Inflammatory mediators and stroke: new opportunities for novel therapeutics.
Contrary to previous dogmas, it is now well established that brain cells can produce cytokines and chemokines, and can express adhesion molecules that enable an in situ inflammatory reaction. The accumulation of neutrophils early after brain injury is believed to contribute to the degree of brain tissue loss. Support for this hypothesis has been drawn from many studies where neutrophil-depletion blockade of endothelial-leukocyte interactions has been achieved by various techniques. The inflammation reaction is an attractive pharmacologic opportunity, considering its rapid initiation and progression over many hours after stroke and its contribution to evolution of tissue injury. While the expression of inflammatory cytokines that may contribute to ischemic injury has been repeatedly demonstrated, cytokines may also provide "neuroprotection" in certain conditions by promoting growth, repair, and ultimately, enhanced functional recovery. Significant additional basic work is required to understand the dynamic, complex, and time-dependent destructive and protective processes associated with inflammation mediators produced after brain injury. The realization that brain ischemia and trauma elicit robust inflammation in the brain provides fertile ground for discovery of novel therapeutic agents for stroke and neurotrauma. Inhibition of the mitogen-activated protein kinase (MAPK) cascade via cytokine suppressive anti-inflammatory drugs, which block p38 MAPK and hence the production of interleukin-1 and tumor necrosis factor-alpha, are most promising new opportunities. However, spatial and temporal considerations need to be exercised to elucidate the best opportunities for selective inhibitors for specific inflammatory mediators.
Barone
F C
FC
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Feuerstein
G Z
GZ
D000818:Animals; D001921:Brain / Q000276:immunology / Q000503:physiopathology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000502:physiology; D002561:Cerebrovascular Disorders / Q000276:immunology / Q000503:physiopathology* / Q000628:therapy*; D018925:Chemokines / Q000096:biosynthesis / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology*; D007375:Interleukin-1 / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D015815:Cell Adhesion Molecules; D018925:Chemokines; D016207:Cytokines; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases