title: Chronic inhibitory effect of riluzole on trophic factor production.
abstract: Riluzole is the only FDA approved drug for the treatment of amyotrophic lateral sclerosis (ALS). However, the drug affords moderate protection to ALS patients, extending life for a few months by a mechanism that remains controversial. In the presence of riluzole, astrocytes increase the production of factors protective to motor neurons. The stimulation of trophic factor production by motor neuron associated cells may contribute to riluzole's protective effect in ALS. Here, we investigated the effects of media conditioned by astrocytes and Schwann cells acutely or chronically incubated with riluzole on trophic factor-deprived motor neuron survival. While acute riluzole incubation induced CT-1 secretion by astrocytes and Schwann cells, chronic treatment stimulated a significant decrease in trophic factor production compared to untreated cultures. Accordingly, conditioned media from astrocytes and Schwann cells acutely treated with riluzole protected motor neurons from trophic factor deprivation-induced cell death. Motor neuron protection was prevented by incubation with CT-1 neutralizing antibodies. In contrast, conditioned media from astrocytes and Schwann cells chronically treated with riluzole was not protective. Acute and chronic treatment of mice with riluzole showed opposite effects on trophic factor production in spinal cord, sciatic nerve and brain. There was an increase in the production of CT-1 and GDNF in the spinal cord and CT-1 in the sciatic nerve during the first days of treatment with riluzole, but the levels dropped significantly after chronic treatment with the drug. Similar results were observed in brain for CT-1 and BDNF while there was no change in GDNF levels after riluzole treatment. Our results reveal that riluzole regulates long-lasting processes involving protein synthesis, which may be relevant for riluzole therapeutic effects. Changing the regimen of riluzole administration to favor the acute effect of the drug on trophic factor production by discontinuous long-term treatment may improve the outcome of ALS patient therapy.
authors.affiliation: Burnett School of Biomedical Science, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Orlando, FL 32827, United States.
authors.forename: Cassandra N
authors.initials: CN
authors.lastname: Dennys
authors.affiliation: Burnett School of Biomedical Science, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Orlando, FL 32827, United States.
authors.forename: JeNay
authors.initials: J
authors.lastname: Armstrong
authors.affiliation: Burnett School of Biomedical Science, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Orlando, FL 32827, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Levy
authors.affiliation: Burnett School of Biomedical Science, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Orlando, FL 32827, United States.
authors.forename: Youn Jung
authors.initials: YJ
authors.lastname: Byun
authors.affiliation: Burnett School of Biomedical Science, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Orlando, FL 32827, United States.
authors.forename: Kristina R
authors.initials: KR
authors.lastname: Ramdial
authors.affiliation: Burnett School of Biomedical Science, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Orlando, FL 32827, United States.
authors.forename: Marga
authors.initials: M
authors.lastname: Bott
authors.affiliation: Orlando Veteran Administration Healthcare System, Orlando, FL 32803, United States.
authors.forename: Fabian H
authors.initials: FH
authors.lastname: Rossi
authors.affiliation: Burnett School of Biomedical Science, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Orlando, FL 32827, United States.
authors.forename: Cristina
authors.initials: C
authors.lastname: Fernández-Valle
authors.affiliation: Burnett School of Biomedical Science, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Orlando, FL 32827, United States.
authors.forename: Maria Clara
authors.initials: MC
authors.lastname: Franco
authors.affiliation: Burnett School of Biomedical Science, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Orlando, FL 32827, United States. Electronic address: Alvaro.Estevez@ucf.edu.
authors.forename: Alvaro G
authors.initials: AG
authors.lastname: Estevez
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009420:Nervous System / Q000254:growth & development* / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019782:Riluzole / Q000494:pharmacology*; D012583:Schwann Cells / Q000737:chemistry / Q000187:drug effects; D013997:Time Factors
chemical_list: D017077:Culture Media, Conditioned; D036341:Intercellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D019782:Riluzole
keywords: ALS; Amyotrophic lateral sclerosis; Astrocytes; BDNF; Cardiotrophin-1; GDNF; Motor neurons; Riluzole; Schwann cells