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Biomedical subjects

R Raghupathi

Publications and source records attributed to R Raghupathi.

At least 37 records · Page 2Linked to original sources
PubMed2000

Postinjury treatment with magnesium chloride attenuates cortical damage after traumatic brain injury in rats.

The neuroprotective effect of magnesium chloride (MgCl2), a compound previously demonstrated to improve behavioral and neurochemical outcome in several models of experimental brain injury, was evaluated in the present study. Male Sprague-Dawley rats were anesthetized and subjected to lateral fluid-percussion brain injury of moderate severity (2.5-2.8 atm). A cannula was implanted in the left femoral vein and at 1 h following injury, animals randomly received a 15 min i.v. infusion of either MgCl2 (125 micromol/rat) or saline. A second group of animals received anesthesia, surgery, and either MgCl2 or vehicle to serve as uninjured (sham) controls. Two weeks following brain injury, animals were sacrificed, brains removed, and coronal sections were taken for quantitative analysis of cortical lesion volume and hippocampal CA3 cell counts. Traumatic brain injury resulted in a lesion in the ipsilateral cortex and loss of pyramidal neurons in the CA3 region of the hippocampus in vehicle-treated animals (p < 0.01 vs. uninjured animals). Administration of MgCl2 significantly reduced the injury-induced damage in the cortex (p < 0.01) but did not alter posttraumatic cell loss in the CA3 region of the ipsilateral hippocampus. The present study demonstrates that, in addition to its beneficial effects on behavioral outcome, MgCl2 treatment attenuates cortical histological damage when administered following traumatic brain injury.

Animals↗
PubMed2000

The novel compound LOE 908 attenuates acute neuromotor dysfunction but not cognitive impairment or cortical tissue loss following traumatic brain injury in rats.

Experimental traumatic brain injury (TBI) initiates massive disturbances in Ca2+ concentrations in the brain that may contribute to neuronal damage. Intracellular Ca2+ may be elevated via influx through voltage-operated cation channels, ligand-gated ionotropic channels, and store-operated cation channels (SOCs). In the present study, we evaluated the neurobehavioral and histological effects of acute posttraumatic administration of (R,S)-(3,4-dihydro-6,7-dimethoxy-isoquinoline-1-yl)-2-phenyl-N,N-di[2-(2 ,3,4-trimethoxyphenyl)ethyl]-acetamide (LOE 908), a broad spectrum inhibitor of voltage-operated cation channels and SOCs. Male Sprague-Dawley rats (n = 53) were trained in the Morris water maze, anesthetized (60 mg/kg pentobarbital, i.p.), and subjected to lateral fluid percussion brain injury (2.5-2.7 atm; n = 38) or surgery without injury (n = 15). At 15 min postinjury, animals were randomized to receive intravenous administration of either a high dose of LOE 908 (4 mg/kg bolus followed by 160 mg/kg over 24 h; n = 13), a low dose of LOE 908 (2 mg/kg bolus followed by 80 mg/kg over 24 h; n = 12), or vehicle (n = 13). Uninjured controls received the high dose of LOE 908 (n = 8) or vehicle (n = 7). Treatment with either dose of LOE 908 significantly improved neuromotor function at 48 h postinjury when compared to vehicle treatment. Although a significant deficit in visuospatial memory was observed in brain-injured animals at this timepoint when compared to uninjured animals, neither dose of LOE 908 attenuated injury-induced cognitive dysfunction. Histological evaluation revealed that neither dose of LOE 908 affected cortical lesion size at 48 h postinjury. These data suggest that broad spectrum cation channel blockers may be beneficial in the treatment of neurological motor dysfunction when administered in the acute posttraumatic period.

Acetamides↗
PubMed2000

Apoptosis after traumatic brain injury.

Apoptosis of neurons and glia contribute to the overall pathology of traumatic brain injury (TBI) in both humans and animals. In both head-injured humans and following experimental brain injury, apoptotic cells have been observed alongside degenerating cells exhibiting classic necrotic morphology. Neurons undergoing apoptosis have been identified within contusions in the acute port-traumatic period, and in regions remote from the site of impact in the days and weeks after trauma. Apoptotic oligodendrocytes and astrocytes have been observed within injured white matter tracts. We review the regional and temporal patterns of apoptosis following TBI and the possible mechanisms underlying trauma-induced apoptosis. While excitatory amino acids, increases in intracellular calcium, and free radicals can all cause cells to undergo apoptosis, in vitro studies have determined that neural cells can undergo apoptosis via many other pathways. It is generally accepted that a shift in the balance between pro- and anti-apoptotic protein factors towards the expression of proteins that promote death may be one mechanism underlying apoptotic cell death. The effect of TBI on regional cellular patterns of expression of survival promoting-proteins such as Bcl-2, Bcl-xL, and extracellular signal regulated kinases, and death-inducing proteins such as Bax, c-Jun N-terminal kinase, tumor-suppressor gene, p53, and the caspase family of proteases are reviewed. Finally, in light of pharmacologic strategies that have been devised to reduce the extent of apoptotic cell death in animal models of TBI, our review also considers whether apoptosis may serve a protective role in the injured brain.

Animals↗
PubMed2000

Age-related differences in acute physiologic response to focal traumatic brain injury in piglets.

INTRODUCTION: The goal of the present study was to determine whether age-related differences in the acute physiologic response to scaled cortical impact injury contribute to differences in vulnerability to traumatic brain injury (TBI). METHODS: Heart rate (HR), mean arterial pressure (MAP), brain temperature (BrT) and cerebral blood flow (CBF) were measured in 22 piglets (7 of age 5 days, 8 of age 1 month, 7 of age 4 months) at baseline and for 3 h following scaled cortical impact injury. RESULTS: There were no age-dependent variations from baseline in HR, MAP or BrT following injury. CBF increased in the 5-day-old animals following injury while CBF in the 1- and 4-month-old animals decreased following injury (p = 0.0049). CONCLUSION: CBF was shown to have a significant age-dependent response to TBI with the youngest animals exhibiting increased CBF following injury.

Acute Disease↗
PubMed2000

Maturation-dependent response of the piglet brain to scaled cortical impact.

OBJECT: The goal of this study was to investigate the relationship between maturational stage and the brain's response to mechanical trauma in a gyrencephalic model of focal brain injury. Age-dependent differences in injury response might explain certain unique clinical syndromes seen in infants and young children and would determine whether specific therapies might be particularly effective or even counterproductive at different ages. METHODS: To deliver proportionally identical injury inputs to animals of different ages, the authors have developed a piglet model of focal contusion injury by using specific volumes of rapid cortical displacement that are precisely scaled to changes in size and dimensions of the growing brain. Using this model, the histological response to a scaled focal cortical impact was compared at 7 days after injury in piglets that were 5 days, 1 month, and 4 months of age at the time of trauma. Despite comparable injury inputs and stable physiological parameters, the percentage of hemisphere injured differed significantly among ages, with the youngest animals sustaining the smallest lesions (0.8%, 8.4%, and 21.5%, for 5-day-, 1-month-, and 4-month-old animals, respectively, p = 0.0018). CONCLUSIONS: These results demonstrate that, for this particular focal injury type and severity, vulnerability to mechanical trauma increases progressively during maturation. Because of its developmental and morphological similarity to the human brain, the piglet brain provides distinct advantages in modeling age-specific responses to mechanical trauma. Differences in pathways leading to cell death or repair may be relevant to designing therapies appropriate for patients of different ages.

Age Factors↗
PubMed1999

Overexpression of Bcl-2 is neuroprotective after experimental brain injury in transgenic mice.

The cell death regulatory protein, Bcl-2, has been suggested to participate in the pathophysiology of various neurological disorders, including traumatic brain injury (TBI). The cognitive function and histopathologic sequelae after controlled cortical impact brain injury were evaluated in transgenic (TG) mice that overexpress human Bcl-2 protein (n = 13) and their wild type (WT) controls (n = 9). Although brain-injured Bcl-2 TG mice exhibited similar posttraumatic deficits in a Morris water maze (MWM) test of spatial memory as their WT counterparts at 1 week postinjury, the preinjury learning ability of Bcl-2 TG mice was impaired significantly compared with their WT littermates (P < 0.05). In contrast, histopathologic analysis revealed significantly attenuated tissue loss in the ipsilateral hemisphere (p < 0.01) and decreased tissue loss in ipsilateral hippocampal area CA3 (P < 0.001) and the dentate gyrus (P < 0.01) in brain-injured Bcl-2 TG mice compared with brain-injured WT mice. Immunohistochemical evaluation of glial fibrillary acidic protein also revealed a significant decrease in reactive astrocytosis in the ipsilateral dorsal thalamus (P < 0.05) and the ventral thalamus (P < 0.01) in brain-injured Bcl-2 TG mice. These results suggest that overexpression of Bcl-2 protein may play a protective role in neuropathologic sequelae after TBI.

Animals↗
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

Genetic approaches to neurotrauma research: opportunities and potential pitfalls of murine models.

Genetic strategies provide new ways to define the molecular cascades that regulate the responses of the mammalian nervous system to injury. Genetic interventions also provide opportunities to manipulate and control key molecular steps in these cascades, so as to modify the outcome of CNS injury. Most current genetic strategies involve the use of mice, an animal that has not heretofore been used extensively for neurotrauma research. Therefore, one purpose of the present review is to consider how mice respond to neural trauma, focusing especially on recent information that reveals important differences between mice and rats, and between different inbred strains of mice. The second aim of this review is to provide a brief introduction to the opportunities, caveats, and potential pitfalls of studies that use genetically modified animals for neurotrauma research.

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

Regional patterns of neuronal death after deep hypothermic circulatory arrest in newborn pigs.

OBJECTIVES: Deep hypothermic circulatory arrest (DHCA) widely used during neonatal heart surgery, carries a risk of brain damage. In adult normothermic ischemia, brain cells in certain regions die, some by necrosis and others by apoptosis (programmed cell death). This study characterized regional brain cell death after DHCA in newborn pigs. METHODS: Eighteen piglets underwent 90 minutes of DHCA and survived 6 hours, 2 days, or 1 week. Six piglets underwent surgery alone or deep hypothermic cardiopulmonary bypass and survived 2 days. Three piglets received no intervention (control). Brain injury was assessed by neurologic and histologic examination and correlated with perioperative factors. Apoptosis and necrosis were identified by light microscopic analysis of cell structure and in situ DNA fragmentation (TUNEL). RESULTS: All groups subjected to DHCA had brain injury by neurologic and histologic examination, whereas the other groups did not. DHCA damaged neurons in the neocortex and hippocampus and occasionally in the striatum and cerebellum. Damaged neurons in the neocortex were mainly apoptotic and in the hippocampus, a mixture of necrotic and apoptotic neurons. Apoptosis and necrosis were apparent in all DHCA groups even though neurologic deficits improved over the week's survival. Neocortical and hippocampal damage correlated with blood glucose, hematocrit, and arterial PO(2) during and after cardiopulmonary bypass. CONCLUSIONS: In neonates, neocortical and hippocampal neurons are selectively vulnerable to death after DHCA. Both apoptosis and necrosis contribute to neuronal death, beginning early in reperfusion and continuing for days. These data suggest the need for several neuroprotective strategies tailored to the region and death process, initiated during the operation and continued after the operation.

Analysis of Variance↗
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

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

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↗