Caspase inhibitors protect against neuronal apoptosis induced by cerebrospinal fluid from multiple sclerosis patients.
Neuronal apoptosis has recently been implicated in multiple sclerosis (MS). Apoptotic cell death of neurons is induced in cultures exposed to cerebrospinal fluid (CSF) from MS patients. Since caspases are essential in the regulation of apoptosis, direct evidence was sought linking caspases to CSF-induced neuronal death. Caspase activity was measured in cell extracts from MS CSF-treated cultured neurons by the cleavage of caspase-1 and caspase-3 substrates. Caspase-3 activity, but not caspase-1, was induced in neuronal cultures in response to MS CSF treatment. This caspase-3 activity was inhibited in vitro by Ac-YVAD-cmk and Ac-DEVD-cmk caspase inhibitors. Treatment of MS CSF-incubated neuronal cells with these caspase inhibitors completely preserved neuronal survival and largely attenuated DNA fragmentation detected in situ. These findings show that neuronal cells are rescued from MS CSF-induced death by caspase inhibitors and suggest ways to treat MS.
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Servicio de Bioqui;mica-Investigación, Hospital Ramón y Cajal, Ctra. Colmenar km 9.1, 28034 Madrid, Spain.
Alvarez-Cermeño
J C
JC
Regidor
I
I
Plaza
J
J
Salinas
M
M
Alcázar
A
A
D000293:Adolescent; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000201:enzymology* / Q000276:immunology / Q000503:physiopathology; D002555:Cerebrospinal Fluid / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005333:Fetus; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid / Q000201:enzymology* / Q000276:immunology; D009410:Nerve Degeneration / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D051381:Rats
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases