Biomedical subjects

S D Croll

Publications and source records attributed to S D Croll.

16 recordsLinked to original sources

PubMed2002

Angiopoietin-1 reduces cerebral blood vessel leakage and ischemic lesion volume after focal cerebral embolic ischemia in mice.

Angiopoietin-1 (Ang1) is a ligand for the endothelial specific receptor tyrosine kinase, Tie2, that protects the adult peripheral vasculature from vascular leakage. We tested the hypothesis that increases in levels of Ang1 reduce blood-brain barrier (BBB) leakage in ischemic brain. Mice were subjected to embolic middle cerebral artery (MCA) occlusion. Recombinant adenoviruses expressing Ang1 (Ad-Ang1) or a control gene encoding green fluorescent protein (Ad-GFP), or recombinant Ang1 protein, BowAng1, was administered to mice before MCA occlusion. Regional cerebral blood flow (rCBF), the brain tissue content of Evans Blue, and ischemic lesion volume were measured. Serum levels of Ang1 (183+/-31.9 microg/ml, n=4) were detected in mice receiving Ad-Ang1 or in mice treated with BowAng1 (262+/-35.4 microg/ml, n=7) but not in the control mice (n=11). Six hours after MCA occlusion, mice receiving Ad-GFP (n=8) or control protein (n=7) showed large Evans Blue leakage in the ipsilateral hemisphere (0.46+/-0.05 or 0.55+/-0.16 ng/mg tissue) whereas mice receiving Ad-Ang1 (n=6) or BowAng1 (n=7) had significantly (P<0.05) less Evans Blue leakage (0.26+/-0.07 or 0.14+/-0.03 ng/mg tissue). Infusion of recombinant human vascular endothelial growth factor (rhVEGF(165)) to ischemic mice resulted in significant (P<0.05) increases in Evans Blue leakage (1.24+/-0.34 ng/mg tissue, n=7) compared with the control mice. In contrast, infusion of rhVEGF(165) in ischemic mice receiving Ad-Ang1 did not significantly increase Evans Blue dye in the ipsilateral hemisphere (0.22+/-0.06 ng/mg tissue, n=6). Moreover, 24 h after ischemia mice receiving Ad-Ang1 had a significantly smaller ischemic lesion volume (22.6+/-2.7%, n=8) than the lesion volume in mice receiving Ad-GFP (44.7+/-3.7%, n=8), although rCBF reduced to approximately 20% of the contralateral levels in both groups of mice 10 min after ischemia. Our data demonstrate that Ang1 reduces BBB leakage in ischemic brain and consequently decreases ischemic lesion volume.

Angiogenesis Inducing Agents↗

PubMed2001

Ephrin-B3 is the midline barrier that prevents corticospinal tract axons from recrossing, allowing for unilateral motor control.

Growing axons follow highly stereotypical pathways, guided by a variety of attractive and repulsive cues, before establishing specific connections with distant targets. A particularly well-known example that illustrates the complexity of axonal migration pathways involves the axonal projections of motor neurons located in the motor cortex. These projections take a complex route during which they first cross the midline, then form the corticospinal tract, and ultimately connect with motor neurons in the contralateral side of the spinal cord. These obligatory contralateral connections account for why one side of the brain controls movement on the opposing side of the body. The netrins and slits provide well-known midline signals that regulate axonal crossings at the midline. Herein we report that a member of the ephrin family, ephrin-B3, also plays a key role at the midline to regulate axonal crossing. In particular, we show that ephrin-B3 acts as the midline barrier that prevents corticospinal tract projections from recrossing when they enter the spinal gray matter. We report that in ephrin-B3(-/-) mice, corticospinal tract projections freely recross in the spinal gray matter, such that the motor cortex on one side of the brain now provides bilateral input to the spinal cord. This neuroanatomical abnormality in ephrin-B3(-/-) mice correlates with loss of unilateral motor control, yielding mice that simultaneously move their right and left limbs and thus have a peculiar hopping gait quite unlike the alternate step gait displayed by normal mice. The corticospinal and walking defects in ephrin-B3(-/-) mice resemble those recently reported for mice lacking the EphA4 receptor, which binds ephrin-B3 as well as other ephrins, suggesting that the binding of EphA4-bearing axonal processes to ephrin-B3 at the midline provides the repulsive signal that prevents corticospinal tract projections from recrossing the midline in the developing spinal cord.

Animals↗

PubMed2001

Enhanced hippocampal long-term potentiation in mice lacking heparin-binding growth-associated molecule.

Heparin-binding growth-associated molecule (HB-GAM) (pleiotrophin) is a highly conserved extracellular matrix-associated protein implicated in a diverse range of developmental processes, including the formation and plasticity of neuronal connections. Using gene targeting, we have in the present study created HB-GAM-deficient mice that are viable and fertile and show no gross anatomical abnormalities. The hippocampal structure as well as basal excitatory synaptic transmission in the area CA1 appear normal in the mice lacking HB-GAM. However, hippocampal slices from HB-GAM-deficient mice display a lowered threshold for induction of long-term potentiation (LTP), which reverts back to the wild-type level by application of HB-GAM. HB-GAM expression in hippocampus is activity-dependent and upregulated in several neuropathological conditions. Thus, we suggest that HB-GAM acts as an inducible signal to inhibit LTP in hippocampus.

Animals↗

PubMed2001

BDNF and epilepsy: too much of a good thing?

Various studies have shown that brain-derived neurotrophic factor (BDNF) increases neuronal excitability and is localized and upregulated in areas implicated in epileptogenesis. Seizure activity increases the expression of BDNF mRNA and protein, and recent studies have shown that interfering with BDNF signal transduction inhibits the development of the epileptic state in vivo. These results suggest that BDNF contributes to epileptogenesis. Further analysis of the cellular and molecular mechanisms by which BDNF influences excitability and connectivity in adult brain could provide novel concepts and targets for anticonvulsant or anti-epileptogenic therapy.

Animals↗

PubMed2001

Performance of heterozygous brain-derived neurotrophic factor knockout mice on behavioral analogues of anxiety, nociception, and depression.

Evidence suggests that brain-derived neurotrophic factor (BDNF) may be important in the pathophysiology of depression, in addition to its role as a neurotrophic factor for sensory neurons. The authors conducted a series of experiments examining the behavioral profile of BDNF heterozygous knockout and wild-type mice. The heterozygous and wild-type mice did not differ on measures of activity, exploration, or hedonic sensitivity, or in the forced swim test. When assessed in the learned helplessness paradigm, heterozygous mice were slower to escape after training than were wild-type mice (p = .02). This effect may be accounted for by the fact that these mice demonstrate a reduced sensitivity to centrally mediated pain, apparent on the hot plate and Formalin injection tests of nociception. Overall, heterozygous mice were not more likely to display anxious or depressive-like behaviors and, consequently, may not constitute a murine model of genetic vulnerability to mood and anxiety disorders.

Affect↗

PubMed2000

Angiopoietin-1 protects the adult vasculature against plasma leakage.

Pathological increases in vascular leakage lead to edema and swelling, causing serious problems in brain tumors, in diabetic retinopathy, after strokes, during sepsis and also in inflammatory conditions such as rheumatoid arthritis and asthma. Although many agents and disease processes increase vascular leakage, no known agent specifically makes vessels resistant to leaking. Vascular endothelial growth factor (VEGF) and the angiopoietins function together during vascular development, with VEGF acting early during vessel formation, and angiopoietin-1 acting later during vessel remodeling, maturation and stabilization. Although VEGF was initially called vascular permeability factor, there has been less focus on its permeability actions and more effort devoted to its involvement in vessel growth and applications in ischemia and cancer. Recent transgenic approaches have confirmed the profound permeability effects of VEGF (refs. 12-14), and have shown that transgenic angiopoietin-1 acts reciprocally as an anti-permeability factor when provided chronically during vessel formation, although it also profoundly affects vascular morphology when thus delivered. To be useful clinically, angiopoietin-1 would have to inhibit leakage when acutely administered to adult vessels, and this action would have to be uncoupled from its profound angiogenic capabilities. Here we show that acute administration of angiopoietin-1 does indeed protect adult vasculature from leaking, countering the potentially lethal actions of VEGF and inflammatory agents.

Angiopoietin-1↗

PubMed1999

Peptide immunoreactivity in aged rat cortex and hippocampus as a function of memory and BDNF infusion.

Brain-derived neurotrophic factor (BDNF) modulates neuropeptide levels in hippocampus and cortex of young adult rats. Neuropeptide levels are altered in some age-related disorders, such as Alzheimer's and Parkinson's Disease. BDNF may be able to rectify peptide abnormalities but, because plasticity decreases with age, BDNF may not alter peptide levels as readily in aged animals. To determine if BDNF would regulate peptide levels in aged rats, young, aged memory-impaired, and unimpaired rats were infused with BDNF or vehicle into hippocampus and cortex. Cell profile counts, cell profile areas, fiber counts, and/or fiber terminal densities were measured for sections immunostained for neuropeptide Y (NPY), somatostatin (SOM), cholecystokinin-8 (CCK), and dynorphin A(1-8) (DYN). Results showed that BDNF upregulated cortical NPY-immunoreactivity (ir) and SOM-ir, upregulated hippocampal NPY-ir, and downregulated hippocampal DYN-ir in both aged and young rats. In addition, BDNF significantly and selectively normalized the areas of atrophied deep cortical CCK-ir cell profiles in aged-impaired rats. Finally, decreased CCK-ir fiber density was found in the hippocampal formation of aged memory-impaired rats.

Aging↗

PubMed1999

Brain-derived neurotrophic factor transgenic mice exhibit passive avoidance deficits, increased seizure severity and in vitro hyperexcitability in the hippocampus and entorhinal cortex.

Transgenic mice overexpressing brain-derived neurotrophic factor from the beta-actin promoter were tested for behavioral, gross anatomical and physiological abnormalities. Brain-derived neurotrophic factor messenger RNA overexpression was widespread throughout brain. Overexpression declined with age, such that levels of overexpression decreased sharply by nine months. Brain-derived neurotrophic factor transgenic mice had no gross deformities or behavioral abnormalities. However, they showed a significant passive avoidance deficit. This deficit was dependent on continued overexpression, and resolved with age as brain-derived neurotrophic factor transcripts decreased. In addition, the brain-derived neurotrophic factor transgenic mice showed increased seizure severity in response to kainic acid. Hippocampal slices from brain-derived neurotrophic factor transgenic mice showed hyperexcitability in area CA3 and entorhinal cortex, but not in dentate gyrus. Finally, area CA1 long-term potentiation was disrupted, indicating abnormal plasticity. Our data suggest that overexpression of brain-derived neurotrophic factor in the brain can interfere with normal brain function by causing learning impairments and increased excitability. The results also support the hypothesis that excess brain-derived neurotrophic factor could be pro-convulsant in the limbic system.

Age Factors↗

PubMed1998

Expression of BDNF and trkB as a function of age and cognitive performance.

The expression of the neurotrophic factor BDNF increases during learning-related events and is decreased in the hippocampus of Alzheimer's Disease patients, suggesting that it plays a role in learning, memory, and/or age-related memory deficits. We examined the expression of BDNF and its high affinity receptor, trkB, in young and aged Sprague-Dawley rats. BDNF and trkB mRNA were measured by semi-quantitative in situ hybridization and BDNF protein was measured by ELISA. Significant decreases with age were detected for BDNF mRNA in the pons, BDNF protein in the midbrain, and trkB mRNA in many areas of the brain. Rats were evaluated on the Morris water maze before sacrifice so that BDNF and trkB levels could be related to cognitive status. Regression analyses revealed that decreased trkB mRNA in the pons significantly predicted impaired memory performance in aged rats. These results suggest that decreases in trkB mRNA with age are more widespread than decreases in BDNF, and that BDNF decreases are restricted to more caudal brain regions.

Aging↗

PubMed1998

Co-infusion with a TrkB-Fc receptor body carrier enhances BDNF distribution in the adult rat brain.

Fusion proteins comprising the Fc domain of human IgG and extracellular domains of receptor tyrosine kinases can neutralize the activity of their cognate ligands when administered in molar excess. We have generated a fusion protein using the ectodomain of TrkB (TrkB-Fc). Although the ability of TrkB-Fc to neutralize the activity of brain-derived neurotrophic factor (BDNF) in vitro has been demonstrated, there have been no conclusive demonstrations of its ability to neutralize the activity of BDNF in vivo. We co-infused TrkB-Fc with BDNF into the cortex and hippocampus of adult rats to determine whether TrkB-Fc would interfere with the ability of BDNF to upregulate neuropeptide Y (NPY). We report here that rather than neutralizing the activity of exogenous BDNF, co-infusion with the TrkB-Fc fusion protein greatly increased the volume of tissue in which neuropeptide Y immunostaining was upregulated. In addition, TrkB-Fc greatly enhanced BDNF's distribution through adult brain parenchyma. TrkB-Fc also markedly increased the otherwise limited diffusion of BDNF into brain parenchyma following intraventricular infusion. These results show that rather than neutralizing or sequestering BDNF, the TrkB-Fc, at close to molar equivalence to BDNF, can function as a carrier for BDNF and thus enhance the delivery or penetration of this polypeptide into the brain.

Animals↗

PubMed1997

Cortical spreading depression induces long-term alterations of BDNF levels in cortex and hippocampus distinct from lesion effects: implications for ischemic tolerance.

Cortical spreading depression (CSD) protects hippocampal and cortical neurons from an otherwise lethal ischemic insult delivered days later. The present study was undertaken to evaluate changes in the expression of BDNF following CSD, distinct from lesion effects and its possible involvement in delayed ischemic tolerance. CSD was elicited by KCl application and a cortical lesion was made by hyperosmolar NaCl application. BDNF mRNA was examined by in situ hybridization and Northern blot up to 7 days post-CSD. BDNF protein content was measured by ELISA. In the cortex, BDNF protein was mildly elevated despite minimal increases of mRNA in the NaCl lesion group. CSD specifically up-regulated BDNF mRNA at 4 h, followed by a delayed secondary increase at 2-3 days. BDNF protein exhibited smaller biphasic increases at 24 h and 3-7 days post-CSD which were significantly higher than the NaCl lesion group. In the hippocampus, BDNF protein levels showed a delayed decrease in both groups independent of mRNA changes, but CSD specifically delayed this decrease. Thus, CSD can alter BDNF levels independent of lesion effects. The increased BDNF following CSD in the cortex is consistent with the involvement of BDNF in cortical ischemic tolerance. BDNF could not, however, be directly related to ischemic tolerance in the hippocampus.

Animals↗

PubMed1996

Role of magnetic resonance imaging in the diagnosis of osteomyelitis in diabetic foot infections.

PURPOSE: The role of magnetic resonance imaging (MRI) in the diagnosis of osteomyelitis in foot infections in diabetics was investigated. The accuracy, sensitivity, and specificity of MRI, plain radiography, and nuclear scanning were determined for diagnosing osteomyelitis, and a cost comparison was made. METHODS: Twenty-seven patients with diabetic foot infections were studied prospectively. All patients underwent MRI and plain radiography. Twenty-two patients had technetium bone scans, and 19 patients had Indium scans. Nineteen patients had all four tests performed. Patients with obvious gangrene or a fetid foot were excluded. RESULTS: The diagnosis of osteomyelitis was established by pathologic specimen (n = 18), bone culture (n = 3), or successful response to medical management (n = 6). Osteomyelitis was confirmed in nine of the pathologic specimens. The diagnostic sensitivity, specificity, and accuracy for MRI was 88%, 100%, and 95%, respectively, for plain radiography it was 22%, 94%, and 70%, respectively, for technetium bone scanning it was 50%, 50%, and 50%, respectively, and for Indium leukocyte scanning it was 33%, 69%, and 58%, respectively. The data were analyzed statistically with the two-tailed Fisher's exact test. MRI was the only test that was statistically significant (p < 0.01). CONCLUSIONS: MRI appeared to be the single best test for the diagnosis of osteomyelitis associated with diabetic foot infections. It had a better diagnostic accuracy than conventional modalities and appeared to be more cost-effective than the frequently used Indium scan.

Adult↗

PubMed1994

Regulation of neuropeptides in adult rat forebrain by the neurotrophins BDNF and NGF.

The expression of neuropeptides and neurotrophic factors is altered in the hippocampus after seizure induction in rats. Because the increase in brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) mRNAs precede changes in neuropeptide expression after seizure, it is possible that BDNF and NGF mediate subsequent alterations in peptide expression. To test this hypothesis directly, BDNF or NGF was infused into the hippocampus and cortex of adult rats. To ascertain the regional specificity of any observed effects of neurotrophin administration on neuropeptide expression, infusions into the striatum were also studied. To control for specificity, vehicle was also infused into the same sites. Peptide and mRNA alterations were assessed by Northern analysis, immunohistochemistry and radioimmunoassay. BDNF produced elevations of peptide and mRNA for neuropeptide Y and cholecystokinin in hippocampus and cortex, and somatostatin in cortex. BDNF increased mRNAs for neuropeptide Y, cholecystokinin, substance P and dynorphin in striatum. In contrast, BDNF decreased dynorphin peptide and mRNA in hippocampus. NGF's effects were limited to small mRNA increases, without corresponding changes in peptide levels, for neuropeptide Y in hippocampus and striatum, substance P in cortex and cholecystokinin in striatum. The distinct and limited effects of NGF infusion on neuropeptide expression demonstrate that BDNF's effects are not non-specific results of protein infusion into the brain. These findings indicate that BDNF may play a regionally specific role in modulating neuropeptide expression in the normal brain as well as in various pathophysiological states.

Animals↗

PubMed1992

Evidence for NMDA receptor involvement in environmentally induced dentate gyrus plasticity.

Research has demonstrated environmentally induced plasticity of hippocampal dentate gyrus-evoked potentials. Other research has shown a role of the NMDA receptor in dentate gyrus long-term potentiation (LTP). The authors tested the role of the NMDA receptor in one form of environmentally induced plasticity, in which transferring animals from their home cages to another environment results in significant excitatory postsynaptic potential (EPSP) enhancement and concomitant depression of the population spike. Rats were chronically implanted with stimulating electrodes in the perforant path and recording electrodes in the dentate gyrus bilaterally. Evoked potentials were recorded from freely behaving rats for four 20-minute sessions (1/wk), which took place immediately following an environmental transfer. Rats received 0.00, 0.05, 0.08, or 0.10 mg/kg MK-801 s.c. 30 minutes prior to recording sessions in either an ascending- or descending-dose series. Results showed that MK-801 produced a reduction of the EPSP enhancement, which takes place over the 20-minute session. The effects of MK-801 on spike depression varied as a function of dose series and time within a session, suggesting a long-term effect of MK-801 on spike depression. There was no detected effect of MK-801 on behavior. Results suggest a role of the NMDA receptor in this form of environmentally induced plasticity with different effects of NMDA receptor antagonism on EPSP enhancement and spike depression.

Animals↗

PubMed1984

Corneal hematoma.

Two cases of corneal hematomas initially manifested as corneal blood staining, but were further complicated by the presence of persistent epithelial defects and stromal thinning. Both cases occurred following cataract surgery. Scanning electron and light microscopic examination in the second case demonstrated a loss of keratocytes, stromal collagen breakdown, and epithelial cell degeneration over the center of the hematoma. Large corneal hematomas may cause epithelial degeneration by functioning as barriers to nutrients and metabolic factors from the anterior chamber. Unlike corneal blood staining, conservative treatment is often insufficient therapy for corneal hematomas with associated persistent epithelial defects. Complications from epithelial defects, including corneal thinning, descemetocele, and perforation, may necessitate more aggressive treatment, even surgery. An epithelial defect overlying blood staining should suggest the presence of a corneal hematoma.

Aged↗

PubMedDate not supplied

Vascular growth factors in cerebral ischemia.

During the past decade, there has been a surge of interest in growth factors (GFs) that act selectively on vascular endothelium and perivascular cells. Studies employing mutant mice or the administration of recombinant proteins have suggested that these factors not only mediate the proliferation of endothelial cells, but also regulate vascular differentiation, regression, and permeability. During and after cerebral ischemia, brain vasculature becomes leaky and unstable, and the normally impermeable blood-brain barrier breaks down. Several days after the ischemic insult, endothelial cells begin to proliferate, and angiogenesis occurs. Expression studies have shown that key vascular GFs are regulated, during these processes, in a complex and coordinated manner. The distinct pattern of regulation exhibited by each vascular GF suggests a unique role for each factor during the initial vascular destabilization and subsequent angiogenesis that occurs after cerebral ischemia. Data from studies in other biological systems support these suggested roles. Thus, manipulation of vascular GFs may prove to be an effective means of stabilizing or enriching brain vasculature after ischemia, and ameliorating the detrimental effects of blood-brain barrier breakdown and vessel regression after stroke.

Animals↗