Endocannabinoids and Traumatic Brain Injury

In response to traumatic brain injury, there is local and transient accumulation of 2-AG at the site of injury, peaking at 4 h and sustained up to at least 24 h. Neuroprotection exerted by exogenous 2-AG suggests that the formation of 2-AG may serve as a molecular regulator of pathophysiological events, attenuating the brain damage. Inhibition of this protective effect by SR-141716A, a CB₁ cannabinoid receptor antagonist, and the lack of effect of 2-AG in CB₁ knockout mice suggest that 2-AG and the CB₁ receptor may be important in the pathophysiology of traumatic brain injury. 2-AG exerts its neuroprotective effect after traumatic brain injury, at least in part, by inhibition of NF-κB transactivation. 2-AG also inhibits, at an early stage (2–4 h), the expression of the main proinflammatory cytokines, TNF-α, IL-6, and IL-1β, and is accompanied by reduction of BBB permeability. Moreover, the CB₁, CB₂, and TRVP1 receptors are expressed on microvascular endothelial cells, and their activation by 2-AG counteracts endothelin (ET-1)-induced cerebral microvascular responses (namely, Ca²⁺ mobilization and cytoskeleton rearrangement). This suggests that the functional interaction between 2-AG and ET-1 may provide a potential alternative pathway for abrogating ET-1-inducible vasoconstriction after brain injury and play a role in the neuroprotective effects exerted by 2-AG, as a potent vasodilator.     

Quantification of Axonal Damage in Traumatic Brain Injury

Abstract : Diffuse axonal injury is a primary feature of head trauma and is one of the most frequent causes of mortality and morbidity. Diffuse axonal injury is microscopic in nature and difficult or impossible to detect with imaging techniques. The objective of the present study was to determine whether axonal injury in head trauma patients could be quantified by measuring levels of CSF tau proteins. Tau proteins are structural microtubule binding proteins primarily localized in the axonal compartment of neurons. Monoclonal antibodies recognizing the form of tau found in the CSF of head trauma patients were developed by differential CSF hybridoma screening using CSF from head trauma and control patients. Clones positive for head trauma CSF tau proteins were used to characterize this form of tau and for ELISA development. Using the developed ELISA, CSF tau levels were elevated >1,000-fold in head trauma patients (mean, 1,519 ng/ml of CSF) when compared with patients with multiple sclerosis (mean, 0.014 ng/ml of CSF ; p < 0.001), normal pressure hydrocephalus (nondetectable CSF tau), neurologic controls (mean, 0.031 ng/ml of CSF ; p < 0.001), or nonneurologic controls (nondetectable CSF tau ; p < 0.001). In head trauma, a relationship between clinical improvement and decreased CSF tau levels was observed. These data suggest that CSF tau levels may prove a clinically useful assay for quantifying the axonal injury associated with head trauma and monitoring efficacy of neuroprotective agents. Affinity purification of CSF tau from head trauma patients indicated a uniform cleavage of ~ 18 kDa from all six tau isoforms, reducing their apparent molecular sizes to 30-50 kDa. These cleaved forms of CSF tau consisted of the interior portion of the tau sequence, including the microtubule binding domain, as judged by cyanogen bromide digestion. Consistent with these data, CSF cleaved tau bound taxolpolymerized microtubules, indicating a functionally intact microtubule binding domain. Furthermore, epitope mapping studies suggested that CSF cleaved tau proteins consist of the interior portion of the tau sequence with cleavage at both N and C terminals.     

Delayed Phospholipid Degradation in Rat Brain After Traumatic Brain Injury

Abstract: Lipid second messengers such as arachidonic acid and its metabolites and diacylglycerols (DAGs) are affected in brain injury. Therefore, changes in the pool size and the fatty acid composition of free fatty acids (FFAs) and DAGs were analyzed in different rat brain areas 4 and 35 days after traumatic injury. Cortical impact injury of low-grade severity was applied in the right frontal somatosensory cortex. Four days after injury, FFAs and DAGs were increased by three- and twofold, respectively, in the injured cortex and to a lesser extent in the contralateral cortex compared with sham-operated animals. Docosahexaenoic acid followed by stearic acid, and arachidonic acid, displayed the greatest changes in both FFAs and DAGs. By day 35, free stearic, oleic, and arachidonic acids remained elevated in the damaged cortex (1.5-fold each). DAGs showed the greatest change, reaching values 2.7-fold higher than sham in all frontal and occipital cortical areas, including brainstem. Oleoyl- and arachidonoyl-DAGs (four- and threefold increase, respectively) followed by docosahexaenoyl-DAGs (twofold) contributed to the DAG accumulation. These results reveal that traumatic brain injury triggers a sustained and time-dependent activation of phospholipase-mediated signaling pathways leading to membrane phospholipid degradation and targeting, early on, docosahexaenoyl phospholipid-enriched excitable membranes.     

Efficacy of N-Acetyl Cysteine in Traumatic Brain Injury

In this study, using two different injury models in two different species, we found that early post-injury treatment with N-Acetyl Cysteine (NAC) reversed the behavioral deficits associated with the TBI. These data suggest generalization of a protocol similar to our recent clinical trial with NAC in blast-induced mTBI in a battlefield setting [1], to mild concussion from blunt trauma. This study used both weight drop in mice and fluid percussion injury in rats. These were chosen to simulate either mild or moderate traumatic brain injury (TBI). For mice, we used novel object recognition and the Y maze. For rats, we used the Morris water maze. NAC was administered beginning 30–60 minutes after injury. Behavioral deficits due to injury in both species were significantly reversed by NAC treatment. We thus conclude NAC produces significant behavioral recovery after injury. Future preclinical studies are needed to define the mechanism of action, perhaps leading to more effective therapies in man.     

Cerebrospinal Fluid Taurine after Traumatic Brain Injury

In the experimental setting, taurine is known to be released from swollen cells to reestablish their normal volume. However, its clinical relevance has not been fully understood. This study was undertaken to reveal changes in cerebrospinal fluid (CSF) amino acids concentration in patients with severe traumatic brain injury (TBI). The study included eight patients, in whom a ventricular catheter was inserted to measure intracranial pressure and obtain CSF samples for 5 days. CSF obtained from patients with normal pressure hydrocephalus served as a control. CSF taurine concentration increased 1.8 times control (P < 0.05) after TBI and returned to control value approximately 67 h after injury. Taurine decreased further and remained lower than control thereafter. Phosphoethanolamine showed similar increase, whereas glutamine decreased transiently and arginine remained close to control value. The present data support the period of astrocytic swelling observed after TBI in other morphological studies. The mechanism and consequences of CSF taurine decrease in the subacute stage of TBI need to be elucidated.     

Depletion of Brain Docosahexaenoic Acid Impairs Recovery from Traumatic Brain Injury

Omega-3 fatty acids are crucial for proper development and function of the brain where docosahexaenoic acid (DHA), the primary omega-3 fatty acid in the brain, is retained avidly by the neuronal membranes. We investigated the effect of DHA depletion in the brain on the outcome of traumatic brain injury (TBI). Pregnant mice were put on an omega-3 fatty acid adequate or deficient diet from gestation day 14 and the pups were raised on the respective diets. Continuation of this dietary regime for three generations resulted in approximately 70% loss of DHA in the brain. Controlled cortical impact was delivered to both groups of mice to produce severe TBI and the functional recovery was compared. Compared to the omega-3 adequate mice, the DHA depleted mice exhibited significantly slower recovery from motor deficits evaluated by the rotarod and the beam walk tests. Furthermore, the DHA deficient mice showed greater anxiety-like behavior tested in the open field test as well as cognitive deficits evaluated by the novel object recognition test. The level of alpha spectrin II breakdown products, the markers of TBI, was significantly elevated in the deficient mouse cortices, indicating that the injury is greater in the deficient brains. This observation was further supported by the reduction of NeuN positive cells around the site of injury in the deficient mice, indicating exacerbated neuronal death after injury. These results suggest an important influence of the brain DHA status on TBI outcome.     

创伤性脑损伤中神经炎症相关细胞的研究进展

创伤性脑损伤(traumatic brain injury, TBI), 亦称颅脑损伤或头部外伤, 专指由外伤引起的脑组织损害。然而,从轻度到重度的TBI,改善TBI患者预后的治疗方法都十分匮乏。神经炎症可引起脑外伤后急性继发性损伤,并与慢性神经退行性疾病有关,因此,系统了解参与TBI后神经炎性反应的细胞显得尤为重要。主要对TBI中参与炎症反应的细胞（如小胶质细胞、星形胶质细胞、少突细胞、中性粒细胞和淋巴细胞）的启动以及相互作用的最新研究进展进行了综述,以期为临床研究提供新的策略。     

Changes in Body Temperature Rhythm after Traumatic Brain Injury

We performed this study to determine whether in head injured patients body temperature rhythmicity exists outside the usual spectrum. Temperature data of in total 22 patients with head injury were analyzed using the Regressive and Iterative Cosinor methods. We found that circadian rhythm often remained, and usually was combined with rhythms in ultradian or infradian ranges. Tau shifts over consecutive days were observed in three severely head injured patients (Glasgow Coma Scale score ≤ 8). To validate the results we used surrogate data. Detection of temperature rhythms in this study may serve to estimate the clinical importance of biological rhythms in head injury.     

Changes in Body Temperature Rhythm after Traumatic Brain Injury

We performed this study to determine whether in head injured patients body temperature rhythmicity exists outside the usual spectrum. Temperature data of in total 22 patients with head injury were analyzed using the Regressive and Iterative Cosinor methods. We found that circadian rhythm often remained, and usually was combined with rhythms in ultradian or infradian ranges. Tau shifts over consecutive days were observed in three severely head injured patients (Glasgow Coma Scale score ≤ 8). To validate the results we used surrogate data. Detection of temperature rhythms in this study may serve to estimate the clinical importance of biological rhythms in head injury.     

Controlled Cortical Impact Model for Traumatic Brain Injury

Every year over a million Americans suffer a traumatic brain injury (TBI). Combined with the incidence of TBIs worldwide, the physical, emotional, social, and economical effects are staggering. Therefore, further research into the effects of TBI and effective treatments is necessary. The controlled cortical impact (CCI) model induces traumatic brain injuries ranging from mild to severe. This method uses a rigid impactor to deliver mechanical energy to an intact dura exposed following a craniectomy. Impact is made under precise parameters at a set velocity to achieve a pre-determined deformation depth. Although other TBI models, such as weight drop and fluid percussion, exist, CCI is more accurate, easier to control, and most importantly, produces traumatic brain injuries similar to those seen in humans. However, no TBI model is currently able to reproduce pathological changes identical to those seen in human patients. The CCI model allows investigation into the short-term and long-term effects of TBI, such as neuronal death, memory deficits, and cerebral edema, as well as potential therapeutic treatments for TBI.     

Genetic Influences on Outcome Following Traumatic Brain Injury

Several genes have been implicated as influencing the outcome following traumatic brain injury (TBI). Currently the most extensively studied gene has been APOE. APOE can influence overall and rehabilitation outcome, coma recovery, risk of posttraumatic seizures, as well as cognitive and behavioral functions following TBI. Pathologically, APOE is associated with increased amyloid deposition, amyloid angiopathy, larger intracranial hematomas and more severe contusional injury. The proposed mechanism by which APOE affects the clinciopathological consequences of TBI is multifactorial and includes amyloid deposition, disruption of cytoskeletal stability, cholinergic dysfunction, oxidative stress, neuroprotection and central nervous system plasticity in response to injury. Other putative genes have been less extensively studied and require replication of the clinical findings. The COMT and DRD2 genes may influence dopamine dependent cognitive processes such as executive/frontal lobe functions. Inflammation which is a prominent component in the pathophysiological cascade initiated by TBI, is in part is mediated by the interleukin genes, while apoptosis that occurs as a consequence of TBI may be modulated by polymorphisms of the p53 gene. The ACE gene may affect TBI outcome via mechanisms of cerebral blood flow and/or autoregulation and the CACNA1A gene may exert an influence via the calcium channel and its effect on delayed cerebral edema. Although several potential genes that may influence outcome following TBI have been identified, future investigations are needed to validate these genetic studies and identify new genes that might influence outcome following TBI. Special issue dedicated to John P. Blass.     

Decreased Resting Functional Connectivity after Traumatic Brain Injury in the Rat

Traumatic brain injury (TBI) contributes to about 10% of acquired epilepsy. Even though the mechanisms of post-traumatic epileptogenesis are poorly known, a disruption of neuronal networks predisposing to altered neuronal synchrony remains a viable candidate mechanism. We tested a hypothesis that resting state BOLD-fMRI functional connectivity can reveal network abnormalities in brain regions that are connected to the lesioned cortex, and that these changes associate with functional impairment, particularly epileptogenesis. TBI was induced using lateral fluid-percussion injury in seven adult male Sprague-Dawley rats followed by functional imaging at 9.4T 4 months later. As controls we used six sham-operated animals that underwent all surgical operations but were not injured. Electroencephalogram (EEG)-functional magnetic resonance imaging (fMRI) was performed to measure resting functional connectivity. A week after functional imaging, rats were implanted with bipolar skull electrodes. After recovery, rats underwent pentyleneterazol (PTZ) seizure-susceptibility test under EEG. For image analysis, four pairs of regions of interests were analyzed in each hemisphere: ipsilateral and contralateral frontal and parietal cortex, hippocampus, and thalamus. High-pass and low-pass filters were applied to functional imaging data. Group statistics comparing injured and sham-operated rats and correlations over time between each region were calculated. In the end, rats were perfused for histology. None of the rats had epileptiform discharges during functional imaging. PTZ-test, however revealed increased seizure susceptibility in injured rats as compared to controls. Group statistics revealed decreased connectivity between the ipsilateral and contralateral parietal cortex and between the parietal cortex and hippocampus on the side of injury as compared to sham-operated animals. Injured animals also had abnormal negative connectivity between the ipsilateral and contralateral parietal cortex and other regions. Our data provide the first evidence on abnormal functional connectivity after experimental TBI assessed with resting state BOLD-fMRI.     

丙泊酚镇静对颅脑损伤患者脑氧供需平衡的影响

目的:探讨丙泊酚实施不同程度镇静对颅脑损伤患者脑氧供需平衡的影响。方法:选择急性闭合性颅脑损伤需行机械通气患者46例,随机分为轻度镇静组(A组),设定目标脑电双频谱指数(BIS)值75%;中度镇静组(B组),设定目标BIS值65%。主要观察达设定目标BIS值时丙泊酚靶控输注(TCI)浓度、Ramsay镇静评分、脑氧供需平衡指标颈内静脉血氧饱和度(SjvO_2)和脑氧摄取率(CERO_2)以及心率(HR)、平均动脉压(MAP)。结果:两组设定镇静目标需丙泊酚TCI浓度有明显差异(P0.05),但Ramsay评分比较差异无统计学意义;中度镇静组SjvO_2较基础值增加约12%(P0.05),CERO_2较基础值下降约15%(P0.05);而轻度镇静组对SjvO_2和CERO_2基础值没有影响。两组HR均较基础值减慢(P0.05),但对MAP均没有影响。结论:颅脑损伤患者维持目标镇静BIS值65%,调控丙泊酚靶浓度1.5-1.6μg/mL,更有利于改善脑氧供需平衡。     

藏红花素对小鼠创伤性脑损伤保护作用的研究

目的:研究藏红花素对小鼠创伤性脑损伤的保护作用和可能的机制.方法:采用控制性皮层撞击法建立小鼠创伤性脑损伤模型,通过脑含水量测定和运动功能评分评价藏红花素对小鼠创伤性脑损伤的保护作用.结果:①藏红花素显著减轻创伤性脑损伤后脑水肿程度.②藏红花素显著减轻创伤性脑损伤造成的运动功能损伤.③藏红花素显著提高了脑组织SOD和GPX的活性,降低了MDA水平.结论:藏红花素通过抗氧化活性对小鼠创伤性脑损伤发挥保护作用.     

Foxj1 在脑外伤后的表达变化

目的:探讨脑外伤后Foxj1在脑组织中的表达变化及其意义。方法:建立大鼠脑外伤模型,利用Western blot和免疫组织化学方法检测脑外伤后Foxj1在脑组织中表达的变化。结果:Western blot显示大鼠脑外伤后,Foxj1的表达逐步增高,伤后3 d升至最高点,之后逐渐降低;免疫组织化学的结果与Western blot一致。结论:脑外伤后Foxj1在脑组织中的表达增高,这种增高的表达参与了脑外伤后脑组织的病理生理和生化变化。     

重型颅脑损伤后颅内高压的治疗研究进展

重型颅脑损伤后颅内压增高预示着不良的神经功能预后和极高的死亡率,一直是临床治疗中的研究热点,可采取高渗性脱水,亚低温疗法,巴比妥昏迷治疗及外科手术干预等治疗措施控制颅内压。由于亚低温治疗会增加患者发生肺炎的风险,巴比妥类药物副作用较大,现均已少用。近来研究发现,监测颅内压、脑灌注压、脑组织氧分压并指导临床治疗,可降低死亡率与改善预后。也有研究发现去骨瓣减压术治疗顽固性颅内高压与神经功能预后较差有关。目前关于颅内高压治疗的最佳方案仍存在争议,未来还需根据患者病情,为其制定规范化与个体化的治疗方案,预防继发性颅脑损伤,降低颅内压。本文就近年来重型颅脑损伤后颅内高压的治疗进展进行阐述。