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Wise Young

Publications and source records attributed to Wise Young.

11 recordsLinked to original sources
PubMed2006

Alternative pathways of NF-kappaB activation: a double-edged sword in health and disease.

While the classical pathway of NF-kappaB activation plays critical roles in a wide range of biological processes, the more recently described "non-canonical" NF-kappaB pathway has important but more restricted roles in both normal and pathological processes. The non-canonical NF-kappaB pathway, based on processing of the nf-kappab2 gene product p100 to generate p52, appears to be involved in B-cell maturation and lymphoid development. Deregulated activation of this pathway has been observed in a variety of malignant and autoimmune diseases, thus inhibitors that specifically target p100 processing might be predicted to have potential roles as immunomodulators and in the therapy of malignant diseases. We review current understandings of NF-kappaB activation, particularly the mechanisms of p100 processing under both physiological and pathological conditions.

Autoimmune Diseases↗
PubMed2005

Upregulation of complement inhibitors in association with vulnerable cells following contusion-induced spinal cord injury.

We have previously described the activation of the classical, alternative, and terminal complement cascade pathways after acute contusion spinal cord injury using the New York University (NYU) weight-drop impactor. In the present study, we examined the induction of protein regulators of the complement cascade, factor H (FH), and clusterin, in the same experimental paradigm. The spinal cord of laminectomized adult rats was subjected to mild or severe injury using impactor weight-drop heights of 12.5 and 50 mm, respectively. The spinal cords of control and injured animals were evaluated at 1, 7, and 42 days after injury. Immunocytochemistry revealed a robust increase in the numbers and intensity of staining of FH, and clusterin-positive cells in the injured cord at all three time points, with the highest increases observed at 1 and 42 days after injury. FH and clusterin-positive cells were observed among neurons as well as oligodendrocytes. The increased expression was detected both rostrally and caudally from the injury site, in the latter case at distances up to 20 mm. The precise biological significance of injury-induced upregulation of these proteins remains to be determined. However, FH and clusterin are potent regulators of complement activity targeting upstream (FH) and downstream (clusterin) molecules of the pro-inflammatory cascade, which could be of vital importance in preventing a "runaway" inflammatory reaction in the injured spinal cord.

Animals↗
PubMed2005

Effects of N-methyl-d-aspartate, glutamate, and glycine on the dorsal column axons of neonatal rat spinal cord: in vitro study.

The effects of N-methyl-D-aspartate (NMDA), glutamate, and glycine on the developmental axons of the neonatal rat spinal cord were investigated. Isolated dorsal column preparations from postnatal day (PN) 0 to 14 Long-Evans hooded rats (n = 119) were used in vitro. Compound action potentials (CAPs) were recorded from the cuneate and gracile fasciculi with a glass micropipette electrode. NMDA (100 microM) significantly increased CAP amplitude in PN 0-6 cords by 21.5 +/- 9.2% (mean +/- standard error of the mean, p < 0.001, n = 8) and in PN 7-14 cords by 6.7 +/- 6.6% (p < 0.001, n = 10). NMDA (10 microM) significantly increased the CAP amplitude by 6.3 +/- 2.9% in PN 0-6 cords (p < 0.01, n = 10). The increase of CAP amplitude induced by NMDA (100 microM) in PN 0-6 cords was significantly greater than that in PN 7-14 cords (p < 0.005). Glutamate (100 microM) significantly increased the CAP amplitude by 8.8 +/- 8.1% in PN 0-6 cords (p < 0.001, n = 29) and 6.7 +/- 7.5% in PN 7-14 cords (p < 0.01, n = 14), and glutamate (10 microM) significantly increased by 6.3 +/- 2.9% in PN 0-6 cords (p < 0.01, n = 21). The amplitudes induced by glutamate (100 microM or 10 microM) did not significantly differ between PN 0-6 and PN 7-14 cords. Application of glycine (100 microM) did not significantly alter CAP amplitudes induced by NMDA (100 microM or 10 microM) and glutamate (100 microM or 10 microM). D(-)-2-amino-5-phosphonopentanoic acid (NMDA receptor antagonist) blocked the effects of NMDA and glutamate. These results suggest that NMDA receptor is present on afferent dorsal column axons and may modulate axonal excitability, especially during the 1st week after birth.

Age Factors↗
PubMed2004

Mediators of ischemic preconditioning identified by microarray analysis of rat spinal cord.

Spinal ischemia is a frequent cause of paralysis. Here we explore the biological basis of ischemic preconditioning (IPC), the phenomenon in which a brief period of ischemia can confer protection against subsequent longer and normally injurious ischemia, to identify mediators of endogenous neuroprotection. Using microarrays, we examined gene expression changes induced by brief spinal ischemia using a rat balloon occlusion model. Among the nearly 5000 genes assayed, relatively few showed two-fold changes, and three groups stood out prominently. The first group codes for heat shock protein 70, which is induced selectively and robustly at 30 min after brief ischemia, with increases up to 100-fold. A second group encodes metallothioneins 1 and 2. These mRNAs are increased at 6 and 12 h after ischemia, up to 12-fold. The third group codes for a group of immediate-early genes not previously associated with spinal ischemia: B-cell translocation gene 2 (BTG2), the transcription factors early growth response 1 (egr-1) and nerve growth factor inducible B (NGFI-B), and a mitogen-activated protein kinase phosphatase, ptpn16, an important cell signaling regulator. These mRNAs peak at 30 min and return to baseline or are decreased 6 h after ischemia. Several other potentially protective genes cluster with these induced mRNAs, including small heat shock proteins, and many have not been previously associated with IPC. These results provide both putative mediators of IPC and molecular targets for testing preconditioning therapies.

Animals↗
PubMed2004

Activation of complement pathways after contusion-induced spinal cord injury.

Previous studies have shown that a cellular inflammatory response is initiated, and inflammatory cytokines are synthesized, following experimental spinal cord injury (SCI). In the present study, we tested the hypothesis that the complement cascade, a major component of both the innate and adaptive immune response, is also activated following experimental SCI. We investigated the pathways, cellular localization, timecourse, and degree of complement activation in rat spinal cord following acute contusion-induced SCI using the New York University (NYU) weight drop impactor. Mild and severe injuries (12.5 and 50 mm drop heights) at 1, 7, and 42 days post injury time points were evaluated. Classical (C1q and C4), alternative (Factor B) and terminal (C5b-9) complement pathways were strongly activated within 1 day of SCI. Complement protein immunoreactivity was predominantly found in cell types vulnerable to degeneration, neurons and oligodendrocytes, and was not generally observed in inflammatory or astroglial cells. Surprisingly, immunoreactivity for complement proteins was also evident 6 weeks after injury, and complement activation was observed as far as 20 mm rostral to the site of injury. Axonal staining by C1q and Factor B was also observed, suggesting a potential role for the complement cascade in demyelination or axonal degeneration. These data support the hypothesis that complement activation plays a role in SCI.

Animals↗
PubMed2003

Soluble cell adhesion molecule L1-Fc promotes locomotor recovery in rats after spinal cord injury.

Previous studies suggest that the cell adhesion molecule L1 promotes neurite growth by neutralizing white matter associated inhibitors of axonal growth. We made a soluble chimeric dimer by linking mouse L1 to human Fc. This L1-Fc construct (40 microg/mL) markedly facilitated neurite outgrowth, as well as neuronal adhesion to white matter on frozen sections of spinal cord. We applied L1-Fc intrathecally (200 microg/mL at 0.5 microL/h) to rat spinal cords for 2 weeks after a 25-mm weight drop contusion of the T13 spinal cord. Initial experiments indicated that L1-Fc is present in the spinal cord after 2 weeks of intrathecal infusion and significantly improved locomotor recovery by 6-12 weeks after injury. We then randomized 45 rats to intrathecal infusion of L1-Fc (L1), phosphate-buffered saline controls (PBS), and a mouse monoclonal IgM antibody (M1). By 12 weeks after injury, L1-treated rats recovered significantly (p < 0.005) better locomotor function (BBB score 10.57 +/- 0.25, n = 14) than PBS-treated rats (BBB score 9.00 +/- 0.33, n = 14) or M1-treated (BBB score 8.71 +/- 0.16, n = 14). Only two rats of 22 treated with saline recovered weight-supported ambulation. Of 20 L1-Fc-treated rats, however, 18 recovered weight-supported walking by 12 weeks. The L1-Fc-treated rats also showed more consistent hindlimb contact placing than saline controls. We injected biotinylated dextran amine (BDA) into the motor cortices of 14 rats treated with L1-Fc to label corticospinal axons, comparing these with 13 rats treated with saline. In saline-treated rats, BDA-labeled corticospinal axons often grew up to the impact edge and occasionally into the impact site. L1-treated rats showed longer corticospinal tract growth at the injury site. Three rats had BDA-labeled axons that extended beyond the impact center. One L1-Fc-treated rat showed axonal extension and synapse formation in cord distal to the injury. These results indicate that soluble L1-Fc promotes axonal growth and functional recovery after spinal cord injury. However, the limited corticospinal tract growth across the injury site cannot account for the observed locomotor recovery. Thus, L1 may be stimulating growth of other motor tracts or protecting axons and neurons. More studies are required to elucidate the mechanisms of L1-Fc-induced locomotor recovery.

Animals↗
PubMed2003

Glutamine synthetase induced spinal seizures in rats.

Glutamine synthetase (GS) is a key enzyme in the regulation of glutamate neurotransmission in the central nervous system. It is responsible for converting glutamate to glutamine, consuming one ATP and NH3 in the process. Glutamate is neurotoxic when it accumulates in extracellular fluids. We investigated the effects of GS in both a spinal cord injury (SCI) model and normal rats. 0.1-ml of low (2- micro M) and high (55- micro M) concentrations of GS were applied, intrathecally, to the spinal cord of rats under pentobarbital anesthesia. Immediately after an intrathecal injection into the L1-L3 space, the rats developed convulsive movements. These movements initially consisted of myoclonic twitches of the paravertebral muscles close to the injection site, repeated tonic and clonic contractions and extensions of the hind limbs (hind limb seizures) that spread to the fore limbs, and finally rotational axial movements of the body. An EMG of the paravertebral muscles, fore and hind limbs, showed the extent of the muscle activities. GS (2- micro M) caused spinal seizures in the rats after the SCI, and GS (6- micro M) produced seizures in the uninjured anesthetized rats. Denatured GS (70 degrees C, 1 hour) also produced spinal seizures, although higher concentrations were required. We suggest that GS may be directly blocking the release of GABA, or the receptors, in the spinal cord.

Animals↗
PubMed2002

Cytokine activity contributes to induction of inflammatory cytokine mRNAs in spinal cord following contusion.

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.

Animals↗
PubMed2002

Spinal cord contusion models.

Most human spinal cord injuries involve contusions of the spinal cord. Many investigators have long used weight-drop contusion animal models to study the pathophysiology and genetic responses of spinal cord injury. All spinal cord injury therapies tested to date in clinical trial were validated in such models. In recent years, the trend has been towards use of rats for spinal cord injury studies. The MASCIS Impactor is a well-standardized rat spinal cord contusion model that produces very consistent graded spinal cord damage that linearly predicts 24-h lesion volumes, 6-week white matter sparing, and locomotor recovery in rats. All aspects of the model, including anesthesia for male and female rats, age rather than body weight criteria, and arterial blood gases were empirically selected to enhance the consistency of injury.

Animals↗
PubMed2002

Effects of methylprednisolone on axonal depression induced by hypoxia, gamma-aminobutyric acid, and (+/-)-8-hydroxy-dipropylaminotetralin hydrobromide.

OBJECTIVE: We sought to confirm the effects of methylprednisolone (MP) on axonal depression induced by hypoxia, gamma-aminobutyric acid (GABA), and (+/-)-8-hydroxy-dipropylaminotetralin hydrobromide (8-OH-DPAT). METHODS: Compound action potentials were recorded to assess the effects of MP in neonatal rat spinal cord axons. Longitudinally hemisected spinal cords were superfused for 120 minutes in Ringer's solution saturated with 95% N2 and 5% CO2. The effect of MP on GABA- and 8-OH-DPAT-induced axonal depression was analyzed with oxygenated isolated dorsal columns. RESULTS: Hypoxia (120 min) significantly reduced the response amplitudes in hemicord preparations. MP (30 micromol/L) prevented hypoxia-induced depression of action potential amplitudes. In oxygenated dorsal column preparations, GABA (50 micromol/L) significantly reduced action potential amplitudes. At 10, 30, and 100 micromol/L, MP had no effect on axonal excitability and GABA-induced axonal depression. 8-OH-DPAT (100 micromol/L) significantly reduced the action potential amplitude. MP (10, 30, 50, and 100 micromol/L) reduced 8-OH-DPAT-induced amplitude depression in a dose-dependent manner. CONCLUSION: At the higher concentrations, MP protected spinal cord axons against hypoxia-induced excitability loss. It had an effect on serotonin 1A-induced axonal depression but not on GABA-induced depression.

8-Hydroxy-2-(di-n-propylamino)tetralin↗