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.

Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis

“…Interestingly, riluzole may also confer protection by increasing the trophic support provided by astrocytes [207]. However, chronic riluzole treatment has an inhibitory effect on trophic factor production by astrocytes, suggesting that adjustments in the administration regimen could be beneficial [208]. Different growth factors such as glial cell line-derived neurotrophic factor (GDNF), insulin-like growth factor I (IGF-I), ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) have been evaluated in experimental models of ALS [209–212].…”

High content analysis in amyotrophic lateral sclerosis

“…Some of the events characterizing ALS are: the aggregation and misfolding of proteins, high levels of oxidative stress, excitotoxicity, deficient axonal transport, mitochondrial dysfunctions and inflammation 3 . The neurodegeneration occurring in ALS has also been described as a non-cell autonomous occurrence 4 , meaning that the MN death is a consequence of a pathological state of other cell types, such as microglia 5,67,8 , astrocytes 9–15 and oligodendrocytes 16,17 that either spread their toxicity or simply provide less support compared to a non-pathological condition.…”

“…One possibility is that it may act synergistically on three independent pathways: the inhibition of the glutamic acid release, a non-competitive blockage of the Nmethyl- D-aspartate receptor mediated-responses, and a direct action on the voltage-dependent sodium channels 64 . Additionally, some investigations have shown Riluzole also stimulates the release of trophic factors from gliomas, astrocytes, and Schwann cells 65–67 . The efficacy of this treatment was demonstrated in two double-blind, placebo-controlled clinical trials 68,69 .…”

Increased target reinnervation by rescued cervical motoneurons after ventral root avulsion

“…Other authors have shown the promoting effect of riluzole on dendrite outgrowth (Bergerot et al, 2004) and also stimulation of neurotrophic factor (GDNF and BDNF) production in astrocytes (Mizuta et al, 2001). While acute riluzole incubation induced CT-1 secretion by astrocytes and Schwann cells, chronic treatment induce a significant decrease in trophic factor production compared to untreated cultures (Dennys et al, 2015). !…”