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A J Windebank

Publications and source records attributed to A J Windebank.

At least 55 records · Page 3Linked to original sources
PubMed1997

Long-term alterations in growth factor mRNA expression following seizures.

Although alterations in growth factor mRNA occur during neuronal insults, little is known about the long-term effects of neuronal insults on growth factor expression. We have examined the effects of prolonged post-ictal times on the expression of Brain-derivered nerve factor (BDNF) and Neurotrophin 3 (NT3) following Kainic acid (KA)-induced seizures. In situ hybridization was performed on male Sprague-Dawley rats sacrificed 1-2 weeks following intracranial ventricular KA injections. BDNF mRNA increased bilaterally 1 and 2 weeks after injections, whereas NT3 mRNA decreased contralaterally 1 week and bilaterally 2 weeks post-injection. These observations provide evidence that alterations in growth factor mRNA expression occur even after prolonged post-ictal recovery suggesting a possible role for growth factors in recovery and continued maintenance of surviving neurons within limbic seizure foci.

Animals↗
PubMed1997

Effects of 1,25-dihydroxyvitamin D3 on growth of mouse neuroblastoma cells.

Epitopes of the 1,25-dihydroxyvitamin D(1,25(OH)2D3) receptor have been shown in developing dorsal root ganglia in fetal mice, as well as in cells maintained in culture [Johnson, J.A., Grande, J.P., Windebank, A.J. and Kumar, R., 1,25-Dihydroxyvitamin D3 receptors in developing dorsal root ganglia of fetal rats, Dev. Brain Res., 92 (1996) 120-124]. To investigate a possible role for 1,25(OH)2D3 in neural cell growth and development, a murine neuroblastoma cell line that expresses 1,25(OH)2D3 receptors, was treated with 1,25(OH)2D3. Treatment with 1,25(OH)2D3 resulted in a decrease in cell proliferation, a change in cell morphology, and the expression of protein markers of mature neuronal cells. The decrease in cell proliferation was accompanied by an increase in the expression of nerve growth factor (NGF). Anti-NGF monoclonal antibody added to the growth medium blocked the decrease in cell proliferation caused by 1,25(OH)2D3 treatment. Our results show that the sterol hormone 1,25(OH)2D3, causes a decrease in the proliferation of mouse neuroblastoma cells through alterations in the expression of NGF.

Animals↗
PubMed1997

Acidity is involved in the development of neuropathy caused by oxidized cellulose.

Recently we demonstrated that oxidized cellulose (OC), a surgical topical hemostatic agent, induces subjacent nerve fiber degeneration by a diffusible chemical mechanism. Since OC is highly acidic, we examined the role of acidity in the development of neuropathy by OC in this study. Fifteen minutes' exposure to culture media containing OC (2 mg/ml, pH 3.47 or 10 mg/ml, pH 2.57) suppressed the subsequent neurite outgrowth of precultured rat DRG neurons in vitro. However, the neurotoxicity of OC disappeared when the pH of the media was restored to 7.42. Topical application of 20 mg OC lowered the pH in the subperineurium of the adjacent rat sciatic nerve to around 3, and kept it below 4 for 2 h in vivo. Application of 0.1 ml neutralized physiological saline containing 40 mg OC did not produce pathological changes in the adjacent rat sciatic nerve in vivo, in contrast to the marked subperineurial nerve damage by direct application of 20 or 40 mg OC observed in our previous study. These results strongly indicate that local neurotoxicity of OC is due to its high acidity. Further care is needed to avoid direct application of large amounts of OC to peripheral nerve.

Acids↗
PubMed1997

Calmodulin in ischemic neurotoxicity of rat hippocampus in vitro.

To determine whether calmodulin plays a role in neurodegeneration after ischemia, effects of the selective calmodulin inhibitors calmidazolium and W7 were studied in organotypic cultures of rat hippocampus. Protection of pyramidal cells in the CA1 region of the hippocampus by calmidazolium and W7 against hypoxia/hypoglycemia suggests that activation of intracellular calmodulin plays a significant role in ischemic neuronal injury. Both ryanodine and TMB-8, inhibitors of intracellular Ca2+ release, failed to prevent ischemic neuronal injury. These results indicate that calmodulin, a major intracellular Ca2+ binding protein, plays a significant role in experimental ischemia-induced hippocampal neuronal injury in vitro.

Animals↗
PubMed1997

Inhibition of axonal growth from sensory neurons by excess nerve growth factor.

Fifteen-day embryonic rat dorsal root ganglion (DRG) neurons were exposed to 1 to 200 ng/ml nerve growth factor (NGF). Maximal neurite outgrowth was obtained with 10 to 20 ng/ml. Neurite outgrowth was reduced to 89% of maximal by increasing NGF to 50 ng/ml, to 66% by 100 ng/ml, and to 18% by 200 ng/ml NGF. Identical effects were seen with mouse 2.5S NGF and recombinant human NGF. Neuron cell counts demonstrated that significant cell death did not occur. In time course experiments, significant inhibition, compared with control, began within 1 hour of adding 200 ng/ml and 3 hours of adding 50 ng/ml NGF. The inhibitory effect of NGF on neurite outgrowth was reversed within 3 hours when DRG were incubated with 5 ng/ml NGF after treatment with 50 or 200 ng/ml NGF medium for 12 hours. The inhibition demonstrated for neurons did not occur in PC12 cells; axonal growth was not inhibited by up to 1,000 ng/ml NGF. Excess brain-derived neurotrophic factor or neurotrophin-3 did not inhibit neurite outgrowth. We conclude that high concentrations of NGF produces specific and reversible arrest of neurite outgrowth from sensory neurons. This observation has important clinical implications, because these inhibitory concentrations have been exceeded when NGF has been administered into the central nervous system of humans and animals.

Animals↗
PubMed1997

Correlation between PMP-22 messenger RNA expression and phenotype in hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies (HNPP) is associated with a deletion in chromosome 17p11.2, which includes the gene for the peripheral myelin protein 22 (PMP-22). A "gene dosage" effect is probably the mechanism underlying HNPP, but the amount of PMP-22 mRNA in sural nerves of HNPP patients is highly variable and the role of PMP-22 underexpression in impairing myelination has yet to be clarified. We have studied 6 genetically proven HNPP patients, to evaluate the relationship between PMP-22 mRNA levels, and clinical, neurophysiological, and neuropathological findings. Underexpression of PMP-22 mRNA correlates with disease severity and with mean axon diameter and g ratio, but not with myelin thickness, number of "tomacula," or nerve conduction parameters. Our findings further confirm that underexpression of PMP-22 is the main pathogenetic mechanism underlying the severity of clinical symptoms and signs in HNPP. Smaller axons in sural nerves of HNPP patients with lower PMP-22 levels suggests that underexpression of PMP-22 may also affect axon development.

Charcot-Marie-Tooth Disease↗
PubMed1997

Underexpression of messenger RNA for peripheral myelin protein 22 in hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies (HNPP) is associated with a deletion in chromosome 17p11.2, including the gene for the peripheral myelin protein 22 (PMP-22). Because of the proposal that a decreased dosage of the PMP-22 gene was the cause of HNPP, we evaluated sural nerves from eight patients with the 17p11.2 deletion and from five normal controls. The relative amount of PMP-22 mRNA was significantly lower in HNPP patients compared with normal controls (p < 0.02) using a semiquantitative reverse transcriptase-polymerase chain reaction. There was no significant decrease of Pzero mRNA. Sural nerves from HNPP patients showed normal immunostaining with monoclonal antibodies against PMP-22, Pzero, and myelin basic protein, and only rare myelinated fibers, classified as "tomacula," showed a patchy staining of the compact myelin with monoclonal antibody against PMP-22. The significant underexpression of PMP-22 mRNA in HNPP patients compared with normal controls demonstrates that a decreased dosage of the PMP-22 gene is the most likely pathogenetic mechanism in HNPP.

Base Sequence↗
PubMed1997

Subacute diabetic proximal neuropathy.

OBJECTIVE: To evaluate the clinical, electrophysiologic, autonomic, and neuropathologic characteristics and the natural history of subacute diabetic proximal neuropathy and its response to immunotherapy. MATERIAL AND METHODS: For the 12-year period from 1983 to 1995, we conducted a retrospective review of medical records of Mayo Clinic patients with diabetes who had subacute onset and progression of proximal weakness. The responses of treated versus untreated patients were compared statistically. RESULTS: During the designated study period, 44 patients with subacute diabetic proximal neuropathy were encountered. Most patients were middle-aged or elderly, and no sex preponderance was noted. The proximal muscle weakness often was associated with reduced or absent lower extremity reflexes. Associated weight loss was a common finding. Frequently, patients had some evidence of demyelination on nerve conduction studies, but it invariably was accompanied by concomitant axonal degeneration. The cerebrospinal fluid protein concentration was usually increased. Diffuse and substantial autonomic failure was generally present. In most cases, a sural nerve biopsy specimen suggested demyelination, although evidence of an inflammatory infiltrate was less common. Of 12 patients who received treatment (with prednisone, intravenous immune globulin, or plasma exchange), 9 had improvement of their conditions, but 17 of 29 untreated patients (59%) with follow-up also eventually had improvement, albeit at a much slower rate. Improvement was usually incomplete. CONCLUSION: We suggest that the entity of subacute diabetic proximal neuropathy is an extensive and severe variant of bilateral lumbosacral radiculoplexopathy, with some features suggestive of an immune-mediated cause. It differs from chronic inflammatory demyelinating polyradiculoneuropathy in that most cases have a more restricted distribution and seem to be monophasic and self-limiting. The efficacy of immunotherapy is unproved, but such intervention may be considered in the severe and progressive cases or ones associated with severe neuropathic pain.

Acute Disease↗
PubMed1996

Calcium in suramin-induced rat sensory neuron toxicity in vitro.

Suramin is an experimental chemotherapeutic agent and a neurotoxin which causes a dose-dependent peripheral neuropathy in vivo and inhibits dorsal root ganglion (DRG) neurite outgrowth in vitro. The mechanism of suramin-induced cyto- and neurotoxicity remains unclear. Calcium is a key signal transducer in cellular responses to a variety of physiological and pathogenic stimuli. In the present study, we have determined the role of calcium in suramin-induced neurotoxicity in dorsal root ganglion neurons in vitro. Suramin-induced inhibition of neurite outgrowth and induction of neuronal cell death were dose-related phenomena. A low level of extracellular calcium significantly reduced suramin-induced inhibition of neurite outgrowth and delayed neuronal cell death in vitro. Nimodipine (100 microM), an L-type voltage-sensitive calcium channel (VSCC) inhibitor, mimicked low calcium medium and protected neurite outgrowth in regular calcium medium supplemented with 300 microM suramin. TMB-8 (100 microM), an inhibitor of intracellular calcium release, failed to protect neurite outgrowth against the toxin. Calmidazolium (10 microM), a potent calmodulin inhibitor, and calpain inhibitor peptide (CIP, 10 microM) protected neurite outgrowth against suramin. The results support the hypothesis that the calcium signaling system is important in suramin-induced neurotoxicity. Influx of extracellular calcium is more important than release of intracellular calcium in causing cell injury in vitro.

Animals↗
PubMed1996

1,25-Dihydroxyvitamin D(3) receptors in developing dorsal root ganglia of fetal rats.

We observed immunostaining for the 1,25-dihydroxyvitamin D(3) receptor (VDR) and calbindin-D(28k) in neurons, but not glial cells, of fetal rat dorsal root ganglia (DRG) from days 13 through 21 of gestation. Dispersed cultures of DRG collected from rat fetuses at gestational day 15 also contained epitopes for VDR and calbindin-D(28k) in neurons, but not in glial cells. 1,25-Dihydroxyvitamin D(3), through VDR, may perform significant functions in the development of neuronal cells.

Animals↗
PubMed1996

Expression of high- and low-affinity neurotrophin receptors on human transformed B lymphocytes.

We performed high-sensitivity flow cytometry and Western blotting to study the expression of the low-affinity NGF receptor (p75NGFR) and of the transmembrane tyrosine kinase (Trk) family of high-affinity receptors for the different neurotrophic factors on Epstein-Barr virus (EBV)-transformed human B lymphocytes. Reverse transcriptase (RT) polymerase chain reaction (PCR) with single and multiple sets of primers (multiplex RT-PCR) was used to survey the repertoire of neurotrophin receptor transcripts in this cell line. We demonstrated that transformed B cells express detectable levels of Trk b and its mRNA. Conversely, negative results were obtained for p75NGFR, Trk a, and Trk c. Exposure of EBV-transformed B lymphocytes to brain-derived neurotrophic factor (BDNF) triggered the phosphorylation of Trk b, as demonstrated by Western blots of cell lysates probed with monoclonal antibody against phosphotyrosine.

B-Lymphocytes↗
PubMed1996

Suramin induces phosphorylation of the high-affinity nerve growth factor receptor in PC12 cells and dorsal root ganglion neurons.

Suramin is a polysulfonated naphthylurea with demonstrated antineoplastic activity. Toxicity includes adrenal insufficiency and peripheral neuropathy. Although the mechanism of antitumor activity is unknown, inhibition of binding of growth factors to their receptors has been suggested. Growth factors inhibited by suramin include platelet-derived growth factor, fibroblast growth factor, transforming growth factor, epidermal growth factor, insulin-like growth factor, and nerve growth factor (NGF). In these studies, suramin was shown to be cytotoxic to PC12 cells in a dose-dependent manner. At lower doses and in surviving cells, we observed the induction of neurite outgrowth. To determine the mechanism of suramin-induced neurite outgrowth, PC12 cells were exposed to suramin and/or NGF for various time periods and treated cells were analyzed, by western blot analysis, for expression of tyrosine phosphoproteins. There was a similarity in the pattern of tyrosine-phosphorylated proteins in PC12 cells stimulated with suramin or NGF. Of particular interest was the rapid phosphorylation (by 1 min) of the high-affinity NGF (TrkA) receptor. Activation of other members of the signal-transduction cascade (Shc, p21ras, Raf-1, ERK-1) revealed similar phosphorylation levels induced by suramin and NGF. Parallel studies were performed in rat dorsal root ganglion cultures; suramin potentiated neurite outgrowth and activated the NGF receptor on these cells. This finding of specific patterns of tyrosine phosphorylation of cellular proteins in response to suramin treatment demonstrated that suramin is a partial agonist for the NGF receptor in both PC12 cells and dorsal root ganglion neurons.

Animals↗
PubMed1996

Localization and expression of ciliary neurotrophic factor (CNTF) in postmortem sciatic nerve from patients with motor neuron disease and diabetic neuropathy.

Ciliary neurotrophic factor (CNTF) is thought to play an important role in the maintenance of the mature motor system. The factor is found most abundantly in myelinating Schwann cells in the adult sciatic nerve. Lack of neuronal growth factors has been proposed as one possible etiology of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Growth factor replacement therapies are currently being evaluated as a treatment for motor neuron disease. In this report we determined whether the expression of CNTF in sciatic nerve differed in patients with motor neuron disease compared to controls or patients with another form of axonopathy. We identified 8 patients (7 with ALS and 1 with SMA) with motor neuron disease and 6 patients with diabetic motor neuropathy who had autopsy material available. Immunoperoxidase staining showed reduced CNTF expression in nerves of patients with motor neuron disease but not in patients with diabetic motor neuropathy. Decreased CNTF appears be associated with primary motor neuron disease rather than a generalized process of axon loss. This result supports suggestions that CNTF deficiency may be an important factor in the development of motor neuron disease.

Adult↗
PubMed1996

Hereditary neuralgic amyotrophy.

Hereditary neuralgic amyotrophy with predilection for the brachial plexus is an autosomal dominant disorder associated with recurrent, episodic, painful brachial neuropathies. Mildly dysmorphic facial features including hypotelorism, long nasal bridge and upslanting palpebral fissures are present in affected people in some pedigrees with this disease. The molecular basis of hereditary neuralgic amyotrophy is unknown and the specific gene which leads to it has not been identified. The feature of brachial neuropathy is shared with hereditary neuropathy with liability to pressure palsies, another autosomal dominant disorder which maps to chromosome 17p11.2-12 and may be clinically confused with hereditary neuralgic amyotrophy. Genetic studies have shown that the two diseases do not map to the same chromosomal region and are, therefore, genetically distinct disorders. Genetic linkage studies with polymerase chain reaction-based DNA markers in two large pedigrees recently localized the hereditary neuralgic amyotrophy gene to the distal long arm of chromosome 17 (17q24-qter).

Adolescent↗
PubMed1996

Lack of progression of neurologic deficit in survivors of paralytic polio: a 5-year prospective population-based study.

We completed a prospective, population-based cohort study of polio survivors in Olmsted County, Minnesota, between 1986 and 1993. We identified 50 individuals who had had paralytic polio between 1935 and 1960, as representative of all 300 cases of paralytic polio in the county. We completed detailed quantitative clinical and electrophysiologic studies at entry and after 5 years. These studies demonstrated stable neuromuscular function within the cohort, although 60% of the individuals were symptomatic. In two-thirds of the symptomatic patients, the causes of their symptoms were unrelated to earlier polio. For the 20% of patients who had unexplained muscle pain, perception of weakness, and fatigue, a mechanical disorder most likely underlies their symptoms.

Action Potentials↗
PubMed1996

The sensitivity and specificity of anti-GM1 antibody testing.

Elevated titers of antibodies directed at ganglioside epitopes have been associated with multifocal motor neuropathy (MMN), motor variant of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), amyolrophic lateral sclerosis (ALS), and other motor neuropathies. Anti-GM1 antibodies were measured in 675 patients: 180 age- and sex-stratified healthy blood bank controls, 132 normal controls who had full neurologic assessment including electromyography, 121 patients with definite ALS, 19 patients with pure sensory neuropathy, and 173 consecutive patient serum samples submitted for GM1 antibody testing. Antibodies to three ganglioside epitopes were determined by ELISA: IgM and IgG anti-monosialo GM1, asialo GM1, and disialo GD1b. Antibody titers for normal subjects and patients with ALS were used to determine normal values and borderline levels below which 99% of normal and 99% of ALS patient titers were found. Clinical evaluation of the next 173 consecutive patients referred for anti-GM1 antibody testing revealed 36 patients with motor neuropathies. Sera from 18 of these patients had titers above the 99% normal threshold and 14 had titers above the ALS and normal borderline threshold. All 14 with elevated sera titers were from patients with motor neuropathy or neuronopathy. Sixteen patients met the clinical and electrophysiologic criteria for MMN; 10 had elevated titers. Ten patients had the motor variant of CIDP without conduction block and three had elevated titers. Anti-IgM asialo GM1 antibodies had the highest sensitivity and specificity. High-titer IgM antibodies against monosialo GM1 occurred only in patients with various forms of pure motor neuropathy (100% specificity). The sensitivity was 50% for this referral-based population.

Adult↗