Biomedical subjects

T K McIntosh

Publications and source records attributed to T K McIntosh.

At least 55 records · Page 3Linked to original sources

PubMed2000

Dynamic mechanical stretch of organotypic brain slice cultures induces differential genomic expression: relationship to mechanical parameters.

Although the material properties of biological tissues are reasonably well established, recent studies have suggested that the biological response of brain tissue and its constituent cells may also be viscoelastic and sensitive to both the magnitude and rate of a mechanical stimulus. Given the potential involvement of changes in gene expression in the pathogenic sequelae after head trauma, we analyzed the expression of 22 genes related to cell death and survival and found that a number of these genes were differentially regulated after mechanical stretch of an organotypic brain slice culture. Twenty-four hours after stretch, the expression of BDNF, NGF, and TrkA was significantly increased, whereas that of bcl-2, CREB, and GAD65 was significantly decreased (MANOVA followed by ANOVA, p < 0.05). Expression of CREB and GAD65 was negatively correlated with strain, whereas expression of APP695 was negatively correlated with strain rate (all p < 0.05). This study demonstrates that a subset of genes involved in cell death and survival are differentially regulated after dynamic stretch in vitro and that the expression of specific genes is correlated with mechanical parameters of that stretch.

Analysis of Variance↗

PubMed1999

Traumatic brain injury in young, amyloid-beta peptide overexpressing transgenic mice induces marked ipsilateral hippocampal atrophy and diminished Abeta deposition during aging.

Traumatic brain injury (TBI) is an epigenetic risk factor for Alzheimer's disease (AD). To test the hypothesis that TBI contributes to the onset and/or progression of AD-like beta-amyloid peptide (Abeta) deposits, we studied the long-term effects of TBI in transgenic mice that overexpress human Abeta from a mutant Abeta precursor protein (APP) minigene driven by a platelet derived (PD) growth factor promoter (PDAPP mice). TBI was induced in 4-month-old PDAPP and wild type (WT) mice by controlled cortical impact (CCI). Because Abeta begins to deposit progressively in the PDAPP brain by 6 months, we examined WT and PDAPP mice at 2, 5, and 8 months after TBI or sham treatment (i.e., at 6, 9, and 12 months of age). Hippocampal atrophy in the PDAPP mice was more severe ipsilateral versus contralateral to TBI, and immunohistochemical studies with antibodies to different Abeta peptides demonstrated a statistically significant reduction in hippocampus and cingulate cortex Abeta deposits ipsilateral versus contralateral to CCI in 9-12 month-old PDAPP mice. Hippocampal atrophy and reduced Abeta deposits were not seen in hippocampus or cingulate cortex of sham-injured PDAPP mice or in any WT mice. These data suggest that the vulnerability of brain cells to Abeta toxicity increases and that the accumulation of Abeta deposits decrease in the penumbra of CCI months after TBI. Thus, in addition to providing unique opportunities for elucidating genetic mechanisms of AD, transgenic mice that recapitulate AD pathology also may be relevant animal models for investigating the poorly understood role that TBI and other epigenetic risk factors play in the onset and/or progression of AD.

Alzheimer Disease↗

PubMed1999

The tumor-suppressor gene, p53, is induced in injured brain regions following experimental traumatic brain injury.

A growing body of evidence suggests that neurons undergo apoptotic cell death following traumatic brain injury (TBI). Since the expression of several tumor suppressor and cell cycle genes have been implicated in neuronal apoptosis, the present study used in situ hybridization (ISH) histochemistry to evaluate the regional and temporal patterns of expression of the mRNAs for the tumor suppressor gene, p53, and the cell cycle gene, cyclin D1, following lateral fluid-percussion (FP) brain injury in the rat. Anesthetized adult male Sprague-Dawley rats (n=16) were subjected to lateral FP brain injury of moderate severity (2.4-2.7 atm), while sham controls (n=6) were surgically prepared but did not receive brain injury. Animals were killed by decapitation at 6 h (n=6 injured and 2 sham), 24 h (n=6 injured and 2 sham), or 3 days (n=4 injured and 2 sham), and their brains processed for ISH. Little to no expression of p53 mRNA was observed in sham brains. At 6 h post-injury, p53 mRNA was induced predominantly in cells that are vulnerable to TBI, such as those in the contused cortex, lateral and medial geniculate nuclei of the thalamus, and the CA(3) and hilar neurons of the hippocampus. Increased p53 mRNA was also detected in hippocampal CA(1) neurons, cells that are relatively resistant to FP brain injury. Levels of p53 mRNA returned to sham levels in all regions of the injured brain by 24 h. In contrast to p53, cyclin D1 mRNA was detectable in the brains of uninjured animals and was not altered by brain injury. These results suggest that the tumor suppressor gene p53, but not cyclin D1, is upregulated and may participate in molecular response to TBI.

Animals↗

PubMed1999

Differential acute and chronic responses of tumor necrosis factor-deficient mice to experimental brain injury.

The present study evaluated behavioral and histopathological outcome after controlled cortical impact (CCI) brain injury in mice deficient in tumor necrosis factor [TNF(-/-)] and their wild-type (wt) littermates. Mice were subjected to CCI brain injury [TNF(-/-), n = 10; wt, n = 10] or served as uninjured controls [TNF(-/-), n = 10; wt, n = 10] and were evaluated for deficits in memory retention at 7 days postinjury. Although both brain-injured wt and TNF(-/-) mice exhibited significant memory dysfunction compared to uninjured controls (P < 0.02), the deficits in memory retention in injured TNF(-/-) mice were significantly less severe than in injured wt mice (P < 0.02). A second group of mice was subjected to CCI brain injury [TNF(-/-), n = 20; wt, n = 20] or served as uninjured controls [TNF(-/-), n = 15; wt, n = 15] and were evaluated over a 4-week period for neurological motor function. In the acute posttraumatic period (48 h postinjury), brain-injured TNF(-/-) mice were significantly less impaired than injured wt mice on composite neuroscore (P < 0.001), rotarod (P < 0.05), and beam balance (P < 0. 02) tests. However, wt mice recovered from brain injury by 2-3 weeks postinjury, whereas TNF(-/-) mice continued to demonstrate persistent motor deficits up to 4 weeks postinjury. Histopathological analysis at 2 and 4 weeks postinjury revealed that brain-injured TNF(-/-) mice had significantly more cortical tissue loss than wt mice (P < 0.02). Our results suggest that although the presence of TNF in the acute posttraumatic period may be deleterious, this cytokine may play a role in facilitating long-term behavioral recovery and histological repair after brain injury.

Animals↗

PubMed1999

Concurrent loss and proliferation of astrocytes following lateral fluid percussion brain injury in the adult rat.

Astrocyte populations were analyzed over a period of 1 month in the hippocampus following lateral fluid percussion (FP) brain injury. Rats (n = 23) were subjected either to a brain injury of moderate severity, or to anesthesia and surgery without injury (n = 7). At 3 days, 1, 2, or 4 weeks postinjury, subgroups of animals were sacrificed and the brains removed and sectioned for histochemical analysis. The density of astrocytes, identified with gold sublimate staining, decreased significantly in the ipsilateral hippocampus of injured rats 3 days following injury, eventually falling to 64% of the total astrocyte population present in uninjured animals by 1 week postinjury. One month postinjury, the density of hippocampal astrocytes had returned to 85% of the total number of astrocytes observed in the hippocampus of uninjured animals. In order to characterize the post-traumatic formation of new astrocytes, immunohistochemistry was performed using antibodies to proliferating cell nuclear antigen (PCNA) and to glial fibriallary acidic protein (GFAP). Positive immunolabeling for both PCNA and GFAP was most abundant at 3 days following FP brain injury in regions where the blood brain barrier was compromised, and was not detectable by 1 month postinjury. These results indicate that astrocyte proliferation after injury may be evoked by mitogens released from vascular sources, and may be an attempt to compensate for some of the astrocytic cell loss observed after injury.

Age Factors↗

PubMed1999

Single-cell molecular biology: implications for the diagnosis and treatment of neurological disease.

The normal functioning of the central nervous system (CNS) requires complex interactions among numerous biological components. The pathophysiology of perturbations in this system is as complex as that of neurological disease. Many methods exist to examine the biological output of dysfunctional cells from a diseased system (e.g., immunohistochemical analysis, electrophysiology, and microdialysis), with one goal being to understand the mechanisms of cell death. This understanding may allow the design of therapeutic strategies to prevent cell death and ensuing behavioral abnormalities. Analysis of messenger RNA (mRNA) levels for various genes in CNS tissue may enhance understanding of neurological disease, since cells differ in the complement and abundance of genes they express. One popular method for detecting changes in gene expression is the Northern blot technique, in which total RNA from a sample is extracted and the RNA molecules are separated by size on a denaturing gel and transferred or "blotted" onto nylon membranes that are then probed with radiolabeled DNA for subsequent autoradiograpic detection of gene expression.

Central Nervous System Diseases↗

PubMed1999

Diffuse axonal pathology detected with magnetization transfer imaging following brain injury in the pig.

This study was designed to evaluate with magnetization transfer imaging (MTI) and conventional magnetic resonance (MR) imaging the manifestation of diffuse axonal injury (DAI) in an animal model of injury via nonimpact coronal plane rotational acceleration. A second objective was to investigate the diagnostic use of quantitative MTR imaging based on statistical parameters in a single subject, as opposed to grouped analysis. Seven mini-swine were subjected to brain trauma known to produce isolated DAI and to MR imaging at two time points. Following sacrifice, the brains were harvested for histopathologic examination. Magnetization transfer ratio (MTR) maps were generated for double-blinded comparison of regions with abnormal MTR values and regions with documented DAI. Positive and negative predictive values for MTR detection of DAI were 67 and 56%, respectively, and in acute studies alone, 89 and 61%. Gains in sensitivity over conventional imaging for detection of DAI were demonstrated.

Animals↗

PubMed1999

Postinjury magnesium treatment attenuates traumatic brain injury-induced cortical induction of p53 mRNA in rats.

Administration of magnesium has been shown to be neuroprotective in experimental models of traumatic brain injury (TBI). The present study examined the effect of magnesium on posttraumatic regional induction of p53, a gene associated with induction of cell death. Male Sprague-Dawley rats (350-400 g, n = 26) were anesthetized with sodium pentobarbital and subjected to either lateral fluid percussion brain injury of moderate severity (2.4-2.6 atm; n = 22) or sham surgery (n = 4). At 15 min postinjury, animals randomly received an intravenous bolus of either 125 micromol magnesium chloride (n = 12) or saline vehicle (n = 10). Expression of p53 mRNA was not observed in any uninjured animal. By 6 h postinjury in vehicle-treated, brain-injured animals, p53 mRNA was induced in the cortex, dentate hilus, and CA3 regions of the hippocampus and geniculate nuclei of the thalamus, ipsilateral to the impact site. Posttraumatic magnesium treatment significantly reduced the number of labeled cells in the injured cortex (P < 0.05), but not in the hippocampus or thalamus. p53 mRNA expression returned to near baseline in all animals by 24 h postinjury. These data suggest that the neuroprotective effects of magnesium treatment may be related, in part, to a downregulation in expression of a gene associated with induction of cell death and further support the utility of magnesium as a pharmacotherapy for TBI.

Animals↗

PubMed1999

A comparison of manual and semi-automated methods in the assessment of axonal injury.

Diffuse axonal injury (DAI) in the central nervous system is a common cause of post-traumatic coma and may result in varying degrees of disability up to and including the vegetative state. Experimental studies in man and animals have previously relied upon semi-quantitative grading systems for determining the relationship between the extent of DAI and the clinical features of patients. Using beta-amyloid precursor protein immunocytochemistry for the detection of DAI in sections of corpus callosum from 15 cases of fatal head injury, we have developed a quantitative image analysis technique for the assessment of axonal injury. This new method is objective and reproducible and should allow better correlation with biomechanical, radiological, and clinical parameters to increase our understanding of DAI.

Adolescent↗

PubMed1999

Temporal patterns of poly(ADP-ribose) polymerase activation in the cortex following experimental brain injury in the rat.

The activation of poly(ADP-ribose) polymerase, a DNA base excision repair enzyme, is indicative of DNA damage. This enzyme also undergoes site-specific proteolysis during apoptosis. Because both DNA fragmentation and apoptosis are known to occur following experimental brain injury, we investigated the effect of lateral fluid percussion brain injury on poly(ADP-ribose) polymerase activity and cleavage. Male Sprague-Dawley rats (n = 52) were anesthetized, subjected to fluid percussion brain injury of moderate severity (2.5-2.8 atm), and killed at 30 min, 2 h, 6 h, 24 h, 3 days, or 7 days postinjury. Genomic DNA from injured cortex at 24 h, but not at 30 min, was both fragmented and able to stimulate exogenous poly(ADP-ribose) polymerase. Endogenous poly(ADP-ribose) polymerase activity, however, was enhanced in the injured cortex at 30 min but subsequently returned to baseline levels. Slight fragmentation of poly(ADP-ribose) polymerase was detected in the injured cortex in the first 3 days following injury, but significant cleavage was detected at 7 days postinjury. Taken together, these data suggest that poly(ADP-ribose) polymerase-mediated DNA repair is initiated in the acute posttraumatic period but that subsequent poly(ADP-ribose) polymerase activation does not occur, possibly owing to delayed apoptosis-associated proteolysis, which may impair the repair of damaged DNA.

Animals↗

PubMed1999

Alterations in ionized and total blood magnesium after experimental traumatic brain injury: relationship to neurobehavioral outcome and neuroprotective efficacy of magnesium chloride.

Experimental evidence suggests that magnesium plays a role in the pathophysiological sequelae of brain injury. The present study examined the variation of blood ionized and total magnesium, as well as potassium, sodium, and ionized calcium, after experimental fluid percussion brain injury in rats. Blood ionized magnesium concentration significantly declined from 0.45 +/- 0.02 to 0.32 +/- 0.02 mM by 30 min postinjury and stayed depressed for the 24-h study period in vehicle-treated rats. Blood total magnesium concentration was 0.59 +/- 0.01 mM and remained stable over time in brain-injured vehicle-treated animals. When magnesium chloride (125 micromol/rat) was administered 1 h postinjury, ionized magnesium levels were restored by 2 h postinjury and remained at normal values up to 24 h following brain trauma. Magnesium treatment also significantly reduced posttraumatic neuromotor impairments 1 and 2 weeks after the insult, but failed to attenuate spatial learning deficits. A significant positive and linear correlation could be established between ionized magnesium levels measured 24 h postinjury and neuromotor outcome at 1 and 2 weeks. We conclude that acute ionized magnesium measurement may be a predictor of long-term neurobehavioral outcome following head injury and that delayed administration of magnesium chloride can restore blood magnesium concentration and attenuate neurological motor deficits in brain-injured rats.

Animals↗

PubMed1999

Regional and temporal alterations in DNA fragmentation factor (DFF)-like proteins following experimental brain trauma in the rat.

DNA fragmentation, an early event in neuronal death following traumatic brain injury, may be triggered by the 40-kDa subunit of DNA fragmentation factor (DFF40). DFF40 is typically bound to the 45-kDa subunit of DFF (DFF45), and activation of DFF40 may occur as a result of caspase-3-mediated cleavage of DFF45 into 30- and 11-kDa fragments. In this study, the intracellular distribution of DFF45 and DFF40 was examined following lateral fluid percussion brain injury of moderate severity (2.4-2.7 atm) in male Sprague-Dawley rats. In the cytosolic fraction (S1) of the injured cortex at 2 and 24 h postinjury, significant decreases in the intensities of DFF45-like proteins at 45- and 32-kDa bands and a concomitant increase in the 11-kDa bands were observed (p < 0.05 vs. uninjured controls). A significant decrease in the intensities of the 32-kDa band in the nuclear (P1) fraction of the injured cortex was observed at 30 min and 2 h postinjury (p < 0.01). Concomitantly, a decrease in DFF40 was observed in the cortical S1 fraction at 2 and 24 h (p < 0.05) and in the P1 fraction at 30 min and 2 h postinjury (p < 0.01). In the hippocampus, DFF45 decreased at 30 min in the P1 and 2 h in the S1 fraction (p < 0.05) and recovered by 24 h postinjury, whereas DFF40 was significantly decreased in the S1 and increased in the P1 fraction at both 2 and 24 h (p < 0.01), which indicated a translocation of DFF40 from cytosol to nucleus. These data are the first to demonstrate that changes in DFF proteins occur after brain trauma and suggest that these changes may play a role in apoptotic cell death via caspase-3-DFF45/DFF40-DNA cleavage observed following traumatic brain injury.

Animals↗

PubMed1999

Prolonged activation of NF-kappaB following traumatic brain injury in rats.

Activation of transcription factor, nuclear factor kappa B (NF-kappaB), has been shown to play a key role in inflammatory response, neuronal survival and signaling. We investigated the regional and temporal distribution of activated NF-kappaB in rats at 1 h, 2 h, 24 h, 48 h, 1 week, 2 weeks, 1 month, 2 months, 6 months, and 1 year following brain injury in rats. Early after trauma (1-2 h), activated NF-kappaB was detected in axons, and subsequently found in the cytoplasm and nucleus of neurons by 24 h and lasting up to 1 week. In addition, by 24 h posttrauma, activated NF-kappaB was detected in microglia/macrophages and astrocytes in injured cortex. Surprisingly, this activation persisted for at least 1 year following injury in the cortex, primarily at the margins of progressively enlarging ventricle. Activated NF-kappaB was also detected in endothelial cells, as early as 1 h, and persisted for up to 1 year. These results suggest that a neuronal response to brain trauma includes the activation of NF-kappaB first in the axon with subsequent translocation to the nucleus. Furthermore, these results demonstrate that remarkably prolonged activation of NF-kappaB in glia is found in the same regions undergoing persistent atrophy, suggesting NF-kappaB activation may play a role in long-term inflammatory processes following brain trauma.

Animals↗

PubMed1999

Sequential pharmacotherapy with magnesium chloride and basic fibroblast growth factor after fluid percussion brain injury results in less neuromotor efficacy than that achieved with magnesium alone.

Combinational pharmacotherapy with individually efficacious agents is a potential strategy for the treatment of traumatic central nervous system (CNS) injury. Basic fibroblast growth factor (bFGF) has been shown to be neuroprotective against excitotoxic, ischemic, and traumatic injury to the CNS, while acute posttraumatic treatment with magnesium (Mg2+) has been shown to decrease the motor and cognitive deficits following experimental brain injury. In this study, bFGF and Mg2+ were evaluated separately and in combination to assess their potential additive effects on posttraumatic neurological recovery and histological cell loss (lesion volume). Twenty minutes after fluid percussion (FP) brain injury of moderate severity (2.2-2.4 atm), anesthetized rats received a 15-min intravenous infusion of either 125 mumol of MgCl2 or vehicle, followed 5 min later by a 24-h constant intravenous infusion of either bFGF (16 micrograms/h) or vehicle. Injured animals had a significant motor deficit when compared to sham (uninjured) animals at both 48 h and 7 days postinjury. At 48 h postinjury, there were no significant differences among injured animals when compared by treatment. By 7 days postinjury, injured animals treated with MgCl2 alone displayed significantly improved motor function when compared to brain-injured, vehicle-treated animals (p < 0.05). Animals treated with either bFGF alone or a combination of MgCl2 and bFGF displayed no significant neurological improvement relative to vehicle-treated injured animals at 7 days. No effect of any drug treatment of combination was observed on the extent of the postinjury lesion volume in the injured cortex. These results suggest that caution must be exercised when combining "cocktails" of potentially neuroprotective compounds in the setting of traumatic brain injury.

Analysis of Variance↗

PubMed1999

Terminally differentiated human neurons survive and integrate following transplantation into the traumatically injured rat brain.

The present study evaluated the survival and integration of human postmitotic neurons (hNT) following transplantation into the traumatically injured rodent brain. Anesthetized male Sprague-Dawley rats (n = 47) were subjected to lateral fluid percussion brain injury of moderate severity (2.4-2.6 atm). Sham animals (n = 28) were surgically prepared, but did not receive brain injury. At 24 h following injury or sham surgery, the rats were re-anesthetized and approximately 100,000 hNT cells (freshly cultured or previously frozen) or vehicle were stereotactically injected into the ipsilateral cortex. Animals were examined for neuromotor function at 48 h, 7 days, and 14 days posttransplantation using a standard battery of motor tests. Animals were sacrificed at 2 weeks postinjury and viability of hNT grafts was assessed by Nissl staining and MOC-1 immunohistochemistry, which recognizes human neural cell adhesion molecules (NCAM) expressed on hNT cells. Transplanted hNT grafts remained viable in 83% of brain-injured animals at 2 weeks following transplantation of either fresh or frozen hNT cells. Glial fibrillary acidic protein (GFAP) immunohistochemistry revealed a marked increase in the number of reactive astrocytes following brain injury in both vehicle and hNT implanted animals. These reactive astrocytes appeared not to impede grafted cells from sending projections into host tissue. Despite the survival of transplanted cells in the traumatically injured brain, hNT cells had no significant effect on posttraumatic neurologic motor function during the acute posttraumatic period. Since hNT cells are transfectable, prolonged survival of these transplanted cells in the posttraumatic milieu suggests that grafted hNT cells may be a suitable means for delivery of therapeutic, exogenous proteins into the CNS for treatment of traumatic brain injury.

Animals↗

PubMed1999

Increased vulnerability of NFH-LacZ transgenic mouse to traumatic brain injury-induced behavioral deficits and cortical damage.

The authors evaluated the neurobehavioral and neuropathologic sequelae after traumatic brain injury (TBI) in transgenic (TG) mice expressing truncated high molecular weight neurofilament (NF) protein fused to beta-galactosidase (NFH-LacZ), which develop Lewy body-like NF-rich inclusions throughout the CNS. TG mice and their wild-type (WT) littermates were subjected to controlled cortical impact brain injury (TG, n = 19; WT, n = 17) or served as uninjured controls (TG, n = 11; WT, n = 11). During a 3-week period, mice were evaluated with an array of neuromotor function tests including neuroscore, beam balance, and both fast and slow acceleration rotarod. Brain-injured WT and TG mice showed significant motor dysfunction until 15 days and 21 days post-injury, respectively (P<.025). Compared with brain-injured WT mice, brain-injured TG mice had significantly greater motor dysfunction as assessed by neuroscore (P<.01) up to and including 15 days post-injury. Similarly, brain-injured TG mice performed significantly worse than brain-injured WT mice on slow acceleration rotarod at 2, 8, and 15 days post-injury (P<.05), and beam balance over 2 weeks post-injury (P<.01). Histopathologic analysis showed significantly greater tissue loss in the injured hemisphere in TG mice at 4 weeks post-injury (P<.01). Together these data show that NFH-LacZ TG mice are more behaviorally and histologically vulnerable to TBI than WT mice, suggesting that the presence of NF-rich inclusions may exacerbate neuromotor dysfunction and cell death after TBI.

Animals↗

PubMed1999

Interleukin-1 receptor antagonist attenuates regional neuronal cell death and cognitive dysfunction after experimental brain injury.

The effect of systemic administration of human recombinant interleukin-1 receptor antagonist (rhIL-1ra) on behavioral outcome and histopathologic damage after lateral fluid-percussion brain injury of moderate severity was evaluated. In study 1, brain-injured Sprague Dawley rats received timed subcutaneous injections beginning 15 minutes after injury of either 100 mg/kg rhIL-1ra (high dose, total dose = 1900 mg/kg), 10 mg/kg rhIL-1ra (low dose, total dose = 190 mg/kg), or vehicle over 7 days. No effect of low-dose rhIL-1ra was observed in study 1. High-dose rhIL-1ra significantly attenuated posttraumatic neuronal loss in the injured hippocampal CA3 region (P < 0.05), dentate hilus (P < 0.05), and cortex (P < 0.05) but impaired recovery of motor function at 7 days after trauma (P < 0.05). In study 2, rats were pretrained to learn a visuospatial task in a Morris water maze, subjected to fluid-percussion brain injury or sham treatment, and randomly assigned to receive multiple subcutaneous injections at timed intervals of 100 mg/kg rhIL-1ra (total dose = 900 mg/kg) or vehicle over 42 hours, followed by continuous infusion of a lower concentration of rhIL-1ra (20 mg/kg/day, total dose = 100 mg/kg), or vehicle for 5 days using subcutaneously implanted osmotic minipumps. Postinjury administration of rhIL-1ra significantly attenuated cognitive deficits compared with vehicle-treated animals at 42 hours (P < 0.05) but did not affect motor function at 48 hours, 1 week, and 2 weeks. These results suggest that inhibitors of cytokine pathways may be therapeutically useful for the treatment of brain trauma.

Animals↗

PubMed1999

Experimental investigation of cerebral contusion: histopathological and immunohistochemical evaluation of dynamic cortical deformation.

We used a new approach, termed dynamic cortical deformation (DCD), to study the neuronal, vascular, and glial responses that occur in focal cerebral contusions. DCD produces experimental contusion by rapidly deforming the cerebral cortex with a transient, nonablative vacuum pulse of short duration (25 milliseconds) to mimic the circumstances of traumatic injury. A neuropathological evaluation was performed on brain tissue from adult rats sacrificed 3 days following induction of either moderate (4 psi, n = 6) or high (8 psi, n = 6) severity DCD. In all animals, DCD produced focal hemorrhagic lesions at the vacuum site without overt damage to other regions. Examination of histological sections showed localized gross tissue and neuronal loss in the cortex at the injury site, with the volume of cell loss dependent upon the mechanical loading (p < 0.001). Axonal pathology shown with neurofilament immunostaining (SMI-31 and SMI-32) was observed in the subcortical white matter inferior to the injury site and in the ipsilateral internal capsule. No axonal injury was observed in the contralateral hemisphere or in any remote regions. Glial fibrillary acidic protein (GFAP) immunostaining revealed widespread reactive astrocytosis surrounding the necrotic region in the ipsilateral cortex. This analysis confirms that rapid mechanical deformation of the cortex induces focal contusions in the absence of primary damage to remote areas 3 days following injury. Although it is suggested that massive release of neurotoxic substances from a contusion may cause damage throughout the brain, these data emphasize the importance of combined injury mechanisms, e.g. mechanical distortion and excitatory amino acid mediated damage, that underlie the complex pathology patterns observed in traumatic brain injury.

Animals↗