Progressive Neurodegeneration After Experimental Brain Trauma

Abstract

Recent clinical studies indicate that traumatic brain injury (TBI) produces chronic and progressive neurodegenerative changes leading to late neurological dysfunction but little is known about the mechanisms underlying such changes. Microglial-mediated neuroinflammation is an important secondary injury mechanism after TBI. In human studies, microglial activation has been found to persist for many years after the initial brain trauma, particularly after moderate-to-severe TBI. In the present study, adult C57Bl/6 mice were subjected to single moderate-level controlled cortical impact and were followed up by longitudinal T2-weighted magnetic resonance imaging in combination with stereological histological assessment of lesion volume expansion, neuronal loss and microglial activation for up to 1 year after TBI. Persistent microglial activation was observed in the injured cortex through 1 year post-injury, and was associated with progressive lesion expansion, hippocampal neurodegeneration, and loss of myelin. Notably, highly activated microglia that expressed major histocompatibility complex class II (CR3/43), CD68 and NADPH oxidase (NOX2) were detected at the margins of the expanding lesion at 1 year post-injury; biochemical markers of neuroinflammation and oxidative stress were significantly elevated at this time point. These data support emerging clinical TBI findings and provide a mechanistic link between TBI-induced chronic microglial activation and progressive neurodegeneration.

Acute Reduction of Microglia Does Not Alter Axonal Injury in a Mouse Model of Repetitive Concussive Traumatic Brain Injury

“…Other studies may also address the effect of microglial reduction in more-severe brain injury, where the role of microglial cells may be distinct. 53,54 A technical note regarding the toxicity of valganciclovir in CD11b-TK mice warrants discussion. It was surprising that valganciclovir administration at intermediate and high doses produced such widespread tissue loss in CD11b-TK mice.…”

Repeated mild traumatic brain injury: potential mechanisms of damage

“…181 TBI-induced release of astrocytederived ATP triggers microglial recruitment. 175 Microglia proliferate and infiltrate toward the injury site, phagocytosing necrotic tissue, cellular debris, and toxic substances, 182 with the time course dependent upon the nature of injury. 183 Also depending on the nature of the TBI, microglia upregulate cell surface marker expression, enhance pro-inflammatary cytokines (interleukin [IL]-1b, IL-6, and TNF-a) and oxidative metabolites (NO, ROS) release and increase protease secretion, thereby exacerbating oxidative stress, neuroinflammation, and axonal pathology.…”

“…183 Also depending on the nature of the TBI, microglia upregulate cell surface marker expression, enhance pro-inflammatary cytokines (interleukin [IL]-1b, IL-6, and TNF-a) and oxidative metabolites (NO, ROS) release and increase protease secretion, thereby exacerbating oxidative stress, neuroinflammation, and axonal pathology. 184 Sustained microglial activation and chronic inflammatory states contribute significantly to the spread of secondary degeneration, 185 playing a pivotal role in long-term and progressive axonal injury, neurodegeneration and neurological impairments 155,180,182,186,187 via mechanisms that include lipid peroxidation and apoptosis. 185,188 Indeed, there is increasing evidence of chronic microglial activation in the cortex, corpus callosum (CC), and thalamus up to 1 y after injury following moderate-severe TBI.…”

Acute or Delayed Treatment with Anatabine Improves Spatial Memory and Reduces Pathological Sequelae at Late Time-Points after Repetitive Mild Traumatic Brain Injury

“…15,16 In mice, chronic microglial activation in combination with progressive lesion expansion has been seen after moderate cortical injury up to 1 year after TBI and up to at least a month after mild closed head injury. 17,18 Our strategy has been to target neuroinflammation in the hope of reducing secondary injury and improving the neuropathological and behavioral outcomes after TBI.…”