Retinoic acid potentiated the protective effect of NGF against staurosporine-induced apoptosis in cultured chick neurons by increasing the trkA protein expression.
Nerve growth factor (NGF) has already been shown to protect neurons and PC12 cells from cell death induced by different stimuli. When chick embryonic neurons were exposed to staurosporine (200 nM, 24 hr), the percentage of apoptotic neurons increased from 15% in controls to 80%, but the treatment with NGF alone did not show any neuroprotection. In the presence of retinoic acid (RA, 5 microM), however, NGF (20 pg/ml) reduced staurosporine-induced damage to 42% apoptotic neurons compared to 58% in the presence of RA (5 icroM) alone. TrkA protein expression in chick neurons was markedly reduced by staurosporine, but was found to be increased in the presence of RA and NGF compared with the treatment with staurosporine alone. The antiapoptotic effect caused by RA and NGF was abolished by the tyrosine kinase inhibitor K-252a, as well as by anti-trkA antibodies and anti-NGF antibodies suggesting that the increase in trkA protein expression contributed to its mechanism of action. In addition, RA-enhanced 2.6-fold the NGF secretion from cultured rat cortical astrocytes and conditioned medium of RA-treated astrocytes reduced the percentage of apoptotic chick neurons after a 24 hr-incubation with staurosporine in the same manner as the external addition of RA and NGF. Increasing the endogenous synthesis of growth factors as well as the expression of their receptors by small, blood-brain barrier-permeable drugs was suggested as a promising concept for neuroprotection.
Ahlemeyer
B
B
Institut für Pharmakologie und Toxikologie, Fachbereich Pharmazie der Philipps-Universität Marburg, Marburg, Germany. ahlemeye@mailer.uni-marburg.de
Hühne
R
R
Krieglstein
J
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D002642:Chick Embryo; D004357:Drug Synergism; D008565:Membrane Proteins / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D020917:Receptor, trkA; D015398:Signal Transduction / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*
D002352:Carrier Proteins; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D014212:Tretinoin; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D019311:Staurosporine