title: Calpain activation induced by glucose deprivation is mediated by oxidative stress and contributes to neuronal damage.
abstract: The mechanisms leading to neuronal death during glucose deprivation have not been fully elucidated, but a role of oxidative stress has been suggested. In the present study we have investigated whether the production of reactive oxygen species during glucose deprivation, contributes to the activation of calpain, a calcium-dependent protease involved in neuronal injury associated with brain ischemia and cerebral trauma. We have observed a rapid activation of calpain, as monitored by the cleavage of the cytoskeletal protein α-spectrin, after glucose withdrawal, which is reduced by inhibitors of xanthine oxidase, phospholipase A2 and NADPH oxidase. Results suggest that phospholipase A2 and NADPH oxidase contribute to the early activation of calpain after glucose deprivation. In particular NOX2, a member of the NADPH oxidase family is involved, since reduced stimulation of calpain activity is observed after glucose deprivation in hippocampal slices from transgenic mice lacking a functional NOX2. We observed an additive effect of the inhibitors of xanthine oxidase and phospholipase A2 on both ROS production and calpain activity, suggesting a synergistic action of these two enzymes. The present results provide new evidence showing that reactive oxygen species stimulate calpain activation during glucose deprivation and that this mechanism is involved in neuronal death.
authors.affiliation: Departamento de Neuropatología Molecular, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México, D.F. CP 04510, Mexico. Electronic address: b.paramo@postgrad.manchester.ac.uk.
authors.forename: Blanca
authors.initials: B
authors.lastname: Páramo
authors.forename: Teresa
authors.initials: T
authors.lastname: Montiel
authors.forename: Diego R
authors.initials: DR
authors.lastname: Hernández-Espinosa
authors.forename: Marlene
authors.initials: M
authors.lastname: Rivera-Martínez
authors.forename: Julio
authors.initials: J
authors.lastname: Morán
authors.forename: Lourdes
authors.initials: L
authors.lastname: Massieu
mesh_terms: D000818:Animals; D002154:Calpain / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000172:deficiency* / Q000494:pharmacology; D006624:Hippocampus / Q000473:pathology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D051379:Mice; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D054467:Phospholipases A2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D054467:Phospholipases A2; D002154:Calpain; D005947:Glucose
keywords: Calpain; DHE; Et; GD; Glucose deprivation; IP(3)R; NADPH oxidase; NOX; Neuronal death; Reactive oxygen species; RyR; XaO; dihydroethidium; ethidium; glucose deprivation; inositol 1,4,5-triphosphate receptor; ryanodine receptor; xanthine oxidase