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The Journal of Neuroscience, February 27, 2008, 28(9):2221-2230; doi:10.1523/JNEUROSCI.5643-07.2008

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Cellular/Molecular
Mechanisms of Microglia-Mediated Neurotoxicity in a New Model of the Stroke Penumbra

Vikas Kaushal^1,2 and Lyanne C. Schlichter^1,2

¹Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C4, and ²Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5B 1W8

Correspondence should be addressed to Lyanne C. Schlichter, Toronto Western Hospital, MC9-417, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8. Email: schlicht{at}uhnres.utoronto.ca

After an ischemic stroke, neurons in the core are rapidly committed to die, whereas neuron death in the slowly developing penumbra is more amenable to therapeutic intervention. Microglia activation contributes to delayed inflammation, but because neurotoxic mechanisms in the penumbra are not well understood, we developed an in vitro model of microglia activation and propagated neuron killing. To recapitulate inflammatory triggers in the core, microglia were exposed to oxygen glucose-deprived neurons and astrocytes. To model the developing penumbra, the microglia were washed and allowed to interact with healthy naive neurons and astrocytes. We found that oxygen–glucose deprivation (OGD)-stressed neurons released glutamate, which activated microglia through their group II metabotropic glutamate receptors (mGluRs). Microglia activation involved nuclear factor B (NF-B), a transcription factor that promotes their proinflammatory functions. The activated microglia became neurotoxic, killing naive neurons through an apoptotic mechanism that was mediated by tumor necrosis factor- (TNF-), and involved activation of both caspase-8 and caspase-3. In contrast to some earlier models (e.g., microglia activation by lipopolysaccharide), neurotoxicity was not decreased by an inducible nitric oxide synthase (iNOS) inhibitor (S-methylisothiourea) or a peroxynitrite scavenger [5,10,15,20-tetrakis(N-methyl-4'-pyridyl)porphinato iron (III) chloride], and did not require p38 mitogen-activated protein kinase (MAPK) activation. The same microglia neurotoxic behavior was evoked without exposure to OGD-stressed neurons, by directly activating microglial group II mGluRs with (2S,2'R,3'R)-2-(2'3'-dicarboxycyclopropyl) glycine or glutamate, which stimulated production of TNF- (not nitric oxide) and mediated TNF--dependent neurotoxicity through activation of NF-B (not p38 MAPK). Together, these results support potential therapeutic strategies that target microglial group II mGluRs, TNF overproduction, and NF-B activation to reduce neuron death in the ischemic penumbra.

Key words: microglia activation; metabotropic glutamate receptors; neurodegeneration; neuroinflammation; neuron death; TNF-

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Received May 18, 2007; revised Jan. 18, 2008; accepted Jan. 20, 2008.

Correspondence should be addressed to Lyanne C. Schlichter, Toronto Western Hospital, MC9-417, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8. Email: schlicht{at}uhnres.utoronto.ca

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The Utility of a New In Vitro Model of the Stroke Penumbra

Trisha A. Dwyer, Damien E. Earl, and Liping Wang
J. Neurosci. 2008 28: 6537-6538. [Full Text]  

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