Pathogenesis Of Diffuse Axonal Injury Research Articles

Myelin Damage in Diffuse Axonal Injury.

Diffuse axonal injury (DAI) is characterized by delayed axonal disconnection. Although the effect of DAI on axonal pathology has been well documented, there is limited information regarding the role of myelin in the pathogenesis of DAI. We used a modified Marmarou method to create a moderate DAI model in adult rat and examined the corpus callosum and brain stem for myelin pathology and dynamic glial responses to DAI. During the first week following DAI, Luxol Fast Blue staining and western blot analysis for MBP showed significant loss of myelin in the corpus callosum and the brain stem. Increased apoptosis of mature oligodendrocyte, as depicted by its marker CC-1, was observed. Conversely, there was an increased number of Olig2-positive cells accompanied by hypertrophic microglia/macrophage and mild reactive astrocytes. Electron microscopy revealed degenerating axons in the corpus callosum and marked myelin abnormalities in the brain stem in the early stage of DAI. Brain stem regions exhibited myelin intrusions or external protrusions with widespread delamination and myelin collapse, leading to degeneration of accompanying axons. Our results show distinct pathologic processes involving axon and myelin between the corpus callosum and the brain stem in DAI. Oligodendrocyte selective vulnerability and subsequent demyelination may contribute to axonal degeneration in the brain stem. Defining the cause of ongoing oligodendrocyte death and promoting myelin regeneration may provide important targets for therapeutic interventions of DAI.

1G42 伸長方向制御した神経軸索の衝撃引張ひずみ耐性評価

Traumatic brain injury caused by traffic accidents, blow, falls and contact sports, is an important public health problem. Diffuse Axonal Injury (DAI) shows a symptom of no consciousness without either cerebral contusion or hematoma. It is thought that DAI is occurred at the damage of the cell level within the brain widely. However, the pathogenesis of DAI is not yet fully clarified, and the effective diagnosis and cure are not established. The ultimate goal in this study is to clarify the threshold for neuronal damage DAI at the cell level of the brain. Therefore, we exposed axons in cultured neuronal cells to the impulsive strain and the effect of the impulsive strain on axonal injury was evaluated at the cell level. Neural stem cells (NSCs) were used as cultured neuronal cells. NSCs can be proliferate and differentiate into neurons and glia. When cultured in medium, NSCs extend the axons towards any direction. However, the in vivo neuronal cells of the human have a characteristic of the orientation. Therefore, the direction of axons growth is controlled by using micro grooves which matched with the size of the cell. Culture surface is used by micro grooves on polydimethylsiloxane (PDMS). It is transcribed from micro groove were generated by using photolithography on resist material (SU8) and the Si substrate. This study has investigated the effects of impulsive strain on axons in cultured neurons differentiated from NSCs.

Chronic upregulation of activated microglia immunoreactive for galectin-3/Mac-2 and nerve growth factor following diffuse axonal injury

BackgroundDiffuse axonal injury in patients with traumatic brain injury (TBI) can be associated with morbidity ranging from cognitive difficulties to coma. Magnetic resonance imaging scans now allow early detection of axonal injury following TBI, and have linked cognitive disability in these patients to white matter signal changes. However, little is known about the pathophysiology of this white matter injury, and the role of microglial activation in this process. It is increasingly recognized that microglia constitute a heterogeneous population with diverse roles following injury. In the present studies, we tested the hypothesis that following diffuse axonal injury involving the corpus callosum, there is upregulation of a subpopulation of microglia that express the lectin galectin-3/Mac-2 and are involved in myelin phagocytosis.MethodsAdult mice were subject to midline closed skull injury or sham operation and were sacrificed 1, 8, 14 or 28 days later. Immunohistochemistry and immunofluorescence techniques were used to analyze patterns of labelling within the corpus callosum qualitatively and quantitatively.ResultsActivated microglia immunoreactive for galectin-3/Mac-2 were most abundant 1 day following injury. Their levels were attenuated at later time points after TBI but still were significantly elevated compared to sham animals. Furthermore, the majority of galectin-3/Mac-2+ microglia were immunoreactive for nerve growth factor in both sham and injured animals.ConclusionsOur results suggest that galectin-3/Mac-2+ microglia play an important role in the pathogenesis of diffuse axonal injury both acutely and chronically and that they mediate their effects, at least in part by releasing nerve growth factor.

Both MK801 and NBQX reduce the neuronal damage after impact-acceleration brain injury.

To understand the pathogenesis of diffuse axonal injury, we investigated the temporal and spatial profiles of neuronal degeneration in impact-acceleration injury in rats using Fluoro-Jade (FJ) staining. Impact-acceleration injury was produced in Wistar rats by the method described by Marmarou et al. with some modifications. Animals were sacrificed 1, 2, 7, 14, or 28 days after injury. Paraffin-embedded coronal sections were stained with HE or FJ, or analyzed immunohistochemically for GFAP or amyloid precursor protein (APP). FJ-positive degenerative neurons were found primarily in the dorsal brainstem and thalamus from 1 to 2 days following injury and these were associated with GFAP expression. However, FJ-positive cells were rarely found after 7 days. In all rats, significant expression of APP was observed primarily in the cingulum, cerebral peduncle and pontomedullary junction. FJ also stained these injured axons. Intrathecal administration of both NMDA and AMPA/kinate glutamate receptor antagonists MK-801 and NBQX, respectively, reduced the neuronal injury. NBQX showed more significant effects on axonal injury than MK-801. These observations indicate that not only axonal damage, but also primary neuronal damage occurs in this impact-acceleration injury model. It is also suggested that NBQX can act both directly on neuronal cells and white matter and that NMDA could have a significant protective effect against not only neuronal, but also axonal injury.