Stroke andtraumaticbraininjury (TBI) damage white and grey matter. Loss of oligodendrocytes and their myelin, impairs axonal function. Remyelination involves oligodendrogenesis during which new myelinating oligodendrocytes are generated by diferentiated oligodendrocyte progenitor cells (OPCs). This article briely reviews the processes of oligodendrogenesis in adult rodent brains, and promising experimental therapies targeting the neurovascular unit that reduce oligodendrocyte damage and amplify endogenous oligodendrogenesisafter stroke and TBI.
brain, thus augmenting cerebral inflammatory responses and leading to further neuronal damage and edema formation. Accumulating evidence shows that inflammation and activation of MMPs play key roles in the disruption of the BBB andbrain edema formation afterinjury [28,38–40]. Furthermore, multiple studies have shown that suppression of inflammation inhibited BBB disruption and edema [5,41,42]. MMP-9 functions to degrade the extracellular matrix, including major components of the basal lamina and tight junctions as well as interendothelial tight junction proteins, causing BBB disruption after TBI [28,38]. In addition, excessive accumulation of leukocytes causes the release of cytotoxic enzymes, inflammatory mediators, and reactive oxygen species, thereby potentially damaging the microvascular endothelium and leading to BBB disruption and edema [31,38,39]. In the current study, we showed that wogonin treatment decreased the number of microglia, macrophages, and neutrophils recruited to the injured areas of the brain, reduced NF-kB activation and translocation to the nucleus, and interacted NF-kB binding activity, expression of inflammatory mediators (IL-1b, IL-6, MIP-2, and COX-2), and MMP-9 activity in the injured brain. This reduction in inflammation was associated with the protection of 2 tight junction proteins, ZO-1 and claudin-5, suggesting that wogonin may act to protect endothelial tight junctions, thereby keeping the BBB intact. Hence, the anti-edematous effect of wogonin observed in our study is likely to be related to the inhibition of inflammation. However, the beneficial effects of Figure 7. Effects of 40 mg?kg 21 wogonin on TLR4 expresssion. (A) Representative immunoblots of toll-like receptor (TLR)-4 protein in the
The levels of cerebral water content, and the regional differences in water content between cor- tical, hippocampal and thalamic areas that we report in this study, are in line with previous re- ports [26,38]. Liraglutide (200 μg/kg) BID significantly mitigated TBI induced water content increase in the hippocampus and thalamus by 39% and 48%, respectively. In contrast, Liraglu- tide did not significantly reduce edema in the cortical region. This might be caused by a local low Liraglutide delivery or different edema pathology in the contusion core, which has been shown to be markedly hypoperfused and sparsely vascularized . In addition to cerebral edema, we found that Liraglutide markedly reduced Evans Blue extravasation in the ipsilateral and contralateral hemisphere. This indicates that GLP-R stimulation prevents endothelial bar- rier dysfunction, and suggests that the reduction in tissue water content, at least partially, is due to reduced vasogenic edema . From Fig. 5B it can be discerned that Evans blue mainly is located pericontusionally in the contralateral hemisphere and to some extent in the contra- lateral cingulate cortex adjacent to the contusion. The increased Evans Blue extravasation in the uninjured contralateral hemisphere is likely due to the high magnitude of the injury.
This therapeutic concentration is achieved by a loading dose (as low as 10 mg/kg) followed by maintenance doses (as high as 60 mg/kg). In rodents, an i.p. dose of 200 mg/kg gives rise to a peak serum concentration of 400 m g/ml 15 minutes post injection that rapidly decreases to about 40 m g/ml by 8 hr post-infusion . In contrast, an injection of 400 mg/kg gives rise to a plasma concentration of approximately 150 m g/ml at 8 hr. A number of studies have utilized 300 mg/kg or 400 mg/kg and have observed HDAC and/or GSK-3 inhibition in the brainand other organs [8,51–53]. Consistent with these studies, we found that 400 mg/kg VPA significantly increased histone acetylation, and reduced b- catenin phosphorylation in hippocampal tissue extracts (Figure 1). Using a dose of 400 mg/kg, we observed that VPA improved motor function, and enhanced spatial learning and memory. Although the VPA-treated animals displayed a quadrant prefer- ence when assessed in a 24 hr probe trial, post-hoc analysis revealed that this difference was due to a preference for the target quadrant (I) relative to only the starting quadrant (III). This implies that although the VPA-treated, injured animals have better long-term memory for the platform position than do vehicle- treated injured animals, the performance of neither group was to the level typically observed for uninjured animals The improve- ment in motor and cognitive performance seen after acute VPA treatment suggests that this compound may reduce TBI-associated neuronal degeneration. Previous studies have reported that valproate can be neuroprotective, both for cells grown in culture and as well as in a rodent models of status epilepticus and ischemic stroke [42,43,52]. For example, Ren et al reported that treatment of rats with 300 mg/kg valproate following middle cerebral artery occlusion (MCAO) significantly reduced infarct size and improved neurologic recovery . Consistent with this, our measurement of cortical contusion
The grid-walking/foot-fault test is known to assay for sensorimotor coordination in neurological diseases such as a cerebral infarction, cortex injury, and Parkinson’s disease that may be affected by motor ability (Zhang et al., 2002; Barth, Jones & Schallert, 1990; Shanina et al., 2006; Chao et al., 2012). In our study, with the injury method developed herein, MTBI characteristics were seen in rats with a behavioral delay in the grid-walking and foot fault test. In several cases, no movements were observed in the initial one minute of the test. A delay in latency results from a temporary unconsciousness that occurs after an MTBI, or may be due to post-concussive symptoms such as a headache, dizziness, or irritability. From induction of MTBI, rats became slow in movement on the metal grid, considerably reducing the number of their steps in addition to latency, along with many rats lying almost motionless. These seem to be an aspect of alterations in plasticity and activation and from hypometabolism as in the study of Shrey, Griesbach & Giza (2011). Reductions in foot-fault steps and foot-fault error rates do not result from improvement in sensorimotor coordination after an MTBI but are more likely to be caused by a reduction in real movements.
Traumaticbraininjury (TBI) is the main cause of trauma-related deaths. Systemic hypotension and intracranial hypertension causes cerebral ischemia by altering metabolism of prostanoids. We describe prostanoid, pupilar and pathological response during resuscitation with hypertonic saline solution (HSS) in TBI. Method: Fifteen dogs were randomized in three groups according to resuscitation after TBI (control group; lactated Ringer’s (LR) group and HSS group), with measurement of thromboxane, prostaglandin, macroscopic and microscopic pathological evaluation and pupil evaluation. Result: Concentration of prostaglandin is greater in the cerebral venous blood than in plasma and the opposite happens with concentration of thromboxane. Pathology revealed edema in groups with the exception of group treated with HSS. Discussion and conclusion: There is a balance between the concentrations of prostaglandin and thromboxane. HSS prevented the formation of cerebral edema macroscopically detectable. Pupillary reversal occurred earlier in HSS group than in LR group.
Mice were lightly anesthetized with isoflurane (i.e., until unresponsive to paw or tail pinch) and fixed on a stereotactic platform. The TBI procedure was performed as described previously (15). Briefly, the skin was treated with betadine ointment, and a midline incision was made through the scalp. A 3.5-mm circular craniotomy was made on the left parietal skull between the bregma and lambda, 0.5 mm lateral to the midline. The skullcap was carefully removed without disruption of the dura. The lesion was produced with a pneumatic impact device using a 3-mm diameter convex tip, mounted 20 6 from the vertical to account for the curvature of the skull. The contact velocity was set at 4.5 m/s with a deformation 1.5 mm below the dura, producing a moderately severe lesion to the cortex. Sham-operated animals were anesthetized and a craniotomy was performed, but were not subjected to head impact. After the procedure, the scalp was sutured, and each animal received a sub- cutaneous injection of warm physiologic saline (1 mL) to prevent dehydration. During surgery and subsequent recovery, body temperature was maintained with a circulating water heating pad.
tabolism.[39,40] Thus, the metabolic and energy demands were thought to be the beneficial effects of hypothermia. However, several investigative studies demonstrated last decade that more modest levels of hypothermia have ef- fectiveness on multiple mechanisms felt to be responsible for secondary braininjury mechanism. Secondary braininjury is initiated at the moment of injury with progression over the ensuing minutes, hours, and days. Secondary injury plays a major role in patient’s prognosis and treat- ment outcome. The pathophysiologic mechanisms about the secondary damage are not totally understood. Overall effects of biomolecular and physiological changes in the braininjury, including neuroinflammatory processes with release of cytokines, excitotoxic substances, cerebral edema, increased intracranial pressure (ICP), and compromised cerebral blood flow with cerebral ischemia and apoptosis, may be involved. Hypothermia affect small variations in the temperature of the brain during or after an ischemic or traumaticinjury change hemodynamic events. Moreover, there are excitatory, calcium dependent intercellular signal- ing, inlammation and edema apoptosis as well as molecular markers of the post-injured brain. In the area of excitatory, early studies showed that extracellular levels of the excit- atory amino acid glutamate and other neurotransmitters af- ter braininjury were reduced following mild posttraumatic hypothermia.[42-45] Mild hypothermia also have positive effect on protect against blood brain barrier permeability af- ter increase the permeability of the tight cerebral capillaries due to both ischemic andtraumaticinjury.[46-48] Increase of permeability cause brain edema, it can be an effect of swelling of brain cells, because of cell membrane damage from hypoxia, and cytotoxic and excitatory substances.
In the present study, we demonstrated that Pla2g3 expression is increased in cerebral cortex but not in cerebellum by chronic oxidative stress with vitamin E deficiency. Pla2g3 is expressed both in neurons and astrocytes but oxidative stress-induced Pla2g3 expression is predomi- nantly in astrocytes in the cerebrum. It is particularly noteworthy that this increased Pla2g3 expression is absent in the astrogliosis induced by the ischemia or traumaticbraininjury to the cerebral cortex, indicating that not the acute oxidative stresses but the chronic oxidative stress is the essential factor for induction of Pla2g3 expression in vivo. Moreover, Pla2g3 expression is not associated with the formation of reactive astrocytes. This brain region-specific astrocytic induction of Pla2g3 may be due to the regional differences of vulnerability to the accumulation of oxidative stress during aging. In fact, cerebellum has been reported to be more resistant to oxidative stress than hippocampus and frontal cortex of human brain , which provides a rational explanation for the cerebral cortex specific induction of Pla2g3 we observed. Addition- ally, Pla2g5 and iPla2 did not increase significantly and Pla2g2e was not detectable by oxidative stress in vivo despite a marked simultaneous increase in TR-AST cells after hydrogen peroxide treatment (S1 Fig), suggesting that the regulation of PLA2s gene expression varies among the
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Prigatano and Pribman (1982) used, for the first time, a visual facial recognition paradigm and reported an association between frontal TBI and impairments in emotion recognition. Their findings created new research interests, exploring deeper and with distinct paradigms the relation between frontal traumaticbrain lesions and emotional states. Hence, it began to be noted that participants with TBI exhibited impairment for recognizing emotions but not for recognizing neutral facial expressions (Green, Turner, & Thompson, 2004). Specifically, negative basic emotions like fear and anger are the most difficult for TBI patients to recognize (e.g., Spell & Frank, 2000). Nevertheless, even with the finding of behavioral changes and impaired emotion processing in TBI patients, a great deal of divergence remains regarding not only which emotions are most impaired but also regarding the role played by each cerebral hemisphere and the cerebral localization of those brain injuries that impair adequate processing of each basic emotion.
he concept underlying DTI is that the local proile of the difusion in diferent directions provides important indirect information about the microstructure of the underlying tissues. In the white matter, axonal mem- branes, myelin sheaths, microtubules and neuroila- ments restrict the movement of water. his restriction is dependent on the direction of the axons (i.e. difusion is not equal in all directions). Water difuses freely in direc- tions parallel to axons but it is restricted in directions perpendicular to axons which results in the magnitude of the difusion along axons being greater than the two per- pendicular directions thus leading to an elongated ellip- soidal shape of the difusion tensor described as “aniso- tropic.” here are various ways that the shape and size of a difusion ellipsoid can be quantiied but the two most common indices used are Fractional Anisotropy (FA) for shape, and Mean Difusivity (MD) for size. FA is a scalar measure that ranges from 0 to 1, with 0 indicating com- plete isotropy meaning that water difuses equally in all directions and 1 depicting the most extreme anisotropic scenario in which molecules are difusing along a single axis. Accordingly, in normal white matter FA should be close to 1 and reduced FA is generally thought to relect loss of white matter integrity. DTI, however, is somewhat non-speciic when using these parameters and it is not known whether disruptions in FA and MD are the result of disturbances in axonal membranes, myelin sheath, microtubules, neuroilaments, or other factors.
Endothelin-1 (ET-1) is a 21 amino acid bioactive peptide, which is predominantly synthesized and released by endothe- lial cells and is a potent vasoconstrictor implicated in the pathogenesis of vasospasm and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage (SAH) patients. ET-1 is not only generated by vascular-endothelial and smooth- muscle cells, but also by neurons, astrocytes, and monocytes. Hemoglobin stimulates monocytes ET-mRNA expression, a mechanism that increases ET-1 concentration in the cerebro- spinal luid in SAH. Selective antagonists of the two ET-1 re- ceptors (ETA and ETB) have been used for SAH-induced va- sospasm in animal models, where vasospasm can be limited by blocking the detrimental efects of endogenous ET-1 24,25 .
Materials and Methods: The animals were randomly allocated into five groups: sham group, TB)+ vehicle group % ethanol in saline and TB)+ melatonin groups mg/kg, mg/kg and mg/kg . All rats were intubated and then exposed to diffuse TB), except for the sham group. )mmunohistochemical methods were conducted using glial fibrillary acidic protein GFAP marker and TUNEL assay to evaluate astrocyte reactivity and cell death, respectively.
his article reviews the literature, organizes the major indings, and generates the best evidence-based recommendations on nutrition therapy for head trauma patients. Despite recent advances in head trauma diagnosis and therapy, the mortality associated with this condition remains high. Few therapeutic interventions have been proven to efectively improve this condition. Head trauma causes multiple metabolic and electrolytic disorders; it is characterized by a hypermetabolic state that is associated with intensive catabolism, leading to speciic nutritional needs.
The psychiatry condition of F. (current PTSD and Crack Cocaine Dependence; past diagnosis of TBI), highlights the importance for clinicians to differentiate the co-occurrence of multiples diagnosis from cases in which one disorder is induced by another. In the clinical history of F. it was clear that after a car accident (in which she suffered a TBI), she developed many symptoms specifically related to the trauma and not necessarily to her neurological condition. These symptoms were persistent and did not remit in the first month, progressing to a PTSD diagnosis. Furthermore, despite the reasons that corroborated to F onset of substance use were not fully understood, she developed a pattern of cocaine and crack use in the subsequent years, supporting SUD diagnosis. She had severe functional and psychosocial impairments that culminate to her hospitalization. In this sense, this clinical rational suggested the presence, independently, of all three diagnoses, not ignoring the possibility of a relationship in their course according F’s clinical history. In addition, despite our evaluation was based on DSM-IV diagnosis criteria, we believed that it remains unchanged even if we consider the DSM-V criteria. For example, in PTSD diagnosis, F. already presented symptoms of negative alteration of cognition and mood (e.g., numbing symptoms and cognitive distortion about the cause and consequences of the trauma), which comprehend the new cluster criteria (D criteria). Related to Substance Use Diagnosis, in which DSM-V did not distinguish anymore abuse from dependence, the appropriate nomenclature for F. case would be replaced by Crack Cocaine Use Disorder.
Functional neuroimaging studies in mild traumaticbraininjury (mTBI) have been largely lim- ited to patients with persistent post-concussive symptoms, utilizing images obtained months to years after the actual head trauma. We sought to distinguish acute and delayed effects of mild traumaticbraininjury on working memory functional brain activation patterns < 72 hours after mild traumaticbraininjury (mTBI) and again one-week later. We hypothesized that clinical and fMRI measures of working memory would be abnormal in symptomatic mTBI patients assessed < 72 hours afterinjury, with most patients showing clinical recovery (i.e., improvement in these measures) within 1 week after the initial assessment. We also hypothesized that increased memory workload at 1 week following injury would expose dif- ferent cortical activation patterns in mTBI patients with persistent post-concussive symp- toms, compared to those with full clinical recovery. We performed a prospective, cohort study of working memory in emergency department patients with isolated head injuryand clinical diagnosis of concussion, compared to control subjects (both uninjured volunteers and emergency department patients with extremity injuries and no head trauma). The pri- mary outcome of cognitive recovery was defined as resolution of reported cognitive im- pairment and quantified by scoring the subject’s reported cognitive post-concussive symptoms at 1 week. Secondary outcomes included additional post-concussive symptoms and neurocognitive testing results. We enrolled 46 subjects: 27 with mild TBI and 19 con- trols. The time of initial neuroimaging was 48 (+22 S.D.) hours afterinjury (time 1). At follow up (8.7, + 1.2 S.D., days afterinjury, time 2), 18 of mTBI subjects (64%) reported moderate to complete cognitive recovery, 8 of whom fully recovered between initial and follow-up im- aging. fMRI changes from time 1 to time 2 showed an increase in posterior cingulate activa- tion in the mTBI subjects compared to controls. Increases in activation were greater in those mTBI subjects without cognitive recovery. As workload increased in mTBI subjects, activation increased in cortical regions in the right hemisphere. In summary, we found neu- roimaging evidence for working memory deficits during the first week following mild
Samples were analyzed by a Q Exactive benchtop LC-MS/MS (Thermo Scientific). PMi Preview software (PMi Software, Dublin, Ireland) was used to survey the data files and if necessary add other modifications to the search criteria. Also, Preview results were used to choose the precur- sor and fragment ion mass tolerances (4 ppm, 0.02 Da, respectively), as well as dynamic modi- fications. The following settings were used to search the data using SEQUEST and BYONIC as the search algorithm; dynamic modifications; Oxidation / +15.995 Da (M), Methyl / +14.016 Da (E), Deamidated / +0.984 Da (N, Q), static modifications of TMT 6plex / +229.163 Da (N-Terminus, K), Carbamidomethyl +57.021 (C). The False discovery rate (FDR) was set to 0.01 in both search engines and peptides passing this cutoff value were exported to JMP 8.0.2 software (SAS Institute, Cary, NC) for data cleaning and statistical analysis. Only unique pep- tides were considered for quantification purposes. Proteins identified with 2 or more peptides were used for the quantitative analysis. TBI/sham ratios were calculated after ln transformation of the raw ion counts. The ratios were normalized by central tendency normalization where medians were used. After the median of a peptide from multiple fractions was calculated, one sample t-test was used to test if the sample mean was equal to zero. The multiple-testing cor- rection as per  was applied to identify a “top tier” of significant proteins and prevent identi- fication of false positives at a false discovery rate of 5 percent.
Neurophysiological research relates those symptoms to axonal injury that occurs at different levels depending on injury severity. Axonal injury can occur at any brain site in the division between white and grey matter; different tissue density and acceleration-deceleration movement can torn or lacerate axonal fibers that are connected to neuronal cell bodies. Axonal injury occurs in TBI of all severity levels, although it is not always identifiable by computer tomography (CT) or magnetic resonance image (MRI). In general diffuse axonal injury can be identified in these exams by means of small focal lesions all over the intersection between white and grey matter (Granacher, 2009). Currently, more specific neuroimaging techniques are sensitive to identify even very mild white matter damage, such as Diffusion Tensor Imaging (DTI) (Johnson, Stewart, & Smith, 2012, in press). In addition to diffuse axonal injury, hemorrhages, contusions, ischemia, edema and herniation are also common lesions after a TBI that can manifest hours or days after an accident. In some cases, neurosurgery is necessary to remove edemas or intracranial pressure. Those damages frequently lead to brain tissue reduced volume and enlargement of ventricles (Maas, et al.,, 2008).