Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P30536 (PBS)
 9,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied two patients with an axonal type of polyneuropathy, epidermolysis, and IgM kappa plasma cell dyscrasia. The IgM kappa was deposited in the dermis, was absorbed from the serum by axonal micelle preparations, and was precipitated with chondroitin sulfate in highly purified agarose in 0.15 M NaCl with 0.01 M phosphate buffer, pH 7.8. In contrast, we found none of these abnormalities in three patients with IgM plasma cell dyscrasia and demyelinating neuropathy. Of 78 other macroglobulinemic serum samples from patients without neuropathy, 7 precipitated with a sulfated polysaccharide. This reaction occurred at low ionic strength, 0.05 M barbital buffer, pH 8.1, but did not occur in the higher ionic strength of 0.01 M phosphate with 0.15 M NaCl (PBS). The interaction of the IgM with chondroitin sulfate at relatively high ionic strength could cause both the axonal polyneuropathy and the epidermolysis.
 ...
PMID:Monoclonal IgM kappa antibody precipitating with chondroitin sulfate C from patients with axonal polyneuropathy and epidermolysis. 629 26

Optic nerve transection in adult rats results in the death of approximately 50% of the axotomized retinal ganglion cells (RGCs) by 1 week and nearly 90% by 2 weeks after injury. The capacity of brain-derived neurotrophic factor (BDNF) to prevent this early, severe loss of RGCs was investigated in vivo by intravitreal injections of BDNF [5 micrograms in 5 microliters of bovine serum albumin/phosphate-buffered saline (BSA/PBS)] or vehicle (5 microliters of BSA/PBS). Using quantitative anatomical techniques, we show that (i) all RGCs survived 1 week after a single injection of BDNF at the time of axotomy. (ii) RGC densities decreased in the BDNF-treated retinas by 2 weeks but remained significantly greater than in the untreated controls. (iii) An enhanced RGC survival was obtained with single injections of BDNF from 6 days before to 5 days after axotomy. (iv) Repeated injections resulted in greater numbers of surviving RGCs, an effect that declined to undetectable levels by 6 weeks. (v) There were indications for an endogenous local source of trophic support whose expression was triggered by ocular injury, particularly to the anterior part of the eye. (vi) With multiple BDNF injections, there was profuse axonal sprouting around the optic disc. This remarkable intraretinal growth was not, however, reflected in increased RGC innervation of the peripheral nerve grafts, which are known to facilitate regeneration when used as optic nerve substitutes.
 ...
PMID:Effects of ocular injury and administration of brain-derived neurotrophic factor on survival and regrowth of axotomized retinal ganglion cells. 812 57

The neurotoxicant 2,5-hexanedione (HD) causes the accumulation of neurofilaments in the distal axon and an acceleration of neurofilament transport proximal to the site of their accumulation. It has been proposed that the acceleration of transport is due to the direct reaction of HD with neurofilament proteins and, conversely, that this acceleration is a secondary response to the axon to injury. The objective of this study was to determine whether the response of axons to HD intoxication includes acceleration of neurofilament transport. Pulse labelling was used to analyze neurofilament transport in age-matched rats exposed to HD or PBS. The animals receiving HD were exposed either throughout the period of radiolabel transport, or prior to the pulse labeling of neurofilament proteins. If acceleration of the rate of neurofilament transport was due to the direct reaction of HD with proteins, then neurofilaments synthesized after the exposure period should travel at control rates, since these proteins would not have been exposed to the toxicant. After 28 days of transport, optic nerve proteins were examined using SDS-PAGE, fluorography, and computerized densitometry. In both HD-treated groups, neurofilament transport was accelerated relative to age-matched control animals. In addition, the amount of NFH was decreased relative to other neurofilament subunits. The combination of accelerated transport and a diminished proportion of NFH is similar to the observations of neurofilament axonal transport during growth and development. These observations suggest that this persistent, secondary effect is a reparative response to injury that recapitulates axonal growth and development.
 ...
PMID:Decreased levels of the high molecular weight subunit of neurofilaments and accelerated neurofilament transport during the recovery phase of 2,5-hexanedione exposure. 828 99

We previously observed that the transient developmental suppression of myelination or disruption of mature myelin, by local intraspinal infusion of serum complement proteins along with a complement-fixing, myelin-specific antibody (e.g., anti-Galactocerebroside), facilitated avian brainstem-spinal axonal regeneration after spinal transection. We now report the effects of similar immunological protocols on axonal regeneration in the injured adult rat spinal cord. After a lateral hemisection injury of the T10 spinal cord, infusion of the above reagents, over 14 days at T11, facilitated the regeneration of some brainstem-spinal axons. The hemisection lesion enabled comparisons between the retrograde labeling within an injured brainstem-spinal nucleus and the uninjured contralateral homologue. The brainstem-spinal nucleus examined in detail was the red nucleus (RN), chosen for its relatively compact descending pathway within the dorsolateral cord. Comparing the number of labeled neurons within each RN, of an experimentally myelin suppressed animal, indicated that approximately 32% of injured rubrospinal projections had regenerated into the caudal lumbar cord. In contrast, control-treated animals (e.g., PBS vehicle alone, GalC antibody alone, or serum complement alone) showed little or no axonal regeneration. We also examined the ultrastructural appearance of the treated cords. We noted demyelination over 1-2 segments surrounding the infusion site (T11) and a further two segments of myelin disruption (delamination) on either side of the demyelinated zone. The demyelination is an active process (< 3 days) with microglia and/or macrophages engulfing myelin. Thus, the facilitation of axonal regeneration through the transient suppression of CNS myelin may be fundamental to all higher vertebrates.
 ...
PMID:Regeneration of brainstem-spinal axons after lesion and immunological disruption of myelin in adult rat. 987 63

Nerve growth factor (NGF) enhances cholinergic functioning in animals with a compromised cholinergic basal forebrain (CBF). Immunotoxic lesions targeting low-affinity NGF receptor (p75NGF receptor)-bearing CBF neurons provide a selective model for testing the effects of NGF on residual cholinergic neurons. Rats received PBS or the immunotoxin 192IgG-saporin (192Sap) intracerebroventricularly at two doses (1 or 2.7 microg) known to produce different degrees of cholinergic deficit. Seven weeks after lesioning, half of each group received either NGF or cytochrome c intracerebroventricularly for 7 weeks. The two doses of 192Sap produced 50 and 80% depletions of choline acetyltransferase (ChAT) activity in the neocortex and hippocampus. NGF produced the greatest increase in ChAT activity in controls, intermediate in low-lesioned, and smallest in highly lesioned animals. NGF-treated animals showed reduced weight gain, hyper-responsiveness to acoustic stimuli, and decreased inhibitory avoidance. Although general motor behavior was affected by neither 192Sap nor NGF in an open field task, highly lesioned rats took longer to reach the platform during water maze testing. Impaired spatial orientation in finding a hidden platform at the previously acquired position was mitigated by NGF. Hypertrophic changes of residual CBF neurons, Schwann cell hyperplasia, and aberrant axonal sprouting around the medulla were observed in NGF-treated animals only, independent of the preexisting lesion. Our results indicate that NGF has a limited capacity to enhance functioning of residual CBF neurons. More importantly, NGF augmented fear-related behaviors and adverse neuroproliferative changes that may restrict its therapeutic use.
 ...
PMID:Nerve growth factor (NGF) augments cortical and hippocampal cholinergic functioning after p75NGF receptor-mediated deafferentation but impairs inhibitory avoidance and induces fear-related behaviors. 1063 13

We reported recently that overexpression of neurotrophin-3 (NT-3) by motoneurons in the spinal cord of rats will induce sprouting of corticospinal tract (CST) axons (Zhou et al. [2003] J. Neurosci. 23:1424-1431). We now report that overexpression of brain-derived neurotrophic factor (BDNF) or glial cell-derived neurotrophic factor (GDNF) in the rat sensorimotor cortex near the CST neuronal cell bodies together with overexpression of NT-3 in the lumbar spinal cord significantly increases axonal sprouting compared to that induced by NT-3 alone. Two weeks after unilaterally lesioning the CST at the level of the pyramids, we injected rats with saline or adenoviral vectors (Adv) carrying genes coding for BDNF (Adv.BDNF), GDNF (Adv.GDNF) or enhanced green fluorescent protein (Adv.EGFP) at six sites in the sensorimotor cortex, while delivering Adv.NT3 to motoneurons in each of these four groups on the lesioned side of the spinal cord by retrograde transport from the sciatic nerve. Four days later, biotinylated dextran amine (BDA) was injected into the sensorimotor cortex on the unlesioned side to mark CST axons in the spinal cord. Morphometric analysis of axonal sprouting 3 weeks after BDA injection showed that the number of CST axons crossing the midline in rats treated with Adv.BDNF or Adv.GDNF were 46% and 52% greater, respectively, than in rats treated with Adv.EGFP or PBS (P < 0.05). These data demonstrate that sustained local expression of neurotrophic factors in the sensorimotor cortex and spinal cord will promote increased axonal sprouting after spinal cord injury, providing a basis for continued development of neurotrophic factor therapy for central nervous system damage.
 ...
PMID:Neurotrophic factors expressed in both cortex and spinal cord induce axonal plasticity after spinal cord injury. 1451 51

Brain injury following acute and chronic neurological conditions can involve both neuronal perikaryal and axonal damage, yet considerably less is known about the mechanisms of axonal damage. Oligodendrocytes and myelin are highly vulnerable to AMPA receptor-mediated excitotoxicity. In vitro studies using isolated white matter preparations have shown that AMPA receptor-mediated excitotoxicity results in axonal damage. The effect of AMPA on axons in vivo remains to be determined. We established an in vivo model to determine if axons were vulnerable to AMPA-mediated toxicity, and furthermore, to examine if axonal damage occurred through an AMPA receptor-mediated mechanism. Adult rats received stereotaxic injection of AMPA (2.5 or 25 nmol) or vehicle (PBS) into the external capsule. Axonal damage was detected in the external capsule and cortex in sections immunostained for cytoskeletal components microtubule associated protein-5 (MAP 5), the 200 kDa neurofilament subunit (NF 200) and non-phosphorylated neurofilament-H (SMI 32). Quantification of axonal damage in the external capsule of MAP 5-immunostained sections showed that AMPA caused a significant, dose-dependent increase in axonal damage compared to the vehicle-treated controls. AMPA also induced a dose-dependent increase in myelin and neuronal perikaryal damage. Systemic administration of the AMPA receptor antagonist SPD 502 significantly reduced the amount of AMPA-induced axonal, myelin and neuronal damage. These data suggest that AMPA induces structural damage to the cytoskeleton of axons in vivo, as well as neuronal and myelin damage, and that this occurs through AMPA receptor-mediated mechanisms. AMPA receptor antagonism may have therapeutic potential to salvage both axons and neuronal perikarya in a number of neurological disorders.
 ...
PMID:Intracerebral injection of AMPA causes axonal damage in vivo. 1457 82

Treosulfan (dihydroxybusulfane, DHB, L-threitol-1,4-bis [methane sulfonate]) is a cytostatic alkylating agent with a favorable profile of side effects. Myelin-oligodendrocyte-glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) induced in DA (RT1(av1)) rats resembles multiple sclerosis (MS) in many aspects since central nervous system (CNS) pathology shows inflammation, demyelination and axonal loss. Moreover, DA rats develop a chronic disease course. We here explored the efficacy of treosulfan in the treatment of MOG-induced EAE in DA rats. A single dose of treosulfan (1 g/kg body weight i.p.) at the day of immunization significantly reduced disease severity compared with PBS-treated controls. In addition, after disease had evolved, a single dose of treosulfan (1 g/kg body weight) given i.p. on day 14 post-immunization (p.i.) improved long-term disease outcome. Treatment with treosulfan resulted in reduced mRNA expression of IL-12 and interferon (IFN)-gamma in draining lymph nodes and reduced numbers of IFN-gamma-secreting MOG-specific T cells. No myelosuppression was observed. Treosulfan was applied to different subsets of cultured human blood mononuclear cells in order to asses the effects on human immune cells in vitro: Treosulfan reduced proliferative capacity and increased apoptosis in T cells and antigen-presenting cells. In light of the beneficial effects in EAE in vivo and the in vitro immunosuppressive and pro-apoptotic capacities in cultured human mononuclear immune effector cells, these data may support a potential role of treosulfan, an agent with high immunosuppressive capacity and low toxicity, in the treatment of MS.
 ...
PMID:Action of treosulfan in myelin-oligodendrocyte-glycoprotein-induced experimental autoimmune encephalomyelitis and human lymphocytes. 1459 95

The response of supraspinal neurons to acute or delayed treatment with GDNF following a spinal cord injury was examined. A cervical level 3 hemisection lesion cavity was created by tissue aspiration in adult, female rats. In one experiment gel foam saturated with GDNF was placed into the lesion cavity immediately after injury to determine if the extent of axonal retraction was affected by neurotrophic factor treatment. One week prior to sacrifice animals received a microinjection of biotinylated dextran amine (BDA) into the red nucleus and reticular formation to label descending spinal pathways by anterograde transport mechanisms. Animals were sacrificed 1 or 4 weeks after injury and treatment with GDNF. The terminal end of injured BDA-labeled rubrospinal and reticulospinal tract axons was identified and the distance from the lesion was measured. In comparison to PBS-treated animals, GDNF-treatment resulted in a significant decrease in the extent of axonal retraction of both rubrospinal and reticulospinal tract axons at 1 week after spinal cord injury for both tracts. At 4 weeks after injury the mean distance from the lesion was less than 240 microm following GDNF-treatment for both tracts, compared to over 480 microm following PBS-treatment. In the second experiment injured supraspinal neurons were labeled by retrograde transport of True Blue that had been placed into the lesion cavity. One month later scar tissue was removed from the cavity by aspiration to enlarge the cavity by approximately 500 microm in a rostral direction. GDNF-saturated gel foam was placed into the cavity for 60 min prior to apposition of an autologous peripheral nerve (PN) graft to the rostral cavity wall. One month later Nuclear Yellow was applied to the distal end of the PN graft and animals were sacrificed after 2 days. The number of supraspinal neurons containing both True Blue and Nuclear Yellow was counted as a measure of axonal regeneration by chronically injured neurons. There was a seven-fold increase in the number of regenerating neurons after GDNF-treatment, with the majority (65%) of dual-labeled neurons located within the reticular formation. These results indicate that GDNF has neuroprotective effects when provided acutely after injury and promotes axonal regeneration when provided in a chronic injury situation.
 ...
PMID:Restriction of axonal retraction and promotion of axonal regeneration by chronically injured neurons after intraspinal treatment with glial cell line-derived neurotrophic factor (GDNF). 1465 11

Increased cAMP improves neuronal survival and axon regeneration in mammals. Here, we assess cAMP levels and identify activated pathways in a spontaneously regenerating central nervous system. Following optic nerve crush in goldfish, almost all retinal ganglion cells (RGC) survive and regenerate retinotectal topography. Goldfish received injections of a cAMP analogue (CPT-cAMP), a protein kinase A (PKA) inhibitor (KT5720), both compounds combined, or PBS (control). RGC survival in experimental groups was unaffected at any stage. The rate of axon regeneration was accelerated by the activator and decelerated both by the inhibitor and by combined injections, suggesting a PKA-dependent pathway. In addition, errors in regenerate retinotectal topography were observed when agents were applied in vivo and RGC response to the guidance cue ephrin-A5 in vitro was altered by the inhibitor. Our results highlight that therapeutic manipulation of cAMP levels to enhance axonal regeneration in mammals must ensure that topography, and consequently function, is not disrupted.
 ...
PMID:cAMP regulates axon outgrowth and guidance during optic nerve regeneration in goldfish. 1616 47


1 2 3 4 5 6 Next >>