≤4 years of age had higher peak NLRP3 levels versus patients >4 (15.50 [3.65–25.71] vs. 3.04 [1.52–8.87] ng/mL, respectively; p = 0.048). Controlling for initial GCS in multivariate analysis, peak NLRP3 >6.63 ng/mL was independently associated with poor outcome at 6 months.

Conclusions

In the first report of NLRP1 and NLRP3 in childhood neurotrauma, we found that CSF NLRP3 is elevated in children with severe TBI and independently associated with younger age and poor outcome. Future studies correlating NLRP3 with other markers of inflammation and response to therapy are warranted.

     

Quercetin attenuates neuronal autophagy and apoptosis in rat traumatic brain injury model via activation of PI3K/Akt signaling pathway

Objective: Neuronal autophagy and apoptosis play an irreplaceable role in brain injury pathogenesis and may represent a hopeful target for treatment. Previous studies have demonstrated that administration of quercetin-attenuated brain damage in a variety of brain injury models including traumatic brain injury (TBI). However, whether PI3K/Akt signaling pathway mediates the neuroprotection of quercetin following TBI is not well clarified. We sought to propose a hypothesis that quercetin could attenuate neuronal autophagy and apoptosis via enhancing PI3K/Akt signaling.

Methods: All rats were randomly arranged into four groups as follows: sham group (n = 25), TBI group (n = 25), TBI + quercetin group (n = 25), TBI + quercetin + LY294002 group (n = 25). Quercetin (Sigma, USA, dissolved in 0.9% saline solution) was administered intraperitoneally at a dose of 50 mg/kg at 30 min, 12 h, and 24 h after TBI. The neurological impairment and spatial cognitive function was assessed by the neurologic severity score and Morris water maze, respectively. Immunohistochemistry staining and western blotting was used to evaluate the expression of LC3, p-Akt, caspase-3, Bcl-2, and Bax.

Results: Quercetin treatment significantly attenuated TBI-induced neurological impairment (1–3 days, p < 0.05) and improved cognitive function (5–8 days, p < 0.05). Double immunolabeling demonstrated that quercetin significantly reduced the LC3-positive cells co-labeled with NeuN, whereas significantly enhanced p-Akt-positive cells co-labeled with NeuN. Furthermore, quercetin treatment reduced the expression of LC3、caspase-3 and Bax levels induced following TBI (p < 0.05), and increased the expression of p-Akt and Bcl-2 at 48 h (p < 0.05).

Conclusion: In conclusion, our observations indicate that post-injury treatment with quercetin could inhibit neuronal autophagy and apoptosis in the hippocampus in a rat model of TBI. The neuroprotective effects of quercetin may be related to modulation of PI3K/Akt signaling pathway.     

糖皮质激素对重度颅脑损伤患者血浆TNF-α、IL-1β水平的影响

目的 研究糖皮质激素对颅脑损伤患者血浆肿瘤坏死因子α（TNF-α）、白细胞介素-1β（IL-1β）水平的影响。方法 随机将重度颅脑损伤患者分为激素治疗组（20例）与非激素治疗对照组（22例），激素组给予地塞米松10mg／d，共7d。正常组选择健康体检者15例。采用ELSIA法检测两组患者伤后第1、2、7、14天血浆中TNF一仪、IL-1β含量。结果 在颅脑损伤第1、2天激素组血浆TNF-α、IL-1β水平明显高于正常组（P（0．01），在第7、14天明显低于非激素组（P（0．01），但与正常组无明显差异（P〉0．05）。非激素组血浆TNF-α、IL-1β水平在各时间点均明显高于正常组（P〈0．01）。结论 糖皮质激素对降低颅脑损伤患者血浆TNF-α、IL-1β水平具有明显的延迟性，使损伤早期因TNF-α、IL-1β显著升高引起的有害作用未能消除，至恢复期又使TNF-α、IL-1β明显降低，其神经保护作用不能发挥。     

Takotsubo Cardiomyopathy in Traumatic Brain Injury

Background

Takotsubo cardiomyopathy (TC) is a well-known complication after aneurysmal subarachnoid hemorrhage and has been rarely described in patients with traumatic brain injury (TBI).

Methods

Case report and review of literature.

Results

Here, we report a 73-year-old woman with mild traumatic brain injury (TBI) presenting in cardiogenic shock. Takotsubo cardiomyopathy (TC) was diagnosed by repeated echocardiography. Cardiovascular support by inotropic agents led to hemodynamic stabilization after initiation of levosimendan. Cardiac function fully recovered within 21 days. We performed an in-depth literature review and identified 16 reported patients with TBI and TC. Clinical course and characteristics are discussed in the context of our patient.

Conclusion

Takotsubo cardiomyopathy is under-recognized after TBI and may negatively impact outcome if left untreated.

     

Clinical Impact of Early Hyperglycemia During Acute Phase of Traumatic Brain Injury

Introduction

While tight glucose control has been widely adopted in the critical care setting, the optimal target glucose level following acute traumatic brain injury (TBI) remains debatable. This observational study was conducted to delineate the relationship between glucose levels and clinical outcomes during acute phase (first 5 days) of TBI.

Methods

We retrospectively identified 429 TBI patients admitted to the intensive care unit (ICU) from January 2005 to December 2006. Of those, 380 patients were retained for final analysis. Collected data included demographics, admission Glasgow Coma Scale (GCS), and APACHE II, glucose on admission and during the first 5 days of admission, and insulin use. Clinical outcomes included mortality, ICU, and hospital length of stay.

Results

The overall hospital mortality was 13.2% (n = 50). Demographics were similar between survivor and nonsurvivor groups; however, nonsurvivors were older and had worse disease severity on admission. Nonsurvivors also had significantly higher glucose levels at admission and during the first 24 h of admission (P < 0.001). Based on the receiver operating characteristic (ROC) curve, admission and day-1 peak glucose were better predictors for mortality compared to hospital days 2–5 glucose levels, with day-1 peak glucose being the best predictor of mortality (AUC = 0.820). A Kaplan–Meier survival analysis also showed that patients with glucose <160 mg/dl during the first day of ICU admission had a significantly better survival rate compared to those with glucose ≥160 mg/dl (P < 0.001). Two glucose bands, <60 and ≥160 mg/dl, were identified to be associated with increased mortality irrespective of injury severity (OR = 1.130; 95% CI 1.034–1.235; P = 0.007; OR = 1.034; 95% CI 1.021–1.047, P < 0.001; respectively).

Conclusions

Findings from our study suggest a glucose level ≥160 mg/dl within the first 24 h of admission following TBI is associated with poor outcomes irrespective of severity of injury, and this presents a timeframe for which active therapeutic interventions may improve clinical outcomes. Prospective efficacy trials are needed to corroborate these findings.     

Functional MRI for Assessment of the Default Mode Network in Acute Brain Injury

Background

Assessment of the default mode network (DMN) using resting-state functional magnetic resonance imaging (fMRI) may improve assessment of the level of consciousness in chronic brain injury, and therefore, fMRI may also have prognostic value in acute brain injury. However, fMRI is much more challenging in critically ill patients because of cardiovascular vulnerability, intravenous sedation, and artificial ventilation.

Methods

Using resting-state fMRI, we investigated the DMN in a convenience sample of patients with acute brain injury admitted to the intensive care unit. The DMN was classified dichotomously into “normal” and “grossly abnormal.” Clinical outcome was assessed at 3 months.

Results

Seven patients with acute brain injury (4 females; median age 37 years [range 14–71 years]; 1 traumatic brain injury [TBI]; 6 non-TBI) were investigated by fMRI a median of 15 days after injury (range 5–25 days). Neurological presentation included 2 coma, 1 vegetative state/unresponsive wakefulness syndrome (VS/UWS), 3 minimal conscious state (MCS) minus, and 1 MCS plus. Clinical outcomes at 3 months included 1 death, 1 VS/UWS, 1 MCS plus, and 4 conscious states (CS; 1 modified Rankin Scale 0; 2 mRS 4; 1 mRS 5). Normal DMNs were seen in 4 out of 7 patients (1 MCS plus, 3 CS at follow-up).

Conclusions

It is feasible to assess the DMN by resting-state fMRI in patients with acute brain injury already in the very early period of intensive care unit admission. Although preliminary data, all patients with a preserved DMN regained consciousness levels at follow-up compatible with MCS+ or better.

     

Genetic Manipulation of Cell Death and Neuroplasticity Pathways in Traumatic Brain Injury

Traumatic brain injury (TBI) initiates a complex cascade of secondary neurodegenerative mechanisms contributing to cell dysfunction and necrotic and apoptotic cell death. The injured brain responds by activating endogenous reparative processes to counter the neurodegeneration or remodel the brain to enhance functional recovery. A vast array of genetically altered mice provide a unique opportunity to target single genes or proteins to better understand their role in cell death and endogenous repair after TBI. Among the earliest targets for transgenic and knockout studies in TBI have been programmed cell death mediators, such as the Bcl-2 family of proteins, caspases, and caspase-independent pathways. In addition, the role of cell cycle regulatory elements in the posttraumatic cell death pathway has been explored in mouse models. As interest grows in neuroplasticity in TBI, the use of transgenic and knockout mice in studies focused on gliogenesis, neurogenesis, and the balance of growth-promoting and growth-inhibiting molecules has increased in recent years. With proper consideration of potential effects of constitutive gene alteration, traditional transgenic and knockout models can provide valuable insights into TBI pathobiology. Through increasing sophistication of conditional and cell-type specific genetic manipulations, TBI studies in genetically altered mice will be increasingly useful for identification and validation of novel therapeutic targets.     

Novel mGluR5 Positive Allosteric Modulator Improves Functional Recovery,Attenuates Neurodegeneration,and Alters Microglial Polarization after Experimental Traumatic Brain Injury

Traumatic brain injury (TBI) causes microglial activation and related neurotoxicity that contributes to chronic neurodegeneration and loss of neurological function. Selective activation of metabotropic glutamate receptor 5 (mGluR5) by the orthosteric agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), is neuroprotective in experimental models of TBI, and has potent anti-inflammatory effects in vitro. However, the therapeutic potential of CHPG is limited due to its relatively weak potency and brain permeability. Highly potent, selective and brain penetrant mGluR5 positive allosteric modulators (PAMs) have been developed and show promise as therapeutic agents. We evaluated the therapeutic potential of a novel mGluR5 PAM, VU0360172, after controlled cortical impact (CCI) in mice. Vehicle, VU0360172, or VU0360172 plus mGluR5 antagonist (MTEP), were administered systemically to CCI mice at 3 h post-injury; lesion volume, hippocampal neurodegeneration, microglial activation, and functional recovery were assessed through 28 days post-injury. Anti-inflammatory effects of VU0360172 were also examined in vitro using BV2 and primary microglia. VU0360172 treatment significantly reduced the lesion, attenuated hippocampal neurodegeneration, and improved motor function recovery after CCI. Effects were mediated by mGluR5 as co-administration of MTEP blocked the protective effects of VU0360172. VU0360172 significantly reduced CD68 and NOX2 expression in activated microglia in the cortex at 28 days post-injury, and also suppressed pro-inflammatory signaling pathways in BV2 and primary microglia. In addition, VU0360172 treatment shifted the balance between M1/M2 microglial activation states towards an M2 pro-repair phenotype. This study demonstrates that VU0360172 confers neuroprotection after experimental TBI, and suggests that mGluR5 PAMs may be promising therapeutic agents for head injury.