Inflammatory gene expression in cerebral ischemia and trauma. Potential new therapeutic targets.
This review summarized evidence in support for the case that ischemia elicits an inflammatory condition in the injured brain. The inflammatory condition consists of cells (neutrophils at the onset and later monocytes) and mediators (cytokines, chemokines, others). It is clear that de novo upregulation of proinflammatory cytokines, chemokines and endothelial-leukocyte adhesion molecules in the brain follow soon after the ischemic insult and at a time when the cellular component is evolving. The significance of the inflammatory response to brain ischemia is not fully understood. Evidence is emerging in support of the possibility that the acute inflammatory reaction to brain ischemia may be causally related to brain damage. This evidence includes: 1) the capacity of cytokines to exacerbate brain damage; 2) the capacity of specific cytokine antagonists such as IL-1ra to reduce ischemic brain damage; 3) that depletion of circulating neutrophils reduces ischemic brain injury; 4) and that antagonists of the endothelial-leukocyte adhesion interactions (e.g., anti-ICAM-1) reduce ischemic brain injury. However, it should be kept in mind that cytokines were also argued to provide beneficial effects in brain injury as inferred from studies with TNF-receptor knock-out mice (p55 and p75 knock-out), which display increased sensitivity to brain ischemia, and the capacity of IL-1 to elicit the state of ischemic tolerance upon repeated administration. Nevertheless, the recent revelation on the capacity of ischemia to induce acute inflammation in the brain provides a new and fertile ground for new explorations for novel therapeutic agents that could confine the neuronal damage that follows ischemia. Furthermore, many of the genes that are upregulated by ischemia have growth-promotion capacity and therefore raise the possibility that such gene products may be useful in counteracting brain damage by enhancing repair and establishing compensatory mechanisms that enhance histological and functional recovery.
Feuerstein
G Z
GZ
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. giora_z_feuerstein@sbphrd.com
Wang
X
X
Barone
F C
FC
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D001930:Brain Injuries / Q000276:immunology / Q000503:physiopathology* / Q000628:therapy; D002545:Brain Ischemia / Q000276:immunology / Q000503:physiopathology* / Q000628:therapy; D002561:Cerebrovascular Disorders / Q000276:immunology / Q000503:physiopathology / Q000628:therapy; D018925:Chemokines / Q000096:biosynthesis*; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000096:biosynthesis; D051379:Mice; D009000:Monocytes / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000906:Antibodies; D018925:Chemokines; D016207:Cytokines; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1