Chymotrypsin-like proteases contribute to human monocytic THP-1 cell as well as human microglial neurotoxicity.
Activated microglia have been observed in various neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis, and multiple sclerosis. They may exacerbate neuronal damage by secreting various toxic molecules. The list of candidate toxins includes proteases. Since it is currently not known which, if any, proteases are involved in human microglia neurotoxicity, we studied the effects of a panel of protease inhibitors on the toxicity of cell-free supernatants of stimulated human microglia and THP-1 monocytic cells to human SH-SY5Y cells. Five structurally distinct inhibitors that are known to inhibit chymotrypsin-like proteases were partially protective. They included chymostatin, AEBSF (Pefabloc SC), alpha1-antichymotrypsin, bromoenol lactone, and 3,4-dichloroisocoumarin. The data suggest that certain protease inhibitors could inhibit microglial-mediated toxicity. They might represent a novel class of drugs with benefit in diseases where overactivity of microglia contributes to the pathogenesis.
Klegeris
Andis
A
Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia, Canada.
McGeer
Patrick L
PL
D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002918:Chymotrypsin / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000473:pathology*; D009000:Monocytes / Q000187:drug effects / Q000473:pathology*; D020258:Neurotoxicity Syndromes / Q000473:pathology*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013268:Stimulation, Chemical; D013347:Subcellular Fractions / Q000737:chemistry; D013702:Temporal Lobe / Q000166:cytology; D013778:Tetrazolium Salts; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D015842:Serine Proteinase Inhibitors; D013778:Tetrazolium Salts; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D002918:Chymotrypsin; C022616:thiazolyl blue