Thrombin: a potential proinflammatory mediator in neurotrauma and neurodegenerative disorders.
Thrombin is well known in its function as the ultimate serine protease in the coagulation cascade. Emerging evidence indicates that thrombin also functions as a potent signaling molecule that regulates physiologic and pathogenic responses alike in a large variety of cell populations and tissues. Accompanying CNS injury and other cerebral vascular damages, prothrombin activation and leakage of active thrombin into CNS parenchyma has been documented. Due to the irreplaceable feature of neurons, over-reactive inflammatory reactions in the CNS often cause irreversible neuronal damage. Therefore, particular attention is required to develop strategies that restrict CNS inflammatory responses to beneficial, in contrast to neurotoxic ones. In this regard, thrombin not only activates endothelial cells and induces leukocyte infiltration and edema but also activates astrocytes, and particularly microglia, as recently demonstrated, to propagate the focal inflammation and produce potential neurotoxic effects. Recently revealed molecular mechanisms underlying these thrombin effects appear to involve proteolytic activation of two different thrombin-responsive, protease-activated receptors (PARs), PAR1 and PAR4, possibly in concert. Potential therapeutic strategies based on appreciation of the current understanding of molecular mechanisms underlying thrombin-induced CNS inflammation are also discussed.
Suo
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Laboratory for Alzheimer's Disease & Aging Research, Veterans Affairs Medical Center, Kansas City, Missouri and Department of Neurology, University of Kansas Medical School, Kansas City, Kansas, USA. zsuo@kumc.edu
Citron
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BA
Festoff
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D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002490:Central Nervous System / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000503:physiopathology*; D017933:Peripheral Nervous System / Q000473:pathology / Q000503:physiopathology; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000502:physiology*; D020196:Trauma, Nervous System / Q000503:physiopathology*
D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators; D013917:Thrombin