Abstract
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.
Highlights
Diffuse axonal injury (DAI) is one of the most common and important pathologic features of traumatic brain injury (TBI), which affects millions of people worldwide (Ma et al, 2016)
Squares show regions of interest (ROIs) focused on the corpus callosum (CC) and brain stem evaluated in the present study (Figure 1A)
DAI rats had a disorganized myelin stained with Luxol fast blue (LFB) (Figures 1B–D)
Summary
Diffuse axonal injury (DAI) is one of the most common and important pathologic features of traumatic brain injury (TBI), which affects millions of people worldwide (Ma et al, 2016). Development of pathological changes in axons following DAI has been well documented including delayed axotomy caused by both initial mechanical force and complex secondary cascade (Vargas and Barres, 2007; Johnson et al, 2013; Jang and Kwon, 2016). There is, limited information regarding the role of myelin and oligodendrocyte in DAI. Oligodendrocytes, as the primary cells responsible for generating and maintaining the myelin sheath, are highly vulnerable to various stimuli, including excitotoxicity, oxidative stress, and inflammation (Bradl and Lassmann, 2010). As all the aforementioned stimuli are features of secondary cascade in DAI, it is expected that DAI has an influence on oligodendrocytes and further cause myelin loss
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