Chondroitin sulfate proteoglycans (CSPGs) play a pivotal role in many neuronal growth mechanisms including axon guidance and the modulation of repair processes following injury to the spinal cord or brain. Many actions of CSPGs in the central nervous system (CNS) are governed by the specific sulfation pattern on the glycosaminoglycan (GAG) chains attached to CSPG core proteins. To elucidate the role of CSPGs and sulfated GAG chains following traumatic brain injury (TBI), controlled cortical impact injury of mild to moderate severity was performed over the left sensory motor cortex in mice. Using immunoblotting and immunostaining, we found that TBI resulted in an increase in the CSPGs neurocan and NG2 expression in a tight band surrounding the injury core, which overlapped with the presence of 4-sulfated CS GAGs but not with 6-sulfated GAGs. This increase was observed as early as 7 days post injury (dpi), and persisted for up to 28 dpi. Labeling with markers against microglia/macrophages, NG2+ cells, fibroblasts, and astrocytes showed that these cells were all localized in the area, suggesting multiple origins of chondroitin-4-sulfate increase. TBI also caused a decrease in the expression of aggrecan and phosphacan in the pericontusional cortex with a concomitant reduction in the number of perineuronal nets. In summary, we describe a dual response in CSPGs whereby they may be actively involved in complex repair processes following TBI.
"Treatment approaches including exercises that enhance endogenous BDNF have the potential to restore neural connectivity and functional recovery , . In addition, chondroitin sulfate proteoglycans (CSPGs) play a pivotal role in many neuronal growth mechanisms following injury to the spinal cord or brain . tPA/plasmin degrades CSPGs including neurocan and phosphacan in the brain and promotes neurite reorganization after seizures . "
[Show abstract][Hide abstract] ABSTRACT: Traumatic brain injury (TBI) is a major cause of death and long-term disability worldwide. To date, there are no effective pharmacological treatments for TBI. Recombinant human tissue plasminogen activator (tPA) is the effective drug for the treatment of acute ischemic stroke. In addition to its thrombolytic effect, tPA is also involved in neuroplasticity in the central nervous system. However, tPA has potential adverse side effects when administered intravenously including brain edema and hemorrhage. Here we report that tPA, administered by intranasal delivery during the subacute phase after TBI, provides therapeutic benefit. Animals with TBI were treated intranasally with saline or tPA initiated 7 days after TBI. Compared with saline treatment, subacute intranasal tPA treatment significantly 1) improved cognitive (Morris water maze test) and sensorimotor (footfault and modified neurological severity score) functional recovery in rats after TBI, 2) reduced the cortical stimulation threshold evoking ipsilateral forelimb movement, 3) enhanced neurogenesis in the dentate gyrus and axonal sprouting of the corticospinal tract originating from the contralesional cortex into the denervated side of the cervical gray matter, and 4) increased the level of mature brain-derived neurotrophic factor. Our data suggest that subacute intranasal tPA treatment improves functional recovery and promotes brain neurogenesis and spinal cord axonal sprouting after TBI, which may be mediated, at least in part, by tPA/plasmin-dependent maturation of brain-derived neurotrophic factor.
PLoS ONE 09/2014; 9(9):e106238. DOI:10.1371/journal.pone.0106238 · 3.23 Impact Factor
"The dura was impacted using an Impact One™ Stereotaxic Impactor device (Leica Biosystems; Buffalo Grove, IL) at 1.5 mm lateral (right hemisphere) to bregma using a tip diameter of 2 mm, a depth of 1 mm, a velocity of 1.5 m/s, and a dwell time of 100 ms. These parameters and the resulting cortical damage are classified as a mild form of the CCI model (Washington et al., 2012; Yi et al., 2012). The cortical cavitation does not extend down into the corpus callosum, but callosal cortical neurons are involved along with the corresponding axons in the corpus callosum. "
[Show abstract][Hide abstract] ABSTRACT: The regenerative capacity of the central nervous system must be optimized to promote repair following traumatic brain injury (TBI) and may differ with the site and form of damage. Sonic hedgehog (Shh) maintains neural stem cells and promotes oligodendrogenesis. We examined whether Shh signaling contributes to neuroblast (doublecortin) or oligodendrocyte progenitor (neural/glial antigen 2 [NG2]) responses in two distinct TBI models. Shh-responsive cells were heritably labeled in vivo using Gli1-CreER(T2);R26-YFP bitransgenic mice with tamoxifen administration on Days 2 and 3 post-TBI. Injury to the cerebral cortex was produced with mild controlled cortical impact. Yellow fluorescent protein (YFP) cells decreased in cortical lesions. Total YFP cells increased in the subventricular zone (SVZ), indicating Shh pathway activation in SVZ cells, including doublecortin-labeled neuroblasts. The alternate TBI model produced traumatic axonal injury in the corpus callosum. YFP cells decreased within the SVZ and were rarely double labeled as NG2 progenitors. NG2 progenitors increased in the cortex, with a similar pattern in the corpus callosum. To further test the potential of NG2 progenitors to respond through Shh signaling, Smoothened agonist was microinjected into the corpus callosum to activate Shh signaling. YFP cells and NG2 progenitors increased in the SVZ but were not double labeled. This result indicates that either direct Smoothened activation in NG2 progenitors does not signal through Gli1 or that Smoothened agonist acts indirectly to increase NG2 progenitors. Therefore, in all conditions, neuroblasts exhibited differential Shh pathway utilization compared with oligodendrocyte progenitors. Notably, cortical versus white matter damage from TBI produced opposite responses of Shh-activated cells within the SVZ.
"Mice were anesthetized with isoflurane (4% for induction, 2–3% for maintenance) and securely positioned in a mouse stereotaxic frame (Stoelting Co). Surgery was performed as described previously (Villapol et al., 2012; Yi et al., 2012). Briefly, an incision was made over the forehead, and the scalp was reflected to expose the skull. "
[Show abstract][Hide abstract] ABSTRACT: Traumatic brain injury triggers an inflammatory cascade, gliosis and cell proliferation following cell death in the pericontusional area and surrounding the site of injury. In order to better understand the proliferative response following controlled cortical impact (CCI) injury, we systematically analyzed the phenotype of dividing cells at several time points post-lesion. C57BL/6 mice were subjected to mild CCI over the left sensory motor cortex. At different time points following injury, mice were injected with BrdU four times at 3-hour intervals and then sacrificed. The greatest number of proliferating cells in the pericontusional region was detected at 3 days post-injury (dpi). At 1 dpi, NG2+ cells were the most proliferative population, and at 3 and 7 dpi the Iba-1+ microglial cells were proliferating more. A smaller, but significant number of GFAP+ astrocytes proliferated at all three time points. Interestingly, at 3 dpi we found a small number of proliferating neuroblasts (DCX+) in the injured cortex. To determine the cell fate of proliferative cells, mice were injected four times with BrdU at 3 dpi and sacrificed at 28 dpi. Around 70% of proliferative cells observed at 28dpi were GFAP+ astrocytes. These data suggest either that other proliferating cell types differentiate into astrocytes after injury, or that astrocytes retain their BrdU to a greater extent than other cell types due to a cessation of proliferation. In conclusion, different glial cell types respond differentially to injury, suggesting that each cell type responds to a specific pattern of growth factor stimulation at each time point after injury.
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