Identification of candidate drugs for the treatment of ALS.
A consortium of investigators interested in neurodegenerative diseases collaborated to screen 1040 drugs in multiple neurodegenerative disease assays. One model of amyotrophic lateral sclerosis (ALS) pathogenesis in particular incorporated glutamate exposure in enriched primary rat motor neuron cultures. In this model 78 compounds decreased motor neuron death caused by 100 microM glutamate. Almost all these pharmacological agents act at one or more of the following cellular targets: 1) protein synthesis inhibition; 2) Cox inhibition; 3) regulation of anion flux; 4) modulation of GABA receptors; 5) antioxidant, and 6) cell cycle inhibition. The most prevalent mode of action was the regulation of intracellular calcium. These data extend the understanding of motor neuron degeneration and identify a number of cellular targets for the improvement of combined therapies for neurodegenerative disease.
Vincent
Andrea M
AM
Department of Neorology, University of Michigan, Ann Arbor, Michigan, USA. andreav@umich.edu
Backus
Carey
C
Taubman
Alexander A
AA
Feldman
Eva L
EL
D000690:Amyotrophic Lateral Sclerosis / Q000139:chemically induced / Q000188:drug therapy*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D018757:GABA Modulators / Q000494:pharmacology / Q000627:therapeutic use; D018698:Glutamic Acid; D020287:In Situ Nick-End Labeling / Q000379:methods; D007473:Ion Channels / Q000037:antagonists & inhibitors; D009046:Motor Neurons / Q000187:drug effects* / Q000502:physiology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology
D000975:Antioxidants; D004791:Enzyme Inhibitors; D018757:GABA Modulators; D007473:Ion Channels; D011500:Protein Synthesis Inhibitors; D018698:Glutamic Acid