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Acute retigabine-induced effects on myelinated motor axons in amyotrophic lateral sclerosis.

ABSTRACT: Altered motor neuron excitability in patients with amyotrophic lateral sclerosis (ALS) has been suggested to be an early pathophysiological mechanism associated with motor neuron death. Compounds that affect membrane excitability may therefore have disease-modifying effects. Through which mechanism(s), these compounds modulate membrane excitability is mostly provided by preclinical studies, yet remains challenging to verify in clinical studies. Here, we investigated how retigabine affects human myelinated motor axons by applying computational modeling to interpret the complex excitability changes in a recent trial involving 18 ALS patients. Compared to baseline, the post-dose excitability differences were modeled well by a hyperpolarizing shift of the half-activation potential of slow potassium (K⁺ )-channels (till 2 mV). These findings verify that retigabine targets slow K⁺ -channel gating and highlight the usefulness of computational models. Further developments of this approach may facilitate the identification of early target engagement and ultimately aid selecting responders leading to more personalized treatment strategies.

SUBMITTER: Sleutjes BTHM

PROVIDER: S-EPMC9318643 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Impaired structural motor connectome in amyotrophic lateral sclerosis.

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Project description:Identification of amyotrophic lateral sclerosis (ALS) associated genes. Post mortem spinal cord grey matter from sporadic and familial ALS patients compared with controls. Keywords: other

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Project description:This SuperSeries is composed of the SubSeries listed below.

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Therapeutic vaccine for acute and chronic motor neuron diseases: implications for amyotrophic lateral sclerosis.

Project description:Therapeutic vaccination with Copaxone (glatiramer acetate, Cop-1) protects motor neurons against acute and chronic degenerative conditions. In acute degeneration after facial nerve axotomy, the number of surviving motor neurons was almost two times higher in Cop-1-vaccinated mice than in nonvaccinated mice, or in mice injected with PBS emulsified in complete Freund's adjuvant (P < 0.05). In mice that express the mutant human gene Cu/Zn superoxide dismutase G93A (SOD1), and therefore simulate the chronic human motor neuron disease amyotrophic lateral sclerosis, Cop-1 vaccination prolonged life span compared to untreated matched controls, from 211 +/- 7 days (n = 15) to 263 +/- 8 days (n = 14; P < 0.0001). Our studies show that vaccination significantly improved motor activity. In line with the experimentally based concept of protective autoimmunity, these findings suggest that Cop-1 vaccination boosts the local immune response needed to combat destructive self-compounds associated with motor neuron death. Its differential action in CNS autoimmune diseases and neurodegenerative disorders, depending on the regimen used, allows its use as a therapy for either condition. Daily administration of Cop-1 is an approved treatment for multiple sclerosis. The protocol for non-autoimmune neurodegenerative diseases such as amyotrophic lateral sclerosis, remains to be established by future studies.

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Project description: Not available

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Transcription profiling of human motor cortex in sporadic amyotrophic lateral sclerosis

Project description:We used oligonucleotide microarrays to find differentially expressed genes between control subjects and those affected by sporadic amyotrophic lateral sclerosis. Experiment Overall Design: Complementary RNAs (cRNAs) labelled with Cy5-CTP (Perkin-Elmer) were synthesized from 1 Âµg of total RNA of each sample of human motor cortex using the Low RNA Input Fluorescent Linear Amplification Kit (Agilent Technologies) following the manufacturerâs protocol. A reference cRNA, labelled with Cy3-CTP (Perkin-Elmer), was synthesized from 1 Âµg of sample Diseased 2 RNA. Aliquots (750 ng) of Cy3 and Cy5 labelled cRNA targets were co-hybridized on Whole Human Genome Oligo Microarrays (Agilent Technologies). Microarray hybridization and washing were performed using reagents and instruments (hybridization chambers and rotating oven) as indicated by the manufacturer (Agilent Technologies). Microarrays were scanned at 10-Î¼m resolution using a GenePix Personal 4100A microarray scanner and the GenePix Pro 6.0 acquisition and data-extraction software (Molecular Devices, Corp.).

2008-06-13 | E-GEOD-4595 | biostudies-arrayexpress

Quantitative susceptibility mapping of the motor cortex in amyotrophic lateral sclerosis and primary lateral sclerosis.

Project description:The diagnosis of amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) is often difficult because of a lack of disease biomarkers. The purpose of this study was to investigate quantitative susceptibility mapping (QSM) of the motor cortex as a potential quantitative biomarker for the diagnosis of ALS and PLS.From a retrospective database, QSM images of 16 patients with upper motor neuron disease (nine men [56%], seven women; mean age, 56.3 years; 12 with ALS, four with PLS) and 23 control patients (13 men [56%], 10 women; mean age, 56.6 years) were reviewed. Two neuroradiologists, blinded to diagnosis, qualitatively assessed QSM, T2- and T2*-weighted, and T2-weighted FLAIR images. Relative motor cortex susceptibility was calculated by subtraction of adjacent white matter and CSF signal intensity from mean motor cortex susceptibility on the axial image most representative of the right- or left-hand lobule, and ROC analysis was performed. The Fisher exact and Student t tests were used to evaluate for statistical differences between the groups.Qualitatively, QSM had greater diagnostic accuracy than T2-weighted, T2*-weighted, or T2-weighted FLAIR imaging for the diagnosis of ALS and PLS. Quantitatively, relative motor cortex susceptibility was found to be significantly greater in patients with motor neuron disease than in control patients (46.0 and 35.0 ppb; p < 0.001). ROC analysis showed an AUC of 0.88 (p < 0.0001) and an optimal cutoff value of 40.5 ppb for differentiating control patients from patients with ALS or PLS (sensitivity, 87.5%; specificity, 87.0%).QSM is a sensitive and specific quantitative biomarker of iron deposition in the motor cortex in ALS and PLS.

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Axonal Dysfunction Precedes Motor Neuronal Death in Amyotrophic Lateral Sclerosis.

Project description:Wide-spread fasciculations are a characteristic feature in amyotrophic lateral sclerosis (ALS), suggesting motor axonal hyperexcitability. Previous excitability studies have shown increased nodal persistent sodium conductances and decreased potassium currents in motor axons of ALS patients, both of the changes inducing hyperexcitability. Altered axonal excitability potentially contributes to motor neuron death in ALS, but the relationship of the extent of motor neuronal death and abnormal excitability has not been fully elucidated. We performed multiple nerve excitability measurements in the median nerve at the wrist of 140 ALS patients and analyzed the relationship of compound muscle action potential (CMAP) amplitude (index of motor neuronal loss) and excitability indices, such as strength-duration time constant, threshold electrotonus, recovery cycle and current-threshold relationships. Compared to age-matched normal controls (n = 44), ALS patients (n = 140) had longer strength-duration time constant (SDTC: a measure of nodal persistent sodium current; p < 0.05), greater threshold changes in depolarizing threshold electrotonus (p < 0.05) and depolarizing current threshold relationship (i.e. less accommodation; (p < 0.05), greater superexcitability (a measure of fast potassium current; p < 0.05) and reduced late subexcitability (a measure of slow potassium current; p < 0.05), suggesting increased persistent sodium currents and decreased potassium currents. The reduced potassium currents were found even in the patient subgroups with normal CMAP (> 5mV). Regression analyses showed that SDTC (R = -0.22) and depolarizing threshold electrotonus (R = -0.22) increased with CMAP decline. These findings suggest that motor nerve hyperexcitability occurs in the early stage of the disease, and precedes motor neuronal loss in ALS. Modulation of altered ion channel function could be a treatment option for ALS.

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