Thrombin May Contribute to the Pathophysiology of Central Nervous System Injury

Abstract

Thrombin has multiple functions, including its function as a key enzyme during blood coagulation and other physiologic activities. We studied brain tissue reactions to thrombin that might be present in the central nervous system (CNS) following injury. Thrombin and three different types of controls--buffer, albumin, and plasmin--were individually infused into the rat caudate nucleus by a continuous osmotic mini-pump. Brains were examined by conventional histologic and immunohistologic techniques. Antibodies for bromodeoxyuridine (BrdU), glial fibrillary acidic protein (GFAP), vimentin, and laminin were employed to assess the infiltration of inflammatory cells, proliferation activity of cells, and reaction of astrocytes and mesenchymal cells, respectively. The number of inflammatory cells, number of BrdU-positive cells, area and number of vimentin-positive astrocytes, and the area of GFAP-positive astrocytes were quantitatively analyzed. Thrombin caused infiltration of inflammatory cells, proliferation of mesenchymal cells, induction of angiogenesis, and an increase in vimentin-positive reactive astrocytes. These histologic changes caused by thrombin infusion resembled the inflammation, scar formation, and reactive gliosis in the CNS following injury. These results suggest that thrombin may play an important role in inflammatory responses to CNS injury since thrombin is one of the blood borne factors that may interact with brain tissue after CNS injury. The data further suggest that the therapeutic application of antithrombin agents for CNS injury suppresses inflammation and the excessive gliosis and scar formation, which are barriers to neuronal regeneration.

CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure

“…Degeneration of severed axon tracts appears to lead to gliosis, even in regions remote from the site of trauma in the brain or spinal cord (Barrett et al, 1981;Fitch and Silver, 1997a;Massey, et al, 2006;Murray et al, 1990;Steward and Trimmer, 1997). Cytokines or other molecules that may trigger gliosis include TNF-alpha (Rostworowski et al, 1997), endothelin-1 (Hama et al, 1997), IL-1 (Giulian and Lachman, 1985), IL-6 (Chiang et al, 1994), thrombin (Nishino et al, 1993), and CNTF (Kahn et al, 1995). Some of these may originate as soluble serum factors, or they can be directly produced by astrocytes, activated microglia, or peripheral macrophages.…”

Thrombin induces expression of cytokine‐induced SH2 protein (CIS) in rat brain astrocytes: Involvement of phospholipase A2, cyclooxygenase, and lipoxygenase

“…This occurs in acute trauma such as head injury or stroke, and may also occur in chronic neurodegenerative diseases such as Alzheimer's disease and cerebral-vascular dementia (Banks and Kastin, 1983;Olsson et al, 1996). In vivo, thrombin injected into rat brain induces the infiltration of inflammatory cells, brain edema, reactive gliosis, and neuronal cell death (Nishino et al, 1993). In cultured astrocytes and microglia, thrombin induces inflammatory responses (Meli et al, 2001;Ryu et al, 2000).…”

Ratiometric Activatable Cell‐Penetrating Peptides Provide Rapid In Vivo Readout of Thrombin Activation

“…[3][4][5] Thrombin is a major therapeutic target for thrombosis and stroke intervention/prevention through indirect inhibitors such as heparin or warfarin, and direct inhibitors hirudin (divalent), and argatroban (monovalent). [6,7] In addition to its role in thrombosis and stroke, [8][9][10][11] thrombin is reported as a relevant player in cardiovascular disease, [12,13] renal injury, [14] and cancer. [15] Activatable cell-penetrating peptides (ACPPs) target various cargos, including fluorescent imaging agents, to sites of protease activity in vivo.…”