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Aspirin provides cyclin‐dependent kinase 5‐dependent protection against subsequent hypoxia/reoxygenation damage in culture
Author(s) -
Vartiainen Nina,
KeksaGoldsteine Velta,
Goldsteins Gundars,
Koistinaho Jari
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2002.00959.x
Subject(s) - neuroprotection , cyclin dependent kinase 5 , pharmacology , mapk/erk pathway , hypoxia (environmental) , kinase , protein kinase a , biology , chemistry , mitogen activated protein kinase kinase , biochemistry , organic chemistry , oxygen
Aspirin [acetylsalicylic acid (ASA)] is an anti‐inflammatory drug that protects against cellular injury by inhibiting cyclooxygenases (COX), inducible nitric oxide synthase (iNOS) and p44/42 mitogen‐activated protein kinase (p44/42 MAPK), or by preventing translocation of nuclear factor κB (NF‐κB). We studied the effect of ASA pre‐treatment on neuronal survival after hypoxia/reoxygenation damage in rat spinal cord (SC) cultures. In this injury model, COX, iNOS and NF‐κB played no role in the early neuronal death. A 20‐h treatment with 3 m m ASA prior to hypoxia/reoxygenation blocked the hypoxia/reoxygenation‐induced lactate dehydrogenase (LDH) release from neurons. This neuroprotection was associated with increased phosphorylation of neurofilaments, which are substrates of p44/42 MAPK and cyclin‐dependent kinase 5 (Cdk5). PD90859, a p44/42 MAPK inhibitor, had no effect on ASA‐induced tolerance, but olomoucine and roscovitine, Cdk5 inhibitors, reduced ASA neuroprotection. Hypoxia/reoxygenation alone reduced both the protein amount and activity of Cdk5, and this reduction was inhibited by pre‐treatment with ASA. Moreover, the protein amount of a neuronal Cdk5 activator, p35, recovered after reoxygenation only in ASA‐treated samples. The prevention of the loss in Cdk5 activity during reoxygenation was crucial for ASA‐induced protection, because co‐administration of Cdk5 inhibitors at the onset ofreoxygenation abolished the protection. In conclusion, pre‐treatment with ASA induces tolerance against hypoxia/reoxygenation damage in spinal cord cultures by restoring Cdk5 and p35 protein expression.