Activin is a neuronal survival factor that is rapidly increased after transient cerebral ischemia and hypoxia in mice.
One approach for developing targeted stroke therapies is to identify the neuronal protective and destructive signaling pathways and gene expression that follow ischemic insult. In some neural injury models, the transforming growth factor-beta family member activin can provide neuroprotective effects in vivo and promote neuronal survival. This study tests if activin supports cortical neurons after ischemic challenge in vitro and if signals after cerebral ischemia involve activin in vivo. In a defined cell culture model that uses hydrogen peroxide (H(2)O(2))-free radical stress, activin addition maintained neuronal survival. H(2)O(2) treatment increased activin mRNA twofold in surviving cortical neurons, and inhibition of activin with neutralizing antibodies caused neuronal death. These data identify activin gene changes as a rapid response to oxidative stress, and indicate that endogenous activin acts as a protective factor for cortical neurons in vitro. Similarly, after transient focal cerebral ischemia in adult mice, activin mRNA increased at 1 and 4 h ipsilateral to the infarct but returned to control values at 24 h after reperfusion. Intracellular activated smad signals were detected in neurons adjacent to the infarct. Activin was also increased after 2 h of 11% hypoxia. Activin mRNA increased at 1 h but not 4 or 24 h after hypoxia, similar to the time course of erythropoietin and vascular endothelial growth factor induction. These findings identify activin as an early-regulated gene response to transient ischemia and hypoxia, and its function in cortical neuron survival during oxidative challenge provides a basis to test activin as a potential therapeutic in stroke injury.
Mukerji
Shibani S
SS
Department of Neuroscience, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.
Katsman
Ekaterina A
EA
Wilber
Charles
C
Haner
Noah A
NA
Selman
Warren R
WR
Hall
Alison K
AK
D028341:Activins / Q000235:genetics* / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D002534:Hypoxia, Brain / Q000378:metabolism*; D002546:Ischemic Attack, Transient / Q000378:metabolism* / Q000517:prevention & control; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D012333:RNA, Messenger / Q000032:analysis; D015854:Up-Regulation / Q000235:genetics
D012333:RNA, Messenger; D028341:Activins; D006861:Hydrogen Peroxide