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Updated: May 28, 2026
Clinical Testing and Spinal Cord Removal in a Mouse Model for Amyotrophic Lateral Sclerosis (ALS)
Published on: March 17, 2012
Effect of prolonged riluzole exposure on cultured motoneurons in a mouse model of ALS
J E Schuster1, R Fu, T Siddique
1Dept. of Physiology, Northwestern Univ. Feinberg School of Medicine, 303 E. Chicago Ave., Chicago, IL 60611, USA.
Abstract:
Riluzole is the only FDA-approved drug to treat amyotrophic lateral sclerosis, but its long-term effects on motoneurons are unknown. Therefore, we treated primary mouse spinal cord cultures with 2 μM riluzole for 4-9 days and then used whole cell patch clamp to record the passive and active properties of both wild-type and SOD1(G93A) motoneurons. At this concentration, riluzole blocks >50% of the sodium component of a persistent inward current that plays a major role in determining motoneuron excitability. Prolonged riluzole treatment significantly decreased the amplitude of the persistent inward current. This effect was specific for SOD1(G93A) motoneurons, where the amplitude decreased by 55.4%. In addition, prolonged treatment hyperpolarized the resting membrane potential as well as the voltage onset and voltage maximum of the persistent inward current (∼2-3 mV in each case). These effects appeared to offset one another and resulted in no change in the firing properties. In a subset of cells, acute reapplication of 2 μM riluzole during the recording decreased repetitive firing and the persistent inward current, which is consistent with the normal effects of riluzole. The downregulation of the persistent inward current in response to prolonged riluzole administration is in contrast to the strong upregulation of this same current after descending neuromodulatory drive to the cord is lost following spinal injury. This dichotomy suggests that decreased activation of G protein-coupled pathways can induce upregulation in the persistent inward current but that direct channel block is ineffective.
Insights
Long-term riluzole treatment in mouse models of amyotrophic lateral sclerosis (ALS) reduced persistent inward currents in motoneurons. This suggests direct channel block is ineffective for altering these currents long-term.
Area of Science:
- Neuroscience
- Pharmacology
- Motor Neuron Diseases
Background:
- Riluzole is the sole FDA-approved drug for treating amyotrophic lateral sclerosis (ALS).
- The long-term effects of riluzole on motoneuron function, particularly persistent inward currents, remain largely unknown.
- Persistent inward currents significantly influence motoneuron excitability.
Purpose of the Study:
- To investigate the long-term effects of riluzole on the passive and active properties of wild-type and SOD1(G93A) motoneurons.
- To determine if prolonged riluzole exposure alters persistent inward currents and motoneuron excitability.
Main Methods:
- Primary mouse spinal cord cultures were treated with 2 μM riluzole for 4-9 days.
- Whole cell patch clamp recordings were used to assess passive and active membrane properties.
- Specific focus on sodium-dependent persistent inward currents in wild-type and SOD1(G93A) motoneurons.
Main Results:
- Prolonged riluzole treatment significantly decreased the amplitude of persistent inward currents, particularly in SOD1(G93A) motoneurons (55.4% reduction).
- Hyperpolarization of resting membrane potential and altered voltage onset/maximum of persistent inward currents were observed.
- Despite these changes, overall motoneuron firing properties remained unchanged due to offsetting effects.
Conclusions:
- Long-term riluzole administration downregulates persistent inward currents, contrasting with their upregulation after spinal injury.
- This suggests that direct channel block by riluzole is ineffective in inducing long-term current upregulation.
- G protein-coupled pathway activation may play a role in regulating persistent inward currents.
