Insulin-like growth factor-1 abrogates microglial oxidative stress and TNF-α responses to spreading depression
Article first published online: 30 APR 2013
© 2013 International Society for Neurochemistry
Journal of Neurochemistry
Volume 126, Issue 5, pages 662–672, September 2013
How to Cite
J. Neurochem. (2013) 126, 662–672.
- Issue published online: 23 AUG 2013
- Article first published online: 30 APR 2013
- Accepted manuscript online: 15 APR 2013 07:30AM EST
- Manuscript Accepted: 10 APR 2013
- Manuscript Received: 21 MAR 2013
- National Institute of Neurological Disorders and Stroke. Grant Number: NS-19108
- National Institute of Child Health and Human Disorders. Grant Number: 5 PO1 HD 09402
- University of Chicago
- National Center for Advancing Translational Sciences of the National Institutes of Health. Grant Number: UL1TR000430
- Cornell College Dimensions Fellowship
- oxidative stress;
- reactive oxygen species;
- spreading depression
Spreading depression (SD), the most likely cause of migraine aura and perhaps migraine, occurs with increased oxidative stress (OS). SD increases reactive oxygen species (ROS), and ROS, in turn, can signal to increase neuronal excitability, which includes increased SD susceptibility. SD also elevates tumor necrosis factor-α (TNF-α), which increases neuronal excitability. Accordingly, we probed for the cellular origin of OS from SD and its relationship to TNF-α, which might promote SD, using rat hippocampal slice cultures. We observed significantly increased OS from SD in astrocytes and microglia but not in neurons or oligodendrocytes. Since insulin-like growth factor-1 (IGF-1) mitigates OS from SD, we determined the cell types responsible for this effect. We found that IGF-1 significantly decreased microglial but not astrocytic OS from SD. We also show that IGF-1 abrogated the SD-induced TNF-α increase. Furthermore, TNF-α application increased microglial but not astrocytic OS, an effect abrogated by IGF-1. Next, we showed that SD increased SD susceptibility, and does so via TNF-α. This work suggests that microglia promote SD via increased and interrelated ROS and TNF-α signaling. Thus, IGF-1 mitigation of microglial ROS and TNF-α responses may be targets for novel therapeutics development to prevent SD, and perhaps migraine.
Spreading depression (SD), the likely cause of migraine, occurs with increased TNF-α and oxidative stress (OS), which we show is specific to microglia and astrocytes. We then show TNF-α and SD itself increase susceptibility to subsequent SD. IGF-1 decreases TNF-α and microglial OS from SD. These findings support IGF-1 and microglial OS as potential therapeutic targets against SD and perhaps migraine.