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)

Mutations in Cu/Zn superoxide dismutase (SOD1) have been linked to some familial cases of amyotrophic lateral sclerosis (ALS). In order to reproduce the different degree of toxicity to the mutant protein by mutations, we generated new transgenic mice with two mutations from which the progression of the disease in human family is rapid (L84V) or extremely slow (H46R). By comparing the two transgenic mice with different SOD1 mutations, we demonstrate that the time course and the first symptoms in these mice were likely to human SOD1-mediated familial ALS. In addition, we report here that rats that express a human SOD1 transgene with two different ALS-associated mutations (G93A and H46R) develop striking motor neuron degeneration and paralysis. The larger size of this rat model as compared with the ALS mice will facilitate studies involving manipulations of spinal fluid (implantation of intrathecal catheters for chronic therapeutic studies; CSF sampling) and spinal cord (e.g., direct administration of viral- and cell-mediated therapies). Using this rat model we showed that intrathecal administration of the hepatocyte growth factor attenuates motoneuron death and prolongs the duration of the disease of transgenic rats.
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PMID:[Amyotrophic lateral sclerosis: recent insights from transgenic animal models with SOD1 mutations]. 1565 Dec 92

A 44-year-old man was admitted to our hospital because of a five year history of chronic progressive gait disturbance. Neurological examination revealed mild weakness and atrophy of the upper extremities, but severe of the lower ones, and without sphincter disturbance or apparent sensory impairment. Hyperreflexia and positive pathological reflexes of the lower extremities were apparent. EMG showed a reinnervation pattern and decreased number of motor units in the extremities, suggesting ALS. However, multiple plaques on the head and spinal MRI, a prolonged central conduction time of MEP and SEP, a delayed P100 latency of VEP, and a increased IgG index in the CSF indicated primary progressive type multiple sclerosis. After receiving steroid pulse therapy, the weakness of the lower extremities showed slight improvement. Diffuse inflammation in the spinal cord involving not only the pyramidal tract but also the anterior horn cells/intramedullary ventral roots explained the ALS-like clinical picture.
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PMID:[Primary progressive multiple sclerosis as a differential diagnosis of ALS: a case report]. 1578 6

Abnormal levels of interleukin (IL)-6 were described in patients with ALS, related to an inflammatory process. The authors compared IL-6 and tumor necrosis factor alpha (TNF-alpha) levels in CSF and sera from 10 hypoxemics and 10 normoxemics patients with ALS to those of 10 hypoxemics and 10 normoxemics neurologic controls. The same pattern exists in patients with ALS and controls: the highest levels are found in hypoxic conditions and undetectable levels are found in normoxemic conditions. Elevated IL-6 levels in ALS could correspond to a normal response to hypoxemia.
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PMID:Elevated IL-6 and TNF-alpha levels in patients with ALS: inflammation or hypoxia? 1638 Jun 19

Mutations in copper-zinc superoxide dismutase gene (SOD1) have been linked to some familial cases of ALS. We report here that rats that express a human SOD1 transgene with two different ALS-associated mutations (G93A and H46R) develop striking motor neuron degeneration and paralysis. By comparing the two transgenic rats with different SOD1 mutations, we demonstrate that the time course in these rats was similar to human SOD1-mediated familial ALS. As in the human disease and transgenic ALS mice, pathological analysis shows selective loss of motor neurons in the spinal cords of these transgenic rats. In addition, typical neuronal Lewy body-like hyaline inclusions as well as astrocytic hyaline inclusions identical to those in human familial ALS are observed in the spinal cords. The larger size of this rat model as compared with the ALS mice will facilitate studies involving manipulations of spinal fluid (implantation of intrathecal catheters for chronic therapeutic studies; CSF sampling) and spinal cord (e.g., direct administration of viral- and cell-mediated therapies).
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PMID:Development of a rat model of amyotrophic lateral sclerosis expressing a human SOD1 transgene. 1638 87

Sixty percent of the CSF samples from 21 multiple sclerosis (MS) patients in remission inhibited cellular proliferation of a variety of neuronal and glial cell lines. No inhibition was observed with CSF from relapsing or progressive MS patients (0/19). Two of 82 samples from stationary MS patients were positive. No inhibition was found in MS sera. The CSF samples had no effect on myelination of mouse organotypic cerebellar cultures. Like MS cellular proliferation and subsequent lesion formation, the 'deactivation' of the lesion also is an active defined process, rather than just the cessation of the immunological events. Furthermore, approximately 20% of samples from Huntington's, Alzheimer's and Parkinson's disease patients were also positive. However, no inhibition was seen in CSF from amyotrophic lateral sclerosis patients or controls.
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PMID:Cell proliferation inhibition in remitting multiple sclerosis CSF. 1677 13

Conflicting results have been reported concerning the toxicity of cerebrospinal fluid from patients with amyotrophic lateral sclerosis (ALS-CSF) when added to neuronal cultures. The possible toxic factor(s) and the exact mode of action (e.g. requirement of glial cells) have not been identified so far. Glutamate is a potential candidate for this toxic effect, since antagonists of ionotropic glutamate receptors have been shown to attenuate ALS-CSF toxicity. We studied the effects of ALS-CSF on mixed and motoneuron-enriched chick embryonic spinal cord cultures. We found a toxic action of ALS-CSF in both culture types which could not be attenuated by 5 kDa-filtration or 15 min 90 degrees C heating. Nevertheless, the metabotropic glutamate receptor (mGluR) group I antagonist 1-aminoindan-1,5-dicarboxylic acid, but also the group I agonist (s)-3,5-dihydroxyphenylglycine (DHPG) exerted protective effects against ALS-CSF toxicity. In this experimental setting, DHPG may functionally act via a receptor blockade due to sustained activation. No protective effect was seen with the mGluR group III inhibitor (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG). Addition of DHPG did not increase the protective action of the AMPA inhibitor 6-chloro-4-hydroxyquinoline-2-carboxylic acid (6-CKU). Addition of l-glutamate did not mimic these toxic ALS-CSF effects in motoneuron-enriched cultures. Our experiments demonstrate that ALS-CSF toxicity is mediated by a small heat-resistant molecule which may act directly on neurons. Since blockade of group I mGluRs exerts a protective effect, the possibility of targeting these mGluRs pharmacologically in motoneuron disease should be kept in mind.
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PMID:Protective effect of metabotropic glutamate receptor inhibition on amyotrophic lateral sclerosis-cerebrospinal fluid toxicity in vitro. 1682 Feb 66

The kynurenine pathway (KP) is a major route of L-tryptophan catabolism leading to production of several neurobiologically active molecules. Among them is the excitotoxin quinolinic acid (QUIN) that is known to be involved in the pathogenesis of several major inflammatory neurological diseases. In amyotrophic lateral sclerosis (ALS) degeneration of motor neurons is associated with a chronic and local inflammation (presence of activated microglia and astrocytes). There is emerging evidence that the KP is important in ALS. Recently, we demonstrated that QUIN is significantly increased in serum and CSF of ALS patients. Moreover, most of the factors associated with QUIN toxicity are found in ALS, implying that QUIN may play a substantial role in the neuropathogenesis of ALS. This review details the potential role the KP has in ALS and advances a testable hypothetical model.
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PMID:Implications for the kynurenine pathway and quinolinic acid in amyotrophic lateral sclerosis. 1690 22

We have previously shown in our laboratory that cerebrospinal fluid from ALS patients (ALS-CSF) contains putative toxic factor(s). In the present study we determined the effect of ALS-CSF on the integrity of the Golgi apparatus of spinal motor neurons in the neonatal rats. CSF was injected intrathecally into three-day-old rat pups and subsequently the ultrastructural changes in the motor neurons were studied after 48 h, 1, 2 and 3 weeks. We observed that ALS-CSF causes fragmentation of the Golgi apparatus in a considerable number of motor neurons in the spinal cord. This was further confirmed when motor neurons were stained with an antibody against a medial Golgi protein (MG160). Thus, we suggest that the putative toxin(s) present in ALS-CSF may cause impairment in the protein processing leading to motor neuron death.
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PMID:Cerebrospinal fluid from amyotrophic lateral sclerosis patients causes fragmentation of the Golgi apparatus in the neonatal rat spinal cord. 1745 33

Stem and progenitor cells provide a promising therapeutic strategy for amyotrophic lateral sclerosis (ALS). To comparatively evaluate the therapeutic potentials of human bone marrow-derived mesodermal stromal cells (hMSCs) and umbilical cord blood cells (hUBCs) in ALS, we transplanted hMSCs and hUBCs and their neuroectodermal derivatives (hMSC-NSCs and hUBC-NSCs) into the ALS mouse model over-expressing the G93A mutant of the human SOD1 gene. We used a standardized protocol similar to clinical studies by performing a power calculation to estimate sample size prior to transplantation, matching the treatment groups for gender and hSOD-G93A gene content, and applying a novel method for directly injecting 100,000 cells into the CSF (the cisterna magna). Ten days after transplantation we found many cells within the subarachnoidal space ranging from frontal basal cisterns back to the cisterna magna, but only a few cells around the spinal cord. hMSCs and hMSC-NSCs were also located within the Purkinje cell layer. Intrathecal cell application did not affect survival times of mice compared to controls. Consistently, time of disease onset and first pareses, death weight, and motor neuron count in lumbar spinal cord did not vary between treatment groups. Interestingly, transplantation of hMSCs led to an increase of pre-symptomatic motor performance compared to controls in female animals. The negative outcome of the present study is most likely due to insufficient cell numbers within the affected brain regions (mainly the spinal cord). Further experiments defining the optimal cell dose, time point and route of application and particularly strategies to improve the homing of transplanted cells towards the CNS region of interest are warranted to define the therapeutic potential of mesodermal stem cells for the treatment of ALS.
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PMID:Intrathecal application of neuroectodermally converted stem cells into a mouse model of ALS: limited intraparenchymal migration and survival narrows therapeutic effects. 1751 Jul 31

Reverse transcriptase has been detected in the serum of HIV-negative patients with amyotrophic lateral sclerosis (ALS). An ALS-like disorder in HIV-positive patients can remit with antiretroviral therapy. Using the product enhanced assay technique, we measured reverse transcriptase activity in the serum and CSF of 23 HIV-negative patients with ALS and 21 neurologic disease controls. Results for CSF were not significant, whereas reverse transcriptase was detected in 56% of ALS sera vs 19% of controls.
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PMID:A controlled study of reverse transcriptase in serum and CSF of HIV-negative patients with ALS. 1753 52


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