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Ophthalmic examinations of 55 retired boxers showed nine eyes with contusion angle deformities and no cases of secondary glaucoma due to the trauma, despite an average duration of 33 years since injury. The subjects with chamber angle recessions had more proptotic eyes (average, 19.7 mm) than those without recessions (average, 17.9 mm). The difference between the means was not significant (P less than .05).
After injury in the adult central nervous system, invading and intrinsic cells contribute to the formation of a lesion site that is refractory to axonal growth. To test the hypothesis that the inflammatory response to trauma dictates the extent of axonal growth after spinal cord injury, the time course of lesion evolution was compared in two mouse strains with contrasting cellular responses to peripheral inflammatory challenge. Adult C57Bl/6 and 129X1/SvJ mice received identical contusion injuries to the mid-thoracic spinal cord and were allowed to recover for 6 hours to 9 weeks. Both strains responded with a rapid, transient increase in chemokine expression, but the magnitude of this early response was slightly reduced in the 129X1/SvJ mice. Morphological indicators of inflammation were similar during the first week postinjury. After 7 days postinjury, however, the cellular responses differed between strains. The C57Bl/6 lesion core was chronically occupied by macrophages, devoid of astrocytes, and contained few axonal profiles. In contrast, as the macrophage density decreased a network of astrocytic processes and axons of central and peripheral origin invaded the center of the lesion site in 129X1Sv/J mice. Growth of axons in the 129X1Sv/J mice was accompanied by increased extravascular laminin in the lesion core and a reduced expression of chondroitin sulfate proteoglycan glycosaminoglycan sidechains in the periphery of the lesion. These results demonstrate that the diminished chronic inflammatory response in 129X1/SvJ mice is associated with enhanced cellular repair and increased axonal growth after spinal cord injury.
Susceptibility to neuroinflammatory disease is influenced in part by genetics. Recent data indicate that survival of traumatized neurons is strain dependent and influenced by polygenic loci that control resistance/susceptibility to experimental autoimmune encephalomyelitis (EAE), a model of CNS autoimmune disease. Here, we describe patterns of neurodegeneration and intraparenchymal inflammation after traumatic spinal cord injury (SCI) in mice known to exhibit varying degrees of EAE susceptibility [EAE-resistant (r) or EAE-susceptible (s) mice]. Spinal cords from C57BL/6 (EAE-s), C57BL/10 (EAE-r), BALB/c (EAE-r), and B10.PL (EAE-s) mice were prepared for stereological and immunohistochemical analysis at 6 hours or 3, 7, 14, 28, or 42 days following midthoracic (T9) spinal contusion injury. In general, genetic predisposition to EAE predicted the magnitude of intraparenchymal inflammation but not lesion size/length or locomotor recovery. Specifically, microglia/macrophage activation, recruitment of neutrophils and lymphocytes, and de novo synthesis of MHC class II were greatest in C57BL/6 mice and least in BALB/c mice at all times examined. However, lesion volume and axial spread of neurodegeneration were similar in C57BL/6 and BALB/c mice and were significantly greater than in C57BL/10 or B10.PL mice. Strains with marked intraspinal inflammation also developed the most intense lesion fibrosis. Thus, strain-dependent neuroinflammation was observed after SCI, but without a consistent relationship to EAE susceptibility or lesion progression. Only in C57BL/6 mice was the magnitude of intraspinal inflammation predictive of secondary neurodegeneration, functional recovery, or fibrosis.
In the development of the CNS, radial glial cells are among the first cells derived from neuroepithelial cells. Recent studies have reported that radial glia possess properties of neural stem cells. We analyzed the antigen expression and distribution of radial glia after spinal cord injury (SCI). Sprague-Dawley rats had a laminectomy at Th11-12, and spinal cord contusion was created by compression with 30 g of force for 10 min. In the injury group, rats were examined at 24 h and 1, 4, and 12 weeks after injury. Frozen sections of 20-microm thickness were prepared from regions 5 and 10 mm rostral and caudal to the injury epicenter. Immunohistochemical staining was performed using antibodies to 3CB2 (a specific marker for radial glia), nestin, and glial fibrillary acidic protein (GFAP). At 1 week after injury, radial glia that bound anti-3CB2 MAb had spread throughout the white matter from below the pial surface. From 4 weeks after injury, 3CB2 expression was also observed in the gray matter around the central canal, and was especially strong around the ependymal cells and around blood vessels. In double-immunohistochemical assays for 3CB2 and GFAP or 3CB2 and nestin, coexpression was observed in subpial structures that extended into the white matter as arborizing processes and around blood vessels in the gray matter. The present study demonstrated the emergence of radial glia after SCI in adult mammals. Radial glia derived from subpial astrocytes most likely play an important role in neural repair and regeneration after SCI.
Spinal cord injury (SCI) involves the loss of neurons and glia due to initial mechanical and secondary biochemical mechanisms. Treatment with the sodium channel blocker tetrodotoxin (TTX) reduces acute white matter pathology and increases both axon density and hindlimb function chronically at 6 weeks after injury. We investigated the cellular composition of residual white matter chronically to determine whether TTX also has a significant effect on the numbers and types of cells present. Rats received an incomplete thoracic contusion injury, in the presence or absence of TTX (0.15 nmole) injected focally, beginning at 15 min prior to injury. Six weeks later, cell density was significantly increased in the residual white matter of the dorsal, lateral, and ventral funiculi, both rostral and caudal to the injury site in both TTX-treated and injury control groups. Oligodendrocyte and astrocyte density was similar to normal but large numbers of cells expressing microglia/macrophage markers were present. Labeling with the progenitor markers nestin and NG2 showed that precursor cell density had also doubled or tripled as compared with uninjured controls. Some of these cells were also labeled for antigens that indicate their possible progression along an oligodendrocyte or astrocyte lineage. Our results support the hypothesis that the beneficial effect of TTX in SCI is related to its preservation of axons per se; no effect on chronic white matter cell composition was detected. They highlight the profound changes in cellular composition in preserved white matter chronically at 6 weeks after injury, including the accumulation of endogenous progenitor cells and the persistence of activated macrophages/microglia. The manipulation of these endogenous cells may be used in the future to enhance recovery after SCI.
After spinal cord injury (SCI), about 50% of the oligodendrocytes and astrocytes in the residual white matter at the injury site are lost by 24 h. However, chronically after SCI, the density of oligodendrocytes is normal. Previous studies have shown that the adult rat spinal cord contains a pool of proliferating glial progenitors whose progeny could help restore cell density after injury. To study proliferation in response to injury, we performed SCI on adult female rats at the T8 level, using a standardized contusion model. Animals received bromodeoxyuridine (BrdU) injections during the first week after SCI, and were perfused within 2 h for acute studies, and at 6 weeks for chronic studies. The tissue was analyzed using immunohistochemical detection of BrdU and cell marker antigens. We demonstrate that cell proliferation in the residual white matter is increased at 1-7 days after SCI, peaking on day 3. Dividing cells include oligodendrocytes, astrocytes, microglia/macrophages, and a high proportion of NG2(+) glial precursors. By 6 weeks, some cells that had been labeled 2-4 days after SCI were still present. Double immunohistochemistry showed that while very few of these cells expressed NG2 or the microglia/macrophage marker OX42, about 50% expressed CC1 or glial fibrillary acidic protein (GFAP), markers of mature oligodendrocytes and astrocytes, respectively. The post-injury environment represented by residual white matter is thus permissive to the differentiation of glial precursors. Cells that are stimulated to divide during the first week after SCI develop chronically into mature phenotypes that replace macroglia lost after injury.
Spinal cord injury (SCI) leads to a complex sequence of cellular responses, including astrocyte activation, oligodendrocyte death, and ependymal cell proliferation. Inhibitors of DNA binding (Id1, Id2, Id3) belong to a helix-loop-helix (HLH) gene family. Id genes have been implicated in playing a vital role in the proliferation of many cell types, including astrocytes and myoblasts. In the present study, the expression of Id family members in spinal cord after contusion injury was investigated by in situ hybridization. Id1, Id2, and Id3 mRNA expression was upregulated 5 mm rostral and caudal to the lesion center, and reached maximal levels 3 days after SCI. In addition, cell populations expressing Id1, Id2, and Id3 mRNA were maximally increased 3 days after SCI. The increase in Id2 and Id3 mRNA expression and Id2 and Id3 mRNA+ cells was still observed at 8 days. The Id mRNA expressing cells were phenotyped by combining immunostaining of cell-specific markers with in situ hybridization. Glial fibrillary acidic protein (GFAP)+ astrocytes were found to express all three Id mRNA, whereas S-100alpha+ astrocytes only expressed high levels of Id2 and Id3 mRNA. Cells having a neural progenitor morphology and the marker nestin appeared after SCI and they expressed Id1, Id2, and Id3 mRNA. Interestingly, some Rip+ oligodendrocytes located in the areas close to the central canal expressed Id3 mRNA after injury. In conclusion, Id genes are upregulated in a time-dependent manner in astrocytes, oligodendrocytes, and neural progenitor subpopulations after SCI, suggesting that they play major roles in cellular responses following SCI.
Injury of the spinal cord leads to an inflammatory tissue response, probably mediated in part by cytokines. Because a common therapy for acute spinal cord injury is the use of an antiinflammatory synthetic glucocorticoid (methylprednisolone), we sought to determine mechanisms contributing to inflammation shortly after acute injury. Cytokine mRNAs [interleukin (IL)-1alpha, IL-1beta, tumor necrosis factor (TNF)-alpha, and IL-6] were increased during the first 2 hr following weight-drop compression injury by RNase protection assay, prior to the reported appearance of circulating lymphocytes. This immediate pattern of cytokine mRNA induction could be replicated in cultured, explanted spinal cord slices but not in whole blood of injured animals, which is consistent with a tissue source of cytokine mRNAs. Western blotting detected IL-1beta-like immunoreactivity released into culture medium following explantation and pro-IL-1beta-like immunoreactivity in freshly dissected spinal cord tissue. Pharmacologically blocking IL-1 and TNF-alpha receptors significantly reduced expression of IL-1alpha, IL-1beta, and TNF-alpha mRNAs. Finally, mice lacking both IL-1 and TNF-alpha receptors exhibited diminished induction of TNF-alpha, IL-6, and IL-1ra mRNAs following injury. Therefore, we conclude that contusion injury induces an immediate release of cytokines, which then contributes to the induction of cytokine mRNAs.
The neurosteroid dehydroepiandrosterone (DHEA) has neuroprotective properties after ischemic and excitatory insults to the brain. In the developing embryo, it is produced in discrete regions of the central nervous system (CNS), where it specifically promotes axonal growth of differentiated neurons. To test if DHEA could be beneficial after spinal cord injury (SCI), we used a model of moderate contusive SCI developed and characterized in the mouse. Immediately after surgery, we applied treatment with DHEA or with vehicle only and compared treatment groups (n = 12 in each group) over a 42-day period. Locomotor recovery was assessed in an open field using a standardized 21-point scale, according to gait analysis on paw print recordings and using foot fault analyses on an inclined ladder beam. The DHEA-treated group showed improved function compared to vehicle-treated animals in these tests. More strikingly, DHEA enhanced recovery of left-right coordination and fine motor control. In an attempt to correlate functional recovery with spinal cord neuropathology in the different experimental groups, we studied the area of spared white matter at the epicenter and reactive gliosis/scar formation 42 days post-injury (DPI). DHEA significantly increased the area of white matter spared at the epicenter and reduced the area of reactive gliosis surrounding the lesion. These data demonstrate the effectiveness of DHEA in promoting functional recovery in the adult murine injured spinal cord.
Neurotrophins function through high-affinity tyrosine kinase (Trk) receptors to promote growth and survival of cells in the injured nervous system. To investigate the role of Trk receptors in the adult nervous system, we examined TrkA, TrkB, and TrkC mRNA expression in spinal cord and brain after spinal contusion. At 1 day postinjury, all Trk receptor transcripts were down regulated at and around the site of injury, a situation that persisted through the first week. By 42 days, Trk expression was absent only within the cavity. In addition, truncated TrkB expression was substantially increased in ependymal cells and astrocytes surrounding the lesion cavity of chronically injured spinal cords. Rostral and caudal to the injury site, TrkA, TrkB, and TrkC mRNA expression did not differ from that of uninjured control spinal cords. Furthermore, no changes were observed in TrkB or TrkC expression in the axotomized corticospinal and rubrospinal neurons. These studies suggest that loss of Trk receptors at the injury site may contribute to the early progressive cellular loss in injured spinal cords, while increased presence of truncated TrkB receptors in the chronic injured spinal cord may sequester and restrict BDNF availability to support axonal regeneration and neuronal survival. The persistence of Trk receptors on supraspinal neurons suggests that neurotrophin application can support growth and survival in the acute and chronic injury states.
The secondary loss of neurons and glia over the first 24 h after spinal cord injury (SCI) contributes to the permanent functional deficits that are the unfortunate consequence of SCI. The progression of this acute secondary cell death in specific neuronal and glial populations has not previously been investigated in a quantitative manner. We used a well-characterized model of SCI to analyze the loss of ventral motoneurons (VMN) and ventral funicular astrocytes and oligodendrocytes at 15 min and 4, 8, and 24 h after an incomplete midthoracic contusion injury in the rat. We found that both the length of lesion and the length of spinal cord devoid of VMN increased in a time-dependent manner. The extent of VMN loss at specified distances rostral and caudal to the injury epicenter progressed symmetrically with time. Neuronal loss was accompanied by a loss of glial cells in ventral white matter that was significant at the epicenter by 4 h after injury. Oligodendrocyte loss followed the same temporal pattern as that of VMN while astrocyte loss was delayed. This information on the temporal-spatial pattern of cell loss can be used to investigate mechanisms involved in secondary injury of neurons and glia after SCI.
Blood vessels identified by laminin staining were studied in uninjured spinal cord and at 2, 4, 7, and 14 days following a moderate contusion (weight drop) injury. At 2 days after injury most blood vessels had been destroyed in the lesion epicenter; neurons and astrocytes were also absent, and few ED1+ cells were seen infiltrating the lesion center. By 4 days, laminin associated with vessel staining was increased and ED1+ cells appeared to be more numerous in the lesion. By 7 days after injury, the new vessels formed a continuous cordon oriented longitudinally through the lesion center. ED1+ cells were abundant at this time point and were found in the same area as the newly formed vessels. Astrocyte migration from the margins of the lesion into the new cordon was apparent. By 14 days, a decrease in the number of vessels in the lesion center was observed; in contrast, astrocytes were more prominent in those areas. In addition to providing a blood supply to the lesion site, protecting the demise of the newly formed vascular bridge might provide an early scaffold to hasten axonal regeneration across the injury site.
Matrix metalloproteinases (MMPs) are associated with blood-brain opening and may be involved in the pathophysiology of acute brain injury. Previous research demonstrated that knockout mice deficient in MMP-9 subjected to transient focal cerebral ischemia had reduced blood-brain barrier (BBB) disruption and attenuated cerebral infarction. In this study, we examined MMP-9 up-regulation, BBB disruption, and brain edema formation after cortical impact injury in rats. Cortical contusion was induced by controlled cortical impact. Animals were sacrificed at intervals after injury. MMP up-regulation was assessed by gelatin zymography, and BBB integrity was evaluated using Evans blue dye with a spectrophotometric assay. Brain water content was measured by comparing wet and dry weights of each hemisphere as an indicator of brain edema. Zymograms showed elevated MMP-9 as early as at 3 hours after injury, reaching a maximum at 18 hours. Peak levels of BBB disruption occurred 6 hours after injury. Brain edema became progressively more severe, peaking 24 hours after injury. Compared to control group, treatment with MMP-inhibitor GM6001 significantly reduced BBB disruption 6 hours and brain water content (85.9 +/- 0.5% vs. 82.6 +/- 0.3%; p < 0.05) 24 hours after injury. These findings suggest that MMP-9 may contribute to BBB disturbance and subsequent brain edema after traumatic brain injury.
BACKGROUND: Brain oedema associated with cerebral contusion can be life-threatening. Mechanisms of the development of brain oedema are still unclear. METHOD: We investigated the expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (KDR/Flk-1) in the contusional brain tissue obtained during neurosurgery from 5 patients. FINDINGS: VEGF is expressed in some but not all the astrocytes, and KDR/Flk-1 is expressed in vascular endothelial cells in the con-tusional tissue as early as 3 hours after onset. CONCLUSION: The results suggested that the VEGF is induced in the contusional tissue in the very early period after onset, and that it increases capillary permeability via KDR/Flk-1 resulting in vasogenic type brain oedema.
The pathogenesis of contusions was studied in a series of acute fatal closed head injuries. Important factors include: 1. whether the head was in motion or stationary; 2. the direction and magnitude of the force; 3. the presence of depressed fractures and lacerations; and 4. roughness of the overlying bone. In the young adult group, the frequent high velocity motor vehicle accidents create a dominant pattern of injury to the frontal and temporal lobes, usually sparing the occipital lobes and cerebellum.
Twenty-five cases of cerebral contusions of various age were examined immunohistochemically for neuronal uptake of albumin and fibrinogen. The neurons in the damaged areas were heavily stained in all cases, even in those of only a few minutes' survival, and they remained positive for serum proteins until they disappeared from the lesions. In hematoxylin and eosin-stained sections, neuronal changes were observed from the first minutes after the lesion but they were indistinguishable from the shrunken "dark" neurons that occur as artifacts in poorly fixed material. However, in contrast to the artificially changed cells, the truly damaged ones took up serum proteins. It is concluded that staining with antisera against serum proteins may serve as early markers for neuronal injury before reliable histological changes have developed.
The inflammatory reaction following experimental brain contusion was studied by immunohistochemistry in 22 rats during the first 16 days after trauma. An inflammatory mononuclear cell response was evident on day 2, with a maximum on days 5-6 and signs remained still 16 days after the trauma. The time course of the cellular infiltration adjacent to the lesion correlated with blood brain barrier dysfunction in the contralateral side of the traumatized hemisphere. The cellular infiltrate comprised NK cells, T-helper cells and T-cytotoxic/suppressor cells as well as monocytes/macrophages. Most of the macrophages appeared to be activated by T-cells. Surprisingly, polymorphonuclear cells appeared less engaged than mononuclear cells in the inflammation. The demonstration of immunocompetent cells and the induction of MHC-1 and MHC-II antigen provides a substrate for inflammatory reactions similar to those that cause neurological damage in inflammatory diseases such as viral infections, multiple sclerosis and experimental allergic encephalitis. Our observations indicate that the role of the inflammatory reactions may have a role, hitherto neglected, in the pathogenesis of secondary traumatic brain injury.
Brain tissue from 11 patients with traumatic cerebral contusions submitted to surgery was studied. Control biopsy specimens were obtained from 5 patients undergoing ventriculo-peritoneal shunts for "communicating" hydrocephalus. After collection, the small fragments were fixed by immersion in glutaraldehyde-osmium and embedded in Epon. Semi-thin sections stained with toluidine blue were observed with the light microscope. Thin sections stained with lead citrate and uranyl acetate were observed using a Jeol electron microscope. In tissues from patients with head trauma a clear space most probably corresponding to fluid accumulation was systematically observed around microvessels. Ultrastructurally endothelial cells from these specimens exhibited signs of marked intracellular oedema, tight junctions being intact. Pinocytotic activity was increased, mainly at the abluminal surface. Swelling of astrocytic perivascular processes and the appearance of macrophagic cells with voluminous lysosomes were also observed. The authors conclude that the oedema of endothelial cells probably represent a central fact in the pathophysiology of traumatic brain oedema and speculate on the putative involvement of stretch-activated receptors in this condition.