Journal of neurotrauma
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Journal of neurotrauma · Apr 2023
LDC7559 Exerts Neuroprotective Effects by Inhibiting GSDMD-dependent Pyroptosis of Microglia in Mice with Traumatic Brain Injury.
Abstract Pyroptosis is considered one of a critical factor in the recovery of neurological function following traumatic brain injury. Brain injury activates a molecular signaling cascade associated with pyroptosis and inflammation, including NLRP3, inflammatory cytokines, caspase-1, gasdermin D (GSDMD), and other pyroptosis-related proteins. In this study, we explored the neuroprotective effects of LDC7559, a GSDMD inhibitor. ⋯ The findings revealed that inflammation and pyroptosis levels were decreased by LDC7559 or si-GSDMD treatment both in vitro and in vivo. Immunofluorescence staining, brain water content, hematoxylin and eosin staining, and behavioral investigations suggested that LDC7559 or si-GSDMD inhibited microglial proliferation, ameliorated cerebral edema, reduced brain tissue loss, and promoted brain function recovery. Taken together, LDC7559 may inhibit pyroptosis and reduce inflammation by inhibiting GSDMD, thereby promoting the recovery of neurological function.
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Journal of neurotrauma · Apr 2023
Longitudinal Patterns of Functional Connectivity in Moderate-to-Severe Traumatic Brain Injury.
Longitudinal neuroimaging studies aid our understanding of recovery mechanisms in moderate-to-severe traumatic brain injury (TBI); however, there is a dearth of longitudinal functional connectivity research. Our aim was to characterize longitudinal functional connectivity patterns in two clinically important brain networks, the frontoparietal network (FPN) and the default mode network (DMN), in moderate-to-severe TBI. This inception cohort study of prospectively collected longitudinal data used resting-state functional magnetic resonance imaging (fMRI) to characterize functional connectivity patterns in the FPN and DMN. ⋯ Findings of early improvement but a tapering and possible decline in connectivity thereafter suggest that compensatory effects are time-limited. These later reductions in connectivity mirror growing evidence of behavioral and structural decline in chronic moderate-to-severe TBI. Targeting such declines represents a novel avenue of research and offers potential for improving clinical outcomes.
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Journal of neurotrauma · Apr 2023
Examining Suicidality in Adolescents Who Have Sustained Concussions.
Previous studies have reported an association between concussion and suicidality in high school students in the United States. When controlling for multiple life stressors in adolescence (e.g., bullying, substance use, poor grades), however, the relationship between concussion and suicidality was either attenuated or became non-significant in one study. Rather than assessing concussion as a possible risk factor for suicidality, this study examined predictors of ideation, planning, and attempts among youth who experienced concussion in the past year. ⋯ Among boys with prior year concussion, being bullied (OR = 2.29) and depression (OR = 9.50) predicted suicidal ideation. Additional models were used to examine the association between having one or more modifiable stressors and suicidality, revealing that having three or more modifiable stressors was associated with a substantial increase in proportions of youth reporting suicidality. Among adolescents experiencing a concussion, treating depression and substance use, stopping bullying, and increasing physical activity may be associated with reduced risk for suicidality.
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Journal of neurotrauma · Apr 2023
Effects of physical exertion on early changes in blood-based brain biomarkers: implications for the acute point of care diagnosis of concussion.
Blood-based brain biomarkers (BBM) such as glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) have potential to aid in the diagnosis of concussion. Recently developed point-of-care test devices would enable BBMs to be measured in field settings such military and sport environments within minutes of a suspicious head hit. However, head hits in these environments typically occur in the setting of vigorous physical exertion, which can itself increase BBMs levels. ⋯ Thus, exertion appeared to be associated with immediate decreases in serum GFAP and very acute (45 min) increases in UCH-L1. These changes were related to the duration of exertion, but not to changes in brain white matter integrity. Our results have important implications for how these BBMs might be used to aid in the on-scene diagnosis of concussion occurring in the setting of physical exertion.
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Journal of neurotrauma · Apr 2023
Innate and peripheral immune alterations after TBI are regulated in a gut microbiota-dependent manner in mice.
Traumatic brain injury (TBI) patients are at high risk for disruption of the gut microbiome. Previously, we have demonstrated that broad-spectrum antibiotic exposure after TBI drastically alters the gut microbiota and modulates neuroinflammation, neurogenesis, and long-term fear memory. However, these data did not determine if the impact of antibiotic exposure on the brain's response to injury was mediated directly by antibiotics or indirectly via modulation of the gut microbiota. ⋯ At 7 days post-injury, GF-VNAM had increased microglial activation, reduced infiltration of T cells, and decreased neurogenesis. Similarly, SPF mice exposed to antibiotics prior to but not after injury demonstrated similar alterations in neuroinflammation and neurogenesis compared with control mice. These data support our hypothesis implicating the gut microbiota as an important modulator of the neuroinflammatory process and neurogenesis after TBI and provide an exciting new approach for neuroprotective therapeutics for TBI.