Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurotrophic factors are molecules that regulate neuronal survival, nervous system plasticity and many other physiological functions of neuronal and glial cells, as well as some non-neuronal tissues. They have been involved in the etiopathogenesis of some neurodegenerative disorders, and some of them have been proposed as potential treatments for these diseases on the basis of in vitro experiments and animal models. The main neurotrophic factor families with potential therapeutic applications include the family of neurotrophins (NGF, BDNF or NT-3), GDNF and related neurotrophic factor, CNTF and the members of the IGF family. Some of these molecules have already been tested in clinical trials with contradictory results. One of the major challenges to their clinical use is the difficulty to deliver them into the central nervous system. Nevertheless, solid rational exists for the possible use of neurotrophic factors in the treatment of Alzheimer's and Parkinson's diseases, peripheral neuropathies or amyotrophic lateral sclerosis. This review compiles the essential aspects of neurotrophic factors and the current studies of their clinical relevance and therapeutic potentialities. Future directions for further research are also discussed.
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PMID:[Neurotrophic factors: basis for their clinical application]. 1259 Mar 77

Ciliary neurotrophic factor (CNTF) maintains survival of adult motor neurons. Mice lacking the CNTF gene develop mild, progressive motor neuron loss. In the normal human population, 1 to 2.3% are homozygous for a null allele, and reports suggest this mutant is associated with a younger onset of amyotrophic lateral sclerosis (ALS). We have tested this hypothesis in a study of 400 subjects with ALS and 236 controls. There was no difference in age of onset, clinical presentation, rate of progression, or disease duration for those with one or two copies of the null allele, excluding CNTF as a major disease modifier in ALS.
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PMID:Ciliary neurotrophic factor genotype does not influence clinical phenotype in amyotrophic lateral sclerosis. 1283 31

Transgenic rats expressing a mutated form of the human Cu/Zn superoxide dismutase (hSOD1(G93A)) develop an amyotrophic lateral sclerosis (ALS)-like phenotype, including motor neurone degeneration and reactive gliosis in the spinal cord. This study aimed at examining the presence of endogenous neural progenitors in the lumbar spinal cord of these rats at the end-stage of the disease. Immunohistochemical data clearly demonstrated the induced expression of the stem cell factor reported as a chemoattractant and survival factor for neural stem cells as well as nestin (neuro-epithelial stem cell intermediate filament) in the spinal cord sections. While the stem cell factor immunolabelling appeared diffuse throughout the gray matter, nestin labelling was restricted to clusters within the ventral horn. Interestingly, as paralysis regularly develops asymmetrically, induction of nestin was only detected on the ipsilateral side of the predominant symptoms. Finally, immunohistochemical detection of the stem cell factor receptor (c-Kit) revealed its specific induction which coincided with nestin immunolabelling. Together, these results are indicative of endogenous recruitment of neural progenitors within lesioned tissues and could support the development of treatments involving endogenous or exogenous stem cells.
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PMID:Unilateral induction of progenitors in the spinal cord of hSOD1(G93A) transgenic rats correlates with an asymmetrical hind limb paralysis. 1654 Feb 43

About 10% of amyotrophic lateral sclerosis (ALS) cases are familial. We identified a five-generation Chinese family with autosomal dominant familial ALS (FALS). We performed a detailed family study, clinical and electromyographic validation, and SOD1, VEGF and CNTF mutation analyses. Forty-five living members (16 affected) were studied and DNA samples collected. Genealogical data were collected for deceased members. Based on the duration between symptom onset to ventilator dependence, they were divided into rapidly progressive (range 1-18 months, mean (SD) duration = 12.08 (+/-6.10) months, mean (SD) age of symptom onset = 39.75 (+/-9.84) years) and slowly progressive groups (>18 months; mean (SD) age of onset = 37.25 (+/-5.32) years old). We identified a heterozygous mutation of ATT to ACT of SOD1 gene at codon 149 in exon 5 resulting in substitution of isoleucine to threonine. It co-segregated with all affected members and 11 non-symptomatic members. We report a large multigenerational Chinese FALS kindred with I149T mutation in SOD1. No polymorphisms or mutations were found to date in two known modifier genes, namely, VEGF and CNTF, which were associated with heterogeneity in the phenotype within this kindred. Follow-up of the family will be helpful to explore any potential disease markers.
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PMID:Clinical phenotypes of a large Chinese multigenerational kindred with autosomal dominant familial ALS due to Ile149Thr SOD1 gene mutation. 1696 3

Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for motoneurons (MNs), and is considered a potential agent for the treatment of amyotrophic lateral sclerosis (ALS) and other MN diseases. The effectiveness of GDNF may depend significantly upon its route of delivery to MNs. In this study we tested the neuroprotective effects of target-derived and centrally derived GDNF in the G93A-SOD1 mouse model of ALS using a transgenic approach. We found that overexpression of GDNF in the skeletal muscle (Myo-GDNF mice) significantly delayed the onset of disease and increased the life span of G93A-SOD1 mice by 17 days. The duration of disease also increased by 8.5 days, indicating that GDNF slowed down the progression of disease. Locomotor performance in Myo-GDNF/G93A-SOD1 mice was also significantly improved. The behavioral improvement correlated well with anatomical and histological data. We demonstrated that muscle-derived GDNF resulted in increased survival of spinal MNs, and twice as many MNs survived in end-stage double transgenic mice compared to end-stage G93A-SOD1 mice. Muscle-derived GDNF also had profound effects on muscle innervation and axonal degeneration. Significantly higher numbers of completely or partially innervated NMJs and large caliber myelinated axons were found in double transgenic mice. In contrast, we demonstrated that overexpression of GDNF in astrocytes in the CNS (GFAP-GDNF mice) failed to demonstrate any neuroprotective effects in G93A-SOD1 mice both on behavioral and histological levels. These data indicate that retrograde transport and signaling of GDNF is more physiological and effective for ALS treatment than anterogradely transported GDNF.
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PMID:Muscle-derived but not centrally derived transgene GDNF is neuroprotective in G93A-SOD1 mouse model of ALS. 1703 90

The 27 kDa heat shock protein 1 (HSP27) is a member of the ubiquitously expressed small heat shock protein family and has pleiotropic cytoprotective functions. Since HSP27 may act as a motor neuron survival factor, we analyzed the genetic contribution of the human HSPB1 gene (HSPB1) to the etiology of amyotrophic lateral sclerosis (ALS). In a cohort of sporadic ALS patients, we identified three rare genetic variations and one of which (c.-217T>C) targeted a conserved nucleotide of the Heat Shock Element (HSE) in the HSPB1 promoter. Since binding of Heat Shock Factor 1 (HSF1) to this HSE is essential for stress-induced transcription of HSPB1, we examined the effect of the c.-217C allele on transcriptional activity and HSF binding. The basal promoter activity of the HSPB1 c.-217C mutant allele decreased to 50% as compared to the wild-type promoter in neuronal and non-neuronal cells. Following heat shock, the HSE variant attenuated significantly the stress-related increase in transcription. Electrophoretic mobility shift assays demonstrated a dramatically reduced HSF-binding to the c.-217C mutant allele as compared to the c.-217T wild-type allele. In conclusion, our study underscores the importance of the c.-217T nucleotide for HSF binding and heat inducibility of HSPB1. Therefore, our study suggests that the functional HSPB1 variant may represent a genetic modifier in the pathogenesis of motor neuron disease; however, it is necessary to confirm this HSPB1 variant in additional ALS patients.
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PMID:Genetic variant in the HSPB1 promoter region impairs the HSP27 stress response. 1762 84

AIT-082 (an analog of hypoxanthine) is an orally-active nerve growth factor (NGF) agonist under development by NeoTherapeutics as a potential treatment for Alzheimer's disease (AD), stroke and motor neuron disease. A phase II safety and efficacy trial in AD, originally scheduled to begin in the summer of 1997 [283677], began in May 1998 [286975,285562]. The study will enroll more than 60 AD patients [286975]. In February 1998, NeoTherapeutics began a phase I multiple-dose pharmacokinetic study of AIT-082 in 24 healthy elderly volunteers. Subjects of the phase I study will be administered AIT-082 once a day for 7 consecutive days at doses of 100 to 2000 mg per dose [279422]. A limited double-blind, placebo-controlled phase I/II trial in 10 AD patients commenced in Canada in the first quarter of 1997. Treatment with 4000 mg improved memory in 60% of the patients within 3 h, as determined by the word recall test. A decrease in memory was observed in 80% of placebo-treated patients [257132]. A phase I US trial, conducted by the Alzheimer's Disease Cooperative Study, with funding from the National Institute of Aging, began in July 1997. AIT-082 was administered to eight healthy, elderly volunteers as part of an escalating single-dose study. Oral administration of AIT-082 was well-tolerated at high doses [284325] AIT-082 also enhanced memory function in both young adult and aged mice within 2 h of oral administration. Prophylactic treatment prevented or delayed the onset of age-induced memory deficits in mice when administered in drinking water. When memory impairment was produced by brain lesions, the drug restored memory performance and increased the genetic expression of neurotrophin-3 (NT-3), a natural protein growth factor associated with nerve cell function [284325]. AIT-082 appears to have at least three effects on the growth of PC-12 cells in culture. Firstly, it stimulates outgrowth of neurites, secondly it potentiates the growth effects of neurotrophin, and thirdly, it stimulates the synthesis of certain neurotrophins (nerve growth factor, neurotrophin-3 and fibroblast growth factor) and pleiotrophins by astrocytes. These progrowth mechanisms are thought to form the basis of the ability of AIT-082 to restore and prevent age-related working memory deficits in mice [195438]. In October 1997, further preclinical results were presented, demonstrating that treatment with AIT-082 produced an increase in neurotrophic factors following spinal cord injury in rats. This study was conducted at NeoTherapeutics and McMaster University, and was partially funded by the Amyotrophic Lateral Sclerosis Society of Canada. After 7 days of treatment, rats with spinal cord injuries showed an increase in the levels of CNTF and BDNF, naturally occurring growth factors in the spinal cord [267514].
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PMID:AIT-082 NeoTherapeutics Inc. 1846 24

Amyotrophic lateral sclerosis is a debilitating disease that results from the deterioration and loss of motor neurons. The neurotoxic potential of Zn(2+), both in vitro and in vivo, has been well established; however, the mechanism(s) of zinc's toxicity remain unclear. Our laboratory has demonstrated that Zn(2+)-mediated inhibition of neurotrophins can induce cell death. The present study investigates the neurotoxic mechanism(s) of this metal ion by assessing zinc's selectivity in altering the neurotrophin BDNF, but not the neural cytokine CNTF, with respect to motor neuron survival. Embryonic day 15 rat spinal motor neuron cultures were maintained in either BDNF or CNTF. Terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) staining showed that exposure to 100microM Zn(2+) significantly increased the number of pro-apoptotic neurons in cultures maintained with BDNF, while these conditions had no effect on cultures maintained with CNTF. We also demonstrate that BDNF protomer cross-linking efficiency and TrkB receptor cross-linking to BDNF are significantly inhibited by Zn(2+), suggesting that a Zn(2+)-induced change in BDNF conformation inhibits receptor-binding activity. This study reveals a mechanism by which zinc toxicity is mediated via a selective loss in neurotrophin activity resulting in motor neuron death.
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PMID:Zinc induces motor neuron death via a selective inhibition of brain-derived neurotrophic factor activity. 1857 58

Malnutrition is a well-known independent survival factor in ALS patients. Total body impedance analysis (BIA) has been validated for the measurement of fat-free mass. Another physical value obtained by BIA is phase angle (PA) that has been proposed to be an index of malnutrition or a survival prognostic factor in several diseases. We measured PA in a sample of 168 ALS patients and analysed the relationships between PA and neurological, respiratory and nutritional status, and determined whether PA is an independent prognostic factor for survival in ALS. BIA was performed using an Analycor3 instrument with surface electrodes at 50 kHz and 800 microA. PA was obtained using the formula: PA =arctan (Xc/R) (in degrees) where Xc is the body reactance and R the bioelectric resistance. Relationships between quantitative variables were assessed by linear correlation coefficients and through univariate and multivariate linear regression analyses. To assess the prognostic role of PA on survival of patients, we performed survival analyses based on the Kaplan-Meier method using the log rank test, and on univariate and multivariate Cox proportional hazard model. Baseline time was time from multidisciplinary visit (T1) to death or censoring time. PA was always significantly lower in ALS patients than in healthy control subjects published in the literature. PA was lower in our ALS malnourished patients than in non-malnourished patients (3.3+/-1.1 degrees versus 2.5+/-0.6 degrees , p =0.003). In multivariate linear regression analysis, manual muscle testing (p<0.0001), vital capacity (p<0.001), fat-free mass (p<0.0001), time between initial signs and T1 (p<0.002) and age (p<0.001) were independently significantly linked with PA and explained 48% of PA variation. The survival of ALS patients from T1 was significantly linked with PA after adjustment on BMI, CV and time between initial signs and multidisciplinary visit, clinical form, age and sex. Patients with a PA <2.5 degrees had a significantly poorer survival rate than patients with a PA >2.5 degrees . We concluded that in ALS patients, PA is greatly decreased. It is related to the nutritional status of patients, and is also an independent prognostic factor of survival.
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PMID:Phase angle is a prognostic factor for survival in amyotrophic lateral sclerosis. 1872 89

Cerebro Spinal Fluid (CSF) from patients with ALS has been documented to have a toxic effect on motor neurons both in vivo and in vitro. Here we show that the CSF from Amyotrophic Lateral Sclerosis (ALS) patients (ALS-CSF) has the potential to perturb ion channel expression, specifically the Na(v)1.6, and K(v)1.6 channels in newborn rat spinal motor neurons both in vivo and in vitro. ALS-CSF and CSF from nonALS patients (nonALS-CSF) were intrathecally injected into 3-day-old rat pups at the rate of 1 microl/2.5 min using a microinjector. In addition, embryonic rat spinal cord cultures were also exposed to 10% ALS or nonALS-CSF on the 9th day in vitro (9DIV) in serum free DMEM medium. After 48 h of CSF exposure, the cultures and the spinal cord sections were processed for immunostaining of the above mentioned ion channels. We observed a decrease in the expression of Na(v)1.6 and K(v)1.6 channels in motor neurons in ALS-CSF treated group, and the presence of trophic factors like Brain Derived Neurotrophic Factor (BDNF) and Ciliary Neurotrophic Factor CNTF partially reversed the effects produced by ALS-CSF. Altered expression of these voltage-gated channels may interfere with the electrical activity of motor neurons, and thereby lead to the degeneration of neurons.
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PMID:Exposure to cerebrospinal fluid of sporadic amyotrophic lateral sclerosis patients alters Nav1.6 and Kv1.6 channel expression in rat spinal motor neurons. 1910 33


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