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Published on: January 30, 2014
Insulin-like growth factor-1 abrogates microglial oxidative stress and TNF-α responses to spreading depression
Yelena Y Grinberg1, Megan E Dibbern, Victoria A Levasseur
1Department of Neurology, The University of Chicago Medical Center, Chicago, Illinois 60637-1470, USA.
Abstract:
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 maybe targets for novel therapeutics development to prevent SD, and perhaps migraine.
Insights
Spreading depression (SD), linked to migraines, involves oxidative stress (OS) and inflammation. Microglia cells drive this process via reactive oxygen species (ROS) and tumor necrosis factor-alpha (TNF-α), suggesting IGF-1 as a potential therapeutic target.
Area of Science:
- Neuroscience
- Cell Biology
Background:
- Spreading depression (SD) is implicated in migraine aura and pathogenesis.
- SD is associated with increased oxidative stress (OS) and neuronal excitability.
- Tumor necrosis factor-alpha (TNF-α) is elevated by SD and increases neuronal excitability.
Purpose of the Study:
- To investigate the cellular origin of oxidative stress (OS) during spreading depression (SD).
- To explore the relationship between SD-induced OS and tumor necrosis factor-alpha (TNF-α).
- To determine the role of insulin-like growth factor-1 (IGF-1) in mitigating SD-associated OS and TNF-α.
Main Methods:
- Utilized rat hippocampal slice cultures to study spreading depression (SD).
- Measured oxidative stress (OS) in different cell types (neurons, astrocytes, microglia, oligodendrocytes).
- Assessed the effects of insulin-like growth factor-1 (IGF-1) and tumor necrosis factor-alpha (TNF-α) on OS and SD susceptibility.
Main Results:
- SD significantly increased OS in astrocytes and microglia, but not in neurons or oligodendrocytes.
- IGF-1 administration reduced microglial OS and abrogated SD-induced TNF-α increase.
- TNF-α application elevated microglial OS, an effect blocked by IGF-1.
- SD enhanced its own susceptibility through TNF-α signaling.
Conclusions:
- Microglia are identified as key players in promoting SD through interconnected ROS and TNF-α signaling.
- IGF-1 demonstrates potential therapeutic value by mitigating microglial ROS and TNF-α responses.
- Targeting microglial pathways offers a novel strategy for developing therapeutics for SD and potentially migraines.
