Neurotoxic injury pathways in differentiated mouse motor neuron-neuroblastoma hybrid (NSC-34D) cells in vitro--limited effect of riluzole on thapsigargin, but not staurosporine, hydrogen peroxide and homocysteine neurotoxicity
| Autor: | Edward J. Armstrong, Nick Radio, Richelle Hemendinger, Benjamin Rix Brooks |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Programmed cell death
Thapsigargin Neurotoxins Apoptosis Pharmacology Hybrid Cells Toxicology Endoplasmic Reticulum Calcium in biology Cell Line chemistry.chemical_compound Mice Neuroblastoma medicine Neurotoxin Staurosporine Animals Homocysteine Caspase 7 Motor Neurons Riluzole Dose-Response Relationship Drug Chemistry Caspase 3 Amyotrophic Lateral Sclerosis Neurotoxicity Hydrogen Peroxide medicine.disease Neuroprotective Agents Biochemistry Calcium medicine.drug |
| Zdroj: | Toxicology and applied pharmacology. 258(2) |
| ISSN: | 1096-0333 |
| Popis: | The neuroblastoma-spinal motor neuron fusion cell line, NSC-34, in its differentiated form, NSC-34D, permits examining the effects of riluzole, a proven treatment for amyotrophic lateral sclerosis (ALS) on cell death induction by staurosporine (STS), thapsigargin (Thaps), hydrogen peroxide (H(2)O(2)) and homocysteine (HCy). These neurotoxins, applied exogenously, have mechanisms of action related to the various proposed molecular pathogenetic pathways in ALS and are differentiated from endogenous cell death that is associated with cytoplasmic aggregate formation in motor neurons. Nuclear morphology, caspase-3/7 activation and high content imaging were used to assess toxicity of these neurotoxins with and without co-treatment with riluzole, a benzothiazole compound with multiple pharmacological actions. STS was the most potent neurotoxin at killing NSC-34D cells with a toxic concentration at which 50% of maximal cell death is achieved (TC(50)=0.01μM), followed by Thaps (TC(50)=0.9μM) and H(2)O(2) (TC(50)=15μM) with HCy requiring higher concentrations to kill at the same level (TC(50)=2200μM). Riluzole provided neurorescue with a 20% absolute reduction (47.6% relative reduction) in apoptotic cell death against Thaps-induced NSC-34D cell (p≤0.05), but had no effect on STS-, H(2)O(2)- and HCy-induced NSC-34D cell death. This effect of riluzole on Thaps induction of cell death was independent of caspase-3/7 activation. Riluzole mitigated a toxin that can cause intracellular calcium dysregulation associated with endoplasmic reticulum (ER) stress but not toxins associated with other cell death mechanisms. |
| Databáze: | OpenAIRE |
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