"After the experiment, the cultures were fixed in 4% paraformaldehyde and permeated using 0.2% Triton X-100 in PBS for 10 min, as previously described , . The background staining was reduced by blocking nonspecific binding sites with 10% goat serum for 1 h at RT. "
[Show abstract][Hide abstract] ABSTRACT: In response to acute insults to the central nervous system, such as pathogen invasion or neuronal injuries, glial cells become activated and secrete inflammatory mediators such as nitric oxide (NO), cytokines, and chemokines. This neuroinflammation plays a crucial role in the pathophysiology of chronic neurodegenerative diseases. Endogenous ascorbate levels are significantly decreased among patients with septic encephalopathy. Using the bacterial endotoxin lipopolysaccharide (LPS) to induce neuroinflammation in primary neuron/glia cocultures, we investigated how L-ascorbate (vitamin C; Vit. C) affected neuroinflammation. LPS (100 ng/ml) induced the expression of inducible NO synthase (iNOS) and the production of NO, interleukin (IL)-6, and macrophage inflammatory protein-2 (MIP-2/CXCL2) in a time-dependent manner; however, cotreatment with Vit. C (5 or 10 mM) attenuated the LPS-induced iNOS expression and production of NO, IL-6, and MIP-2 production. The morphological features revealed after immunocytochemical staining confirmed that Vit. C suppressed LPS-induced astrocytic and microglial activation. Because Vit. C can be transported into neurons and glia via the sodium-dependent Vit. C transporter-2, we examined how Vit. C affected LPS-activated intracellular signaling in neuron/glia cocultures. The results indicated the increased activation (caused by phosphorylation) of mitogen-activated protein kinases (MAPKs), such as p38 at 30 min and extracellular signal-regulated kinases (ERKs) at 180 min after LPS treatment. The inhibition of p38 and ERK MAPK suppressed the LPS-induced production of inflammatory mediators. Vit. C also inhibited the LPS-induced activation of p38 and ERK. Combined treatments of Vit. C and the inhibitors of p38 and ERK yielded no additional inhibition compared with using the inhibitors alone, suggesting that Vit. C functions through the same signaling pathway (i.e., MAPK) as these inhibitors. Vit. C also reduced LPS-induced IκB-α degradation and NF-κB translocation. Thus, Vit. C suppressed the LPS-stimulated production of inflammatory mediators in neuron/glia cocultures by inhibiting the MAPK and NF-κB signaling pathways.
PLoS ONE 07/2014; 9(7):e97276. DOI:10.1371/journal.pone.0097276 · 3.23 Impact Factor
"While these effects can be accounted for by acute/sub-acute injury mechanisms and their pathological consequences, given the above observations, neuroinflammatory and neurodegenerative processes may extend for years beyond the initial post-injury injury time frame in the TBI patient. These more chronic effects do set the stage for important interactions that occur between the age at the time of injury, aging and age-related vulnerabilities, to later in life neuropsychiatric and progressive neurodegenerative disorders indicating that the lesion in TBI may be much more dynamic (Bigler, 2013). The frontotemporolimbic locus of where TBI induced degenerative changes are most likely to occur in the brain, has a most interesting overlap with brain areas observed in older individuals with increased risk for a variety of age-related neurological and neuropsychiatric disorders. "
[Show abstract][Hide abstract] ABSTRACT: Depending on severity, traumatic brain injury (TBI) induces immediate neuropathological effects that in the mildest form may be transient but as severity increases results in neural damage and degeneration. The first phase of neural degeneration is explainable by the primary acute and secondary neuropathological effects initiated by the injury; however, neuroimaging studies demonstrate a prolonged period of pathological changes that progressively occur even during the chronic phase. This review examines how neuroimaging may be used in TBI to understand (1) the dynamic changes that occur in brain development relevant to understanding the effects of TBI and how these relate to developmental stage when the brain is injured, (2) how TBI interferes with age-typical brain development and the effects of aging thereafter, and (3) how TBI results in greater frontotemporolimbic damage, results in cerebral atrophy, and is more disruptive to white matter neural connectivity. Neuroimaging quantification in TBI demonstrates degenerative effects from brain injury over time. An adverse synergistic influence of TBI with aging may predispose the brain injured individual for the development of neuropsychiatric and neurodegenerative disorders long after surviving the brain injury.
Frontiers in Human Neuroscience 08/2013; 7:395. DOI:10.3389/fnhum.2013.00395 · 2.99 Impact Factor
"It is a heterogeneous phenomenon due to variability in the cause network involving the frontal cortex , BG and thalamus ( Frank , Scheres , & Sherman , 2007 ) . After TBI , the survival and / or reorganization of neural networks is likely to determine a patient ' s recovery potential ( Bigler , 2013 ) . Neural networks depend on structural integrity , and therefore structural analysis should feature when ac - counting for executive function deficits after TBI . "
[Show abstract][Hide abstract] ABSTRACT: Traumatic brain injury (TBI) is associated with neuronal loss, diffuse axonal injury and executive dysfunction. Whereas executive dysfunction has traditionally been associated with prefrontal lesions, ample evidence suggests that those functions requiring behavioral flexibility critically depend on the interaction between frontal cortex, basal ganglia and thalamus.
To test whether structural integrity of this fronto-striato-thalamic circuit can account for executive impairments in TBI we automatically segmented the thalamus, putamen and caudate of 25 patients and 21 healthy controls and obtained diffusion weighted images. We assessed components of executive function using the local-global task, which requires inhibition, updating and switching between actions.
Shape analysis revealed localized atrophy of the limbic, executive and rostral-motor zones of the basal ganglia, whereas atrophy of the thalami was more global in TBI. This subcortical atrophy was related to white matter microstructural organization in TBI, suggesting that axonal injuries possibly contribute to subcortical volume loss. Global volume of the nuclei showed no clear relationship with task performance. However, the shape analysis revealed that participants with smaller volume of those subregions that have connections with the prefrontal cortex and rostral motor areas showed higher switch costs and mixing costs, and made more errors while switching. These results support the idea that flexible cognitive control over action depends on interactions within the fronto-striato-thalamic circuit.
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