期刊
JOURNAL OF NEUROCHEMISTRY
卷 100, 期 5, 页码 1407-1420出版社
WILEY
DOI: 10.1111/j.1471-4159.2006.04330.x
关键词
mitogen-activated protein kinase; neuron death; N-methyl-D-aspartate; tumor necrosis factor alpha
资金
- NCRR NIH HHS [P20 RR017699, 1 P20 RR17699-01, P20 RR017699-077011] Funding Source: Medline
- NIA NIH HHS [1 R15 AG16192-01, 1 R03 AG20294-01] Funding Source: Medline
- NIDCR NIH HHS [R01 DE017102-01A1, R01 DE017102, R01 DE017102-03, R01 DE017102-02] Funding Source: Medline
Multiple cytokines are secreted in the brain during pro-inflammatory conditions and likely affect neuron survival. Previously, we demonstrated that glutamate and tumor necrosis factor alpha (TNF alpha) kill neurons via activation of the N-methyl-D-aspartate (NMDA) and TNF alpha receptors, respectively. This report continues characterizing the signaling cross-talk pathway initiated during this inflammation-related mechanism of death. Stimulation of mouse cortical neuron cultures with TNF alpha results in a transient increase in NMDA receptor-dependent calcium influx that is additive with NMDA stimulation and inhibited by pre-treatment with the NMDA receptor antagonist, DL-2-amino-5-phosphonovaleric acid, or the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione. Pre-treatment with N-type calcium channel antagonist, omega-conotoxin, or the voltage-gated sodium channel antagonist, tetrodotoxin, also prevents the TNF alpha-stimulated calcium influx. Combined TNF alpha and NMDA stimulation results in a transient increase in activity of extracellular signal-regulated kinases (ERKs) and c-Jun N-terminal kinases (JNKs). Specific inhibition of ERKs but not JNKs is protective against TNF alpha and NMDA-dependent death. Death is mediated via the low-affinity TNF alpha receptor, TNFRII, as agonist antibodies for TNFRII but not TNFRI stimulate NMDA receptor-dependent calcium influx and death. These data demonstrate how microglial pro-inflammatory secretions including TNF alpha can acutely facilitate glutamate-dependent neuron death.
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