Tissue-type plasminogen activator rescues neurones from serum deprivation-induced apoptosis through a mechanism independent of its proteolytic activity.
Although the mechanism of action of tissue-type plasminogen activator (tPA) in excitotoxic necrosis is well documented, whether this serine protease can influence the apoptotic cascade remains a subject of debate. Here, we report that tPA protects cultured cortical neurones against apoptotic cell death induced by serum deprivation, an effect associated with a reduction of caspase-3 activation. Interestingly, blocking tPA proteolytic activity by either tPA stop or neuroserpin did not prevent this neuroprotection. Similarly, prevention of the interaction between tPA and its receptor low-density lipoprotein receptor-related protein (LRP) could not alter tPA anti-apoptotic activity. Interestingly, the survival-promoting effect of tPA was blocked by the phosphatidylinositol-3 (PI-3) kinase inhibitor, LY294002, but not by the mitogen-activated protein (MAP) kinase inhibitor, U0126. In conclusion, the present demonstration of an anti-apoptotic effect of tPA, independent of its enzymatic activity, reveals an additional level of complexity in our understanding of this critical mediator of brain physiology and pathology.
Liot
Géraldine
G
INSERM, INSERM-Avenir tPA in the working brain, Caen, France Université de Caen Basse-Normandie, Caen, France GIP Cyceron, Caen, France.
Roussel
Benoit D
BD
Lebeurrier
Nathalie
N
Benchenane
Karim
K
López-Atalaya
José P
JP
Vivien
Denis
D
Ali
Carine
C
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western / Q000379:methods; D002070:Butadienes / Q000494:pharmacology; D002452:Cell Count / Q000379:methods; D002540:Cerebral Cortex / Q000166:cytology; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D009479:Neuropeptides / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D009687:Nuclear Proteins / Q000494:pharmacology; D015843:Serpins / Q000494:pharmacology; D044967:Serum / Q000502:physiology*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000378:metabolism; D000097522:Neuroserpin
D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D005343:Fibrinolytic Agents; D009025:Morpholines; D009479:Neuropeptides; D009570:Nitriles; D009687:Nuclear Proteins; D015843:Serpins; D010959:Tissue Plasminogen Activator; D000097522:Neuroserpin; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one