Inflammatory mediators | Â | Neurotoxicity | Neuroprotection | Effects of hypothermia |
---|---|---|---|---|
1. Cytokines | IL-1β | Endogenous pyrogen Promotion gliosis Increase neurotoxic mediators Increase Ca2+ in neurons Edema formation BBB breakdown Priming endothelium for leukocyte adherence | Increase survival promoting factors Induction of IL-1ra | Reduction increased levels |
 | TNF-α | Inhibition glutamate uptake Promotion gliosis Increase neurotoxic mediators Increase Ca2+ signaling in neurons Stimulation apoptosis of endothelial cells Edema formation BBB breakdown Priming endothelium for leukocyte adherence Increase NF-κB activation | Increase neurotrophic factors Control extracellular Ca2+ Mediation neuronal plasticity Activation repair processes of cerebral microvasculature Induction anti-apoptotic factors Induction anti-oxidants Ischemic tolerance induction | Reduction TNF-α levels Less expression TNF receptor 1 Less NF-κB activation Reflection: Varying properties of soluble and membrane-bound form Region-specific concentration and action Receptor-specific action |
 | IL-6 | Endogenous pyrogen Attraction T lymphocytes | Induction IL-1ra | Reduction IL-6 |
 | TGF-β | Increase β-amyloid precursor Increase glial scar formation | Reduction gliosis Less inflammatory mediators Suppressed release ROS Less brain edema Inhibition neutrophil adherence Reduction apoptosis Induction IL-1ra Promotion angiogenesis | Reflection: Neuroprotection limited to penumbra |
 | IL-10 |  | Less release cytokines and expression receptors Attenuation astrocytic activation |  |
2. HMGB Family | HMGB1 | Stimulation inflammatory mediators Activation microglia Increase NF-κB activation |  | Reduction of brain and plasma HMGB1 Reduction of NF-κB activation |
3. Chemokines | CINC, MCP-1, MIP-1, MRF-1, fractalkine | Regulation and migration of leukocyte trafficking Stimulation BBB permeability Stimulation phagocytosis Increase cytokine secretion Stimulation apoptosis | Scavenge and repair necrotic tissue Angiogenesis | Downregulation MCP-1 |
4. Free oxygen radicals | ROS, NO | Lipid peroxidation Stimulation inflammatory response Disruption protein biochemistry | Â | Suppressed oxidative stress |
 | NO | Induction iron loss of cells Inhibition enzymes DNA replication Stimulation expression inflammatory mediators | Vasodilator | Reduction nNOS No influence iNOS Reflection: Different response in acute and chronic phase |
5. MMPs | MMP-9 (and -2) | BBB breakdown Stimulation leukocyte adherence and transmigration Vasogenic edema Hemorrhagic transformation | Stimulation plasticity, recovery and repair Clearance necrotic cell debris | Reduction MMP-9 No effect on MMP-2 Reflection: Contribution to recovery late after injury |
Adhesion molecules | Â | Â | Â | Â |
1. Selectins | E- and P-selectin | Slow down neutrophils and monocytes Promotion rolling over endothelium | Â | Inhibition E-selectin |
 | P-selectin | Enhancement platelet binding to neutrophils and monocytes |  |  |
 | L-selectin | Guide unstimulated leukocytes |  | No effect on L-selectin |
2. CAMs | ICAM-1and2, VCAM-1 | Stronger attachment leukocytes to endothelium Stimulation diapedesis | Â | Â |
3. Integrins | LFA-1, Mac-1, CD11c | Stimulation adhesion to endothelium Stimulation conformational changes leukocytes for diapedesis | Â | No effect on LFA-1 Delayed upregulation of Mac-1 and CD11c |
Cellular inflammatory response | Â | Â | Â | Â |
1. Glia | Microglia | Phagocytosis to clear dead cells Production inflammatory and cytotoxic mediators | Production neurotrophic factors Facilitation neurogenesis and plasticity Less release toxic mediators Scavenge and removal necrotic debris | Reduction of activation Reflection: Different subsets have different roles |
 | Astrocytes | Production inflammatory and cytotoxic mediators Production chemokines Formation glial scar tissue Enhancement oxidative stress Release glutamate | Production neurotrophic factors Glial scar isolates damaged tissue |  |
2. Endothelial cells (BBB) | Â | BBB breakdown: Hyperpermeability to macromolecules Vasogenic edema Increase intracranial pressure Stimulation inflammatory mediators and adhesion molecules Astrocyte detachment | Â | Reduction BBB disruption for large molecules |
3. Leukocytes | Neutrophils | Release pro-inflammatory and cytotoxic mediators Stimulation lipid peroxidation Release proteolytic enzymes Damage endothelial cell membrane Increase BBB permeability Post-ischemic edema No-reflow phenomenon | Â | Less infiltration |
 | Monocytes | Generation superoxide anions Release pro-inflammatory cytokines | Removal necrotic cell debris and neutrophils | Less infiltration |