title: Involvement of thrombin and mitogen-activated protein kinase pathways in hemorrhagic brain injury.
abstract: Thrombin is thought to play an important role in brain damage associated with intracerebral hemorrhage (ICH). We previously showed that activation of mitogen-activated protein (MAP) kinases and recruitment of microglia are crucial for thrombin-induced shrinkage of the striatal tissue in vitro and thrombin-induced striatal damage in vivo. Here we investigated whether the same mechanisms are involved in ICH-induced brain injury. A substantial loss of neurons was observed in the center and the peripheral region of hematoma at 3 days after ICH induced by intrastriatal injection of collagenase in adult rats. Intracerebroventricular injection of argatroban or cycloheximide, both of which prevent thrombin cytotoxicity in vitro, exhibited a significant neuroprotective effect against ICH-induced injury. ICH-induced neuron loss was also prevented by a MAP kinase kinase inhibitor (PD98059) and a c-Jun N-terminal kinase inhibitor (SP600125). These drugs had no effect on hematoma size or ICH-induced brain edema. Activation of extracellular signal-regulated kinase in response to ICH was observed in both neurons and microglia. Despite their neuroprotective effects, MAP kinase inhibitors did not decrease the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells appearing after ICH. Identification of cell types revealed that TUNEL staining occurred prominently in neurons but not in microglia, whereas inhibition of MAP kinases resulted in appearance of TUNEL staining in microglia. These results suggest that thrombin and the activation of MAP kinases are involved in ICH-induced neuronal injury, and that neuroprotective effects of MAP kinases are in part mediated by arrestment of microglial activities.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Ohnishi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katsuki
authors.forename: Shinji
authors.initials: S
authors.lastname: Fujimoto
authors.forename: Mikako
authors.initials: M
authors.lastname: Takagi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kume
authors.forename: Akinori
authors.initials: A
authors.lastname: Akaike
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D001925:Brain Damage, Chronic / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002543:Cerebral Hemorrhage / Q000150:complications* / Q000378:metabolism* / Q000503:physiopathology; D003513:Cycloheximide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D005911:Gliosis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D010875:Pipecolic Acids / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides; D013917:Thrombin / Q000378:metabolism / Q000633:toxicity*
chemical_list: D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D010875:Pipecolic Acids; D010975:Platelet Aggregation Inhibitors; D011500:Protein Synthesis Inhibitors; D013449:Sulfonamides; D001120:Arginine; D003513:Cycloheximide; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D013917:Thrombin; C031942:argatroban