title: Riluzole is a potent drug to protect neonatal rat hypoglossal motoneurons in vitro from excitotoxicity due to glutamate uptake block.
abstract: Excitotoxic damage to motoneurons is thought to be an important contribution to the pathogenesis of amyotrophic lateral sclerosis (ALS), a slowly developing degeneration of motoneurons that, in most cases of sporadic occurrence, is associated with impaired glial glutamate uptake. Riluzole is the only drug licensed for symptomatic ALS treatment and is proposed to delay disease progression. As riluzole is administered only after full ALS manifestation, it is unclear if its early use might actually prevent motoneuron damage. We explored this issue by using, as a simple in vitro model, hypoglossal motoneurons (a primary target of ALS) of the neonatal rat brainstem slice preparation exposed to excitotoxic stress due to glutamate uptake block by DL-threo-β-benzyloxyaspartate (TBOA). TBOA evoked sustained network bursting, early (1 h) enhancement of the S100B immunostaining of gray matter astrocytes, and activated the motoneuronal stress ATF-3 transcription factor; 4 h later, loss (30%) of motoneuron staining ensued and pyknosis appeared. Riluzole (5 μM; applied 15 min after TBOA) inhibited bursting, decreased the frequency of spontaneous glutamatergic events, reversed changes in S100B immunostaining and prevented late loss of motoneuron staining. These results show that excitotoxicity induced by glutamate uptake block developed slowly, and was sensed by glia and motoneurons with delayed cell death. Our data provide novel evidence for the neuroprotective action of riluzole on motoneurons and glia when applied early after an excitotoxic stimulus.
authors.affiliation: Neurobiology Sector, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cifra
authors.forename: Francesca
authors.initials: F
authors.lastname: Nani
authors.forename: Andrea
authors.initials: A
authors.lastname: Nistri
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001640:Bicuculline / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D003292:Convulsants / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D007002:Hypoglossal Nerve / Q000166:cytology*; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018408:Patch-Clamp Techniques; D051381:Rats; D019782:Riluzole / Q000494:pharmacology* / Q000627:therapeutic use; D013331:Strychnine / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D003292:Convulsants; D018691:Excitatory Amino Acid Antagonists; D058787:GABA-A Receptor Antagonists; D018696:Neuroprotective Agents; C120673:benzyloxyaspartate; D001224:Aspartic Acid; D018698:Glutamic Acid; D019782:Riluzole; D013331:Strychnine; D001640:Bicuculline