The neuroprotective effect of Activin A and B: implication for neurodegenerative diseases.
Activin is a member of the transforming growth factor-beta superfamily which comprises a growing list of multifunctional proteins that function as modulators of cell proliferation, differentiation, hormone secretion and neuronal survival. This study examined the neuroprotective effect of both Activin A and B in serum withdrawal and oxidative stress apoptotic cellular models and investigated the expression of pro- and anti-apoptotic proteins, which may account for the mechanism of Activin-induced neuroprotection. Here, we report that recombinant Activin A and B are neuroprotective against serum deprivation- and toxin- [either the parkinsonism-inducing neurotoxin, 6-hydroxydopamine (6-OHDA) or the peroxynitrite donor, 3-(4-morpholinyl) sydnonimine hydrochloride (SIN-1)] induced neuronal death in human SH-SY5Y neuroblastoma cells. Furthermore, we demonstrate for the first time that transient transfection with Activin betaA or betaB significantly protect SH-SY5Y and rat pheochromocytoma PC12 cells against serum withdrawal-induced apoptosis. This survival effect is mediated by the Bcl-2 family members and involves inhibition of caspase-3 activation; reduction of cleaved poly-ADP ribose polymerase and phosphorylated H2A.X protein levels and elevation of tyrosine hydroxylase expression. These results indicate that both Activin-A and -B share the potential to induce neuroprotective activity and thus may have positive impact on aging and neurodegenerative diseases to retard the accelerated rate of neuronal degeneration.
Kupershmidt
Lana
L
Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Rappaport Family Research Institute, Technion-Faculty of Medicine, Haifa, Israel.
Amit
Tamar
T
Bar-Am
Orit
O
Youdim
Moussa B H
MB
Blumenfeld
Zeev
Z
D028341:Activins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016895:Culture Media, Serum-Free / Q000633:toxicity; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008981:Molsidomine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000633:toxicity; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D016627:Oxidopamine / Q000037:antagonists & inhibitors / Q000633:toxicity; D016716:PC12 Cells; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism
D028341:Activins; D051017:Apoptosis Regulatory Proteins; D016895:Culture Media, Serum-Free; D006657:Histones; D008981:Molsidomine; D018696:Neuroprotective Agents; D016627:Oxidopamine; D011065:Poly(ADP-ribose) Polymerases; D014446:Tyrosine 3-Monooxygenase; C422405:activin A; C044147:activin B; C002385:linsidomine; C475961:gamma-H2AX protein, mouse