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Endotoxin preconditioning protects against the cytotoxic effects of TNFalpha after stroke: a novel role for TNFalpha in LPS-ischemic tolerance
- Source :
- Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 27(10)
- Publication Year :
- 2007
-
Abstract
- Lipopolysaccharide (LPS) preconditioning provides neuroprotection against subsequent cerebral ischemic injury. Tumor necrosis factor-alpha (TNFalpha) is protective in LPS-induced preconditioning yet exacerbates neuronal injury in ischemia. Here, we define dual roles of TNFalpha in LPS-induced ischemic tolerance in a murine model of stroke and in primary neuronal cultures in vitro, and show that the cytotoxic effects of TNFalpha are attenuated by LPS preconditioning. We show that LPS preconditioning significantly increases circulating levels of TNFalpha before middle cerebral artery occlusion in mice and show that TNFalpha is required to establish subsequent neuroprotection against ischemia, as mice lacking TNFalpha are not protected from ischemic injury by LPS preconditioning. After stroke, LPS preconditioned mice have a significant reduction in the levels of TNFalpha (approximately threefold) and the proximal TNFalpha signaling molecules, neuronal TNF-receptor 1 (TNFR1), and TNFR-associated death domain (TRADD). Soluble TNFR1 (s-TNFR1) levels were significantly increased after stroke in LPS-preconditioned mice (approximately 2.5-fold), which may neutralize the effect of TNFalpha and reduce TNFalpha-mediated injury in ischemia. Importantly, LPS-preconditioned mice show marked resistance to brain injury caused by intracerebral administration of exogenous TNFalpha after stroke. We establish an in vitro model of LPS preconditioning in primary cortical neuronal cultures and show that LPS preconditioning causes significant protection against injurious TNFalpha in the setting of ischemia. Our studies suggest that TNFalpha is a twin-edged sword in the setting of stroke: TNFalpha upregulation is needed to establish LPS-induced tolerance before ischemia, whereas suppression of TNFalpha signaling during ischemia confers neuroprotection after LPS preconditioning.
- Subjects :
- Lipopolysaccharides
Male
Lipopolysaccharide
Ischemia
Pharmacology
Neuroprotection
Antibodies
Brain Ischemia
Brain ischemia
chemistry.chemical_compound
Mice
Medicine
Cytotoxic T cell
Animals
Ischemic Preconditioning
Cells, Cultured
Death domain
Mice, Knockout
business.industry
Tumor Necrosis Factor-alpha
medicine.disease
TRADD
Rats
Cerebrovascular Disorders
Disease Models, Animal
Neurology
chemistry
Solubility
Anesthesia
lipids (amino acids, peptides, and proteins)
Tumor necrosis factor alpha
Neurology (clinical)
Cardiology and Cardiovascular Medicine
business
Signal Transduction
Subjects
Details
- ISSN :
- 0271678X
- Volume :
- 27
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
- Accession number :
- edsair.doi.dedup.....1a5b2d7ed079c9d54f0b2cd327ae57a4