Cyclophilin D-induced mitochondrial impairment confers axonal injury after intracerebral hemorrhage in mice

The mitochondrial permeability transition pore is a nonspecific transmembrane channel.Inhibition of mitochondrial permeability transition pore opening has been shown to alleviate mitochondrial swelling,calcium overload,and axonal degeneration.Cyclophilin D is an important component of the mitochondrial permeability transition pore.Whether cyclophilin D participates in mitochondrial impairment and axonal injury after intracerebral hemorrhage is not clear.In this study,we established mouse models of intracerebral hemorrhage in vivo by injection of autologous blood and oxyhemoglobin into the striatum in Thy1-YFP mice,in which pyramidal neurons and axons express yellow fluorescent protein.We also simulated intracerebral hemorrhage in vitro in PC12 cells using oxyhemoglobin.We found that axonal degeneration in the early stage of intracerebral hemorrhage depended on mitochondrial swelling induced by cyclophilin D activation and mitochondrial permeability transition pore opening.We further investigated the mechanism underlying the role of cyclophilin D in mouse models and PC12 cell models of intracerebral hemorrhage.We found that both cyclosporin A inhibition and short hairpin RNA interference of cyclophilin D reduced mitochondrial permeability transition pore opening and mitochondrial injury.In addition,inhibition of cyclophilin D and mitochondrial permeability transition pore opening protected corticospinal tract integrity and alleviated motor dysfunction caused by intracerebral hemorrhage.Our findings suggest that cyclophilin D is used as a key mediator of axonal degeneration after intracerebral hemorrhage;inhibition of cyclophilin D expression can protect mitochondrial structure and function and further alleviate corticospinal tract injury and motor dysfunction after intracerebral hemorrhage.Our findings provide a therapeutic target for preventing axonal degeneration of white matter injury and subsequent functional impairment in central nervous diseases.

Diffuse axonal injury after traumatic cerebral microbleeds: an evaluation of imaging techniques

Previous neuropathological studies regarding traumatic brain injury have primarily focused on changes in large structures, for example, the clinical prognosis after cerebral contusion, intrace- rebral hematoma, and epidural and subdural hematoma. In fact, many smaller injuries can also lead to severe neurological disorders. For example, cerebral microbleeds result in the dysfunc- tion of adjacent neurons and the disassociation between cortex and subcortical structures. These tiny changes cannot be adequately visualized on CT or conventional MRI. In contrast, gradient echo sequence-based susceptibility-weighted imaging is very sensitive to blood metabolites and microbleeds, and can be used to evaluate traumatic cerebral microbleeds with high sensitivity and accuracy. Cerebral microbleed can be considered as an important imaging marker for dif- fuse axonal injury with potential relevance for prognosis. For this reason, based on experimental and clinical studies, this study reviews the role of imaging data showing traumatic cerebral microbleeds in the evaluation of cerebral neuronal injury and neurofunctional loss.

Mild hypothermia for treatment of diffuse axonal injury: a quantitative analysis of diffusion tensor imaging

Fractional anisotropy values in diffusion tensor imaging can quantitatively reflect the consistency of nerve fibers after brain damage, where higher values generally indicate less damage to nerve fibers. Therefore, we hypothesized that diffusion tensor imaging could be used to evaluate the effect of mild hypothermia on diffuse axona[ injury. A total of 102 patients with diffuse axonal injury were randomly divided into two groups： normothermic and mild hypothermic treatment groups. Patient＇s modified Rankin scale scores 2 months after mild hypothermia were significant- ly lower than those for the normothermia group. The difference in average fractional anisotropy value for each region of interest before and after mild hypothermia was 1.32-1.36 times higher than the value in the normothermia group. Quantitative assessment of diffusion tensor imaging indicates that mild hypothermia therapy may be beneficial for patients with diffuse axonal injury.

Prognosis in prolonged coma patients with diffuse axonal injury assessed by somatosensory evoked potential

A total of 43 prolonged coma patients with diffuse axonal injury received the somatosensory evoked potential examination one month after injury in the First Affiliated Hospital, School of Medicine, Zhejiang University in China. Somatosensory evoked potentials were graded as normal, abnormal or absent （grades I-III） according to N20 amplitude and central conduction time. The outcome in patients with grade III somatosensory evoked potential was in each case unfavorable. The prognostic accuracy of grade III somatosensory evoked potential for unfavorable and non-awakening outcome was 100% and 80%, respectively. The prognostic accuracy of grade I somatosensory evoked potential for favorable and wakening outcome was 86% and 100%, respectively. These results suggest that somatosensory evoked potential grade is closely correlated with coma severity and degree of recovery. Somatosensory evoked potential is a valuable diagnostic tool to assess prognosis in prolonged coma patients with diffuse axonal injury.

Susceptibility weighted imaging in the evaluation of hemorrhagic diffuse axonal injury

Diffuse axonal injury（DAI）is axonal and small vessel injury produced by a sudden acceleration of the head by an external force,and is a major cause of death and severe disability（Paterakis et al.,2000）.Prognosis is poorer in patients with apparent hemorrhage than in those without（Paterakis et al.,2000）.Therefore,it is important to identify the presence and precise position of hemorrhagic foci for a more accurate diagnosis.CT and magnetic resonance imaging（MRI）have long been applied in the diagnosis of DAI, but they are not sensitive enough for the detection of small hemorrhagic foci, and cannot meet the requirements for early diagnosis. A major advance in MRI has been the development of susceptibility weighted imaging （SWI）, which has greatly increased the ability to detect small hemorrhagic foci after DAI （Ashwal et al., 2006）.

Dynamic changes in cerebral microcirculation and hypoxia in the early stages of diffuse axonal injury

This study demonstrated that damage to the cerebral microvasculature, the formation of microthrombi and swelling of vascular endothelial cells occur early and peak 12 hours after injury in a rat model of diffuse axonal injury. Moreover, these pathological changes were most evident in the cerebral cortex. Cerebral microcirculatory dysfunction peaked later and had a shorter duration than axonal injury. In addition, the radioactive imaging agent, 99Tcm-4, 9-diaza-2, 3, 10, 10- tetramethyldodecan-2, 11 -dione dioxime, was used to visualize the dynamic changes that occur in tissue with cerebral hypoxia. The results demonstrated that cerebral hypoxia occurs at an early stage in diffuse axonal injury. Cerebral hypoxia was evident 12 hours after injury and declined slightly 24 hours after injury, but was significantly higher than in the control group. The pathological changes that underpin microcirculatory dysfunction did not occur at the same time as axonal injury, but did occur simultaneously with neuronal injury. Cerebral hypoxia plays a key role in promoting the secondary brain injury that occurs after diffuse axonal injury.

8-hydroxy-2-(di-n-propylamino)tetralin intervenes with neural cell apoptosis following diffuse axonal injury

Previous studies have reported a neuroprotective effect of 8-hydroxy-2-（di-n-propylamino）tetralin （8-OH-DPAT） against traumatic brain injury. In accordance with the Marmarou method, rat models of diffuse axonal injury were established. 8-OH-DPAT was intraperitoneally injected into model rats. 8-OH-DPAT treated rats maintained at constant temperature served as normal temperature controls TUNEL results revealed that neural cell swelling, brain tissue necrosis and cell apoptosis occurred around the injured tissue. Moreover, the number of Bax-, Bcl-2- and caspase-3-positive cells increased at 6 hours after diffuse axonal injury, and peaked at 24 hours. However, brain injury was attenuated, the number of apoptotic cells reduced, Bax and caspase-3 expression decreased, and Bcl-2 expression increased at 6, 12, 24, 72 and 168 hours after diffuse axonal injury in normal temperature control and in 8-OH-DPAT-intervention rats. The difference was most significant at 24 hours. All indices in 8-OH-DPAT-intervention rats were better than those in the constant temperature group. These results suggest that 8-OH-DPAT inhibits Bax and caspase-3 expression, increases Bcl-2 expression, and reduces neural cell apoptosis, resulting in neuroprotection against diffuse axonal injury. This effect is associated with a decrease in brain temperature.

Evaluation of non-typical diffuse axonal injury by magnetic resonance techniques

Because diffuse axonal injury（DAI）lacks specific clinical manifestations,it is difficult to evaluate DAI using computer tomography or conventional magnetic resonance imaging（MRI）.This study investigated the value of magnetic resonance techniques using fluid-attenuated inversion recovery（FLAIR）and proton magnetic resonance spectroscopy（1HMRS）for diagnosing DAI.The corpus callosum and basal nuclei were analyzed using morphological and functional imaging.Similar to the DAI group,the non-typical DAI group exhibited similar lesion characteristics on FLAIR,as well as post-injury neurochemical and molecular changes in the corpus callosum,as detected by 1HMRS.However,there were differences in degree and severity of injury.Compared to conventional MRI,FLAIR significantly increased lesion detection.1HMRS determined biochemical metabolism changes in midline structures following DAI,which resulted in increased diagnosis of non-typical DAI,which displayed similar lesion distribution,morphology,and function as DAI.Thus,the experiment proved the value of FLAIR and 1HMRS in non-typical DAI.

Diagnostic value of fluid attenuated inversion recovery versus T_2-weighted image in diffuse axonal injury

BACKGROUND：At present, the most common examination modality for diffuse axonal injury （DAI） is CT or MRI. However, both methods exhibit low sensitivity in the diagnosis of DAI lesions. OBJECTIVE： To investigate the value of fluid attenuated inversion recovery （FLAIR） in the clinical diagnosis of DAI, and to compare with T2-weighted images. DESIGN, TIME AND SETTING： This prospective study was based on imaging analysis, and was performed in the First Affiliated Hospital of Chongqing Medical University （Chongqing, China） between October 2002 and April 2004. PARTICIPANTS： Sixty-three patients with craniocerebral injury were admitted to the Department of Neurosurgery at the First Affiliated Hospital of Chongqing Medical University, including 50 males and 13 females. The patients were included in the experiment and were divided into DAI （n=24） and non-DAI （n=39） groups, according to the emergent CT findings and clinical manifestations. METHODS： Both groups underwent MR examinations, including axial and sagittal T1 weighted images （TR = 450 ms, TE = 8-9 ms）, T2-weighted images （TR = 3 600 ms, TE = 100 ms）, and FLAIR （TR = 10 000 ms, TI = 2 500 ms, TE = 40 ms）, 8-mm thick and 2-mm wide, using a GE Sigma MRI device. MAIN OUTCOME MEASURES： The DAI diagnostic rate and lesion-detecting rate of T2-weighted images and FLAIR were determined. RESULTS： All 63 patients were included in the final analysis. The DAI diagnosis rates of FLAIR and T2-weighted images were 88% （21/24） and 62% （15/24）, respectively, of which the difference was statistically significant （P 〈 0.05）. T2-weighted images and FLAIR detected lesions located in the gray matter-white matter junction in parasagittal areas, the corpus callosum, deep periventricular white matter, basal ganglia, internal capsule, hippocampus, cerebellum, and brain stem, with a detailed amount of 123 and 256, respectively. FLAIR was significantly greater than T2-weighted images （P 〈 0.01）. CONCLUSION： FLAIR is superior to T2-weighted images for improving the DAI diagnostic rate and lesion-detecting rate, as well as revealing the extent and severity of DAI.

Diffusion tensor tractography characteristics of axonal injury in concussion/mild traumatic brain injury

The main advantage of diffusion tensor tractography is that it allows the entire neural tract to be evaluated.In addition,configurational analysis of reconstructed neural tracts can indicate abnormalities such as tearing,narrowing,or discontinuations,which have been used to identify axonal injury of neural tracts in concussion patients.This review focuses on the characteristic features of axonal injury in concussion or mild traumatic brain injury(m TBI)patients through the use of diffusion tensor tractography.Axonal injury in concussion(m TBI)patients is characterized by their occurrence in long neural tracts and multiple injuries,and these characteristics are common in patients with diffuse axonal injury and in concussion(m TBI)patients with axonal injury.However,the discontinuation of the corticospinal tract is mostly observed in diffuse axonal injury,and partial tearing and narrowing in the subcortical white matter are frequently observed in concussion(m TBI)patients with axonal injury.This difference appears to be attributed to the observation that axonal injury in concussion(m TBI)patients is the result of weaker forces than those producing diffuse axonal injuries.In addition,regarding the fornix,in diffuse axonal injury,discontinuation of the fornical crus has been frequently reported,but in concussion(m TBI)patients,many collateral branches form in the fornix in addition to these findings in many case studies.It is presumed that the impact on the brain in TBI is relatively weaker than that in diffuse axonal injury,and that the formation of collateral branches occurs during the fornix recovery process.Although the occurrence of axonal injury in multiple areas of the brain is an important feature of diffuse axonal injury,case studies in concussion(m TBI)have shown that axonal injury occurs in multiple neural tracts.Because axonal injury lesions in m TBI patients may persist for approximately 10 years after injury onset,the characteristics of axonal injury in concussion(m TBI)patients,which are reviewed and categorized in this review,are expected to serve as useful supplementary information in the diagnosis of axonal injury in concussion(m TBI)patients.

Brain-derived neurotrophic factor gene transfection promotes neuronal repair and neurite regeneration after diffuse axonal injury

This study sought to assess the potential of brain-derived neurotrophic factor （BDNF） to promote neuronal repair and regeneration in rats with diffuse axonal injury, and to examine the accompanying neurobiological changes. BDNF gene transfection reduced the severity of the pathological changes associated with diffuse axonal injury in cortical neurons of the frontal lobe and increased neurofilament protein expression. These findings demonstrate that BDNF can effectively promote neuronal repair and neurite regeneration after diffuse axonal injury.

The usefulness of diffusion tensor imaging in detection of diffuse axonal injury in a patient with head trauma

Diffuse axonal injury is the predominant mechanism of injuries in patients with traumatic brain injury. Neither conventional brain computed tomography nor magnetic resonance imaging has shown sufficient sensitivity in the diagnosis of diffuse axonal injury. In the current study, we attempted to demonstrate the usefulness of diffusion tensor imaging in the detection of lesion sites of diffuse axonal injury in a patient with head trauma who had been misdiagnosed as having a stroke. A 44-year-old man fell from a height of about 2 m. Brain magnetic resonance imaging （32 months after onset） showed leukomalactic lesions in the isthmus of the corpus callosum and the left temporal lobe. He presented with mild quadriparesis, intentional tremor of both hands, and trunkal ataxia. From diffusion tensor imaging results of 33 months after traumatic brain injury onset, we found diffuse axonal injury in the right corticospinal tract （centrum semiovale, pons）, both fomices （columns and crus）, and both inferior cerebellar peduncles （cerebellar portions）. We think that diffusion tensor imaging could be a useful tool in the detection of lesion sites of diffuse axonal injury in patients with head trauma.

The occurrence of diffuse axonal injury in the brain:associated with the accumulation and clearance of myelin debris

The accumulation of myelin debris may be a major contributor to the inlfammatory response after diffuse axonal injury. In this study, we examined the accumulation and clearance of myelin debris in a rat model of diffuse axonal injury. Oil Red O staining was performed on sections from the cerebral cortex, hippocampus and brain stem to identify the myelin debris. Seven days after diffuse axonal injury, many Oil Red O-stained particles were observed in the cerebral cortex, hippocampus and brain stem. In the cerebral cortex and hippocampus, the amount of myelin debris peaked at 14 days after injury, and decreased signiifcantly at 28 days. In the brain stem, the amount of myelin debris peaked at 7 days after injury, and decreased signiifcantly at 14 and 28 days. In the cortex and hippocampus, some myelin debris could still be observed at 28 days after diffuse axonal injury. Our ifndings suggest that myelin debris may persist in the rat central ner-vous system after diffuse axonal injury, which would hinder recovery.

Hippocampal expression of apoptotic protease activating factor-1 following diffuse axonal injury under mild hypothermia

The influence of mild hypothermia on neural cell apoptosis remains poorly understood. Therefore, the present study established rat models of diffuse axonal injury （DAI） at 33℃. Morris water maze results demonstrated significantly better learning and memory functions in DAI rats with hypothermia compared with DAI rats with normothermia. Expression of apoptotic protease activating factor-1 in the hippocampal CA1 region was significantly lower in the DAI hypothermia group compared with the DAI normothermia group. Expression of apoptotic protease activating factor-1 positively correlated with latency, but negatively correlated with platform location times and time of swimming in the quadrant area. Results suggested that post-traumatic mild hypothermia in a rat model of DAI could provide cerebral protection by attenuating expression of apoptotic protease activating factor-1.

Recovery of corticospinal tract injured by traumatic axonal injury at the subcortical white matter:a case report

The corticospinal tract （CST） is a major neural tract for mo- tor function in the human brain. In addition, CST is mainly concerned with execution of movement of the hand （Jang, 2014）. However, few studies are reported on the mecha- nism underlying CST recovery after traumatic brain injury （Seo and Jang, 2015）. In this study, we report on a case that showed recovery of an injured CST by traumatic axonal injury （TAI） at subcortical white matter, as detected on fol- low-up diffusion tensor tractography （DTT）.

Present status of studies on diffuse axonal injury

OBJECTIVE: To explain the present status of study on diffuse axonal injury, investigate its pathogenesis and pathophysiological changes, and suggest principles for the diagnosis and treatment. DATA SOURCES: Articles about diffuse axonal injury published in English from January 1994 to October 2006 were searched in Pubmed database using the of 'diffuse axonal injury, pathogenesis, therapy'. STUDY SELECTION: The collected articles were primarily screened to select those associated with diffuse axonal injury, the obviously irrelated articles were excluded, and the rest ones were retrieved manually, and the full-texts were searched. DATA EXTRACTION: Totally 98 articles were collected, 41 of them were involved, and the other 57 were excluded. DATA SYNTHESIS: Diffuse axonal injury is mainly caused by acceleratory or deceleratory injury, and its pathophysiological change is a progressive duration, local axonal injury finally develops to axonal breakage, mainly includes inactivation of natrium channel, intracellular Ca2+ overloading, activation of calcium protease, caspase, etc., and mitochondrial injury. At present, there is still lack of effective therapeutic methods for diffuse axonal injury, so we should actively explore more effective methods to relieve the pain of patients and improve their prognosis. CONCLUSION: At present, diffuse axonal injury has not attracted enough attentions in China, the mechanisms for its diagnosis and attack are still unclear, and the treatments are mainly aiming at the symptoms.

Animal model of repetitive mild traumatic brain injury for human traumatic axonal injury and chronic traumatic encephalopathy

Chronic traumatic encephalopathy（CTE）is a chronic neurodegenerative disease featured with tauopathy.CTE is tightly related with repetitive mild traumatic brain injury（m TBI）,which is interchangeably known as concussion（Mc Kee et al.,2009,2013）.This disease is differentiated by neuropathological features from other neurological diseases that involve tau protein aggregation and tangle formation abnormalities like Alzheimer＇s disease （AD）, frontotemporal dementia, and Parkinson- ism linked to chromosome 17 （FTDP-17）.

Observation on the Clinical Effect of Different Pressures in Hyperbaric Oxygen Therapy on Patients with Diffuse Axonal Injury

Objective:To observe the efficacy and significance of hyperbaric oxygen at different pressures in the treatment of diffuse axonal injury(DAI).Methods:Sixty patients with DAI were randomly divided into 1.8 ATA group(30 cases)and 2.2 ATA group(30 cases).The routine treatment for each group was the same.The 1.8 ATA.group received hyperbaric oxygen therapy under 1.8 ATA on the basis of routine treatment,whereas the 2.2 ATA group received hyperbaric oxygen therapy under 2.2 ATA.on the basis of routine treatment.The therapy was given once a day over 3 consecutive courses,with each course having 10 sessions.The Glasgow Coma Scale(GCS)on day 10,day 20,and day 30 after treatment,as well as the Glasgow Outcome Scale(GOS)after 6 months were compared between the two groups.Results:The mean GCS on day 10,day 20,and day 30 after treatment,as well as the mean GOS after 6 months of treatment in the 2.2 ATA group were significantly higher than those in the 1.8 ATA group(p<0.05).Conclusion:For patients with dififtise axonal injury,hyperbaric oxygen therapy is more effective with 2.2 ATA.compared with 1.8 ATA.

The Effects of Ultra-early Hyperbaric Oxygen Intervention in the Treatment of Diffuse Axonal Injury

Objective:To investigate the efficacy and mechanism of ultra-early hyperbaric oxygen intervention in the treatment of diffuse axonal injury(DAI).Methods:Eighty-six patients with diffuse axonal injury were selected and then divided into an ultra-early hyperbaric oxygen treatment group and a conventional treatment group with 43 patients in each group.The Glasgow Coma Scale(GCS)on the 10h day(10d),20h day(20d),and 30h day(30d)after treatment and the Glasgow Outcome Score(GOS)6 months later were observed and compared between both the groups.Results:The average score of the GCS at 10d,20d,and 30d as welll as the GOS 6 months later in the ultra-early hyperbaric oxygen treatment group were higher than those in the conventional treatment group(P<0.05).Conclusion:Hyperbaric oxygen therapy is one of the unique and effective methods in clinical treatment especially for the treatment of DAI patients and it is worthy of promotion.

Connecting cellular mechanisms and extracellular vesicle cargo in traumatic brain injury

Traumatic brain injury is followed by a cascade of dynamic and complex events occurring at the cellular level. These events include: diffuse axonal injury, neuronal cell death, blood-brain barrier break down, glial activation and neuroinflammation, edema, ischemia, vascular injury, energy failure, and peripheral immune cell infiltration. The timing of these events post injury has been linked to injury severity and functional outcome. Extracellular vesicles are membrane bound secretory vesicles that contain markers and cargo pertaining to their cell of origin and can cross the blood-brain barrier. These qualities make extracellular vesicles intriguing candidates for a liquid biopsy into the pathophysiologic changes occurring at the cellular level post traumatic brain injury. Herein, we review the most commonly reported cargo changes in extracellular vesicles from clinical traumatic brain injury samples. We then use knowledge from animal and in vitro models to help infer what these changes may indicate regrading cellular responses post traumatic brain injury. Future research should prioritize labeling extracellular vesicles with markers for distinct cell types across a range of timepoints post traumatic brain injury.