Involvement of thrombin and mitogen-activated protein kinase pathways in hemorrhagic brain injury

Autor: Masatoshi Ohnishi, Hiroshi Katsuki, Toshiaki Kume, Mikako Takagi, Shinji Fujimoto, Akinori Akaike
Rok vydání: 2007
Předmět:
Male
mitogen-activated protein kinase
MAP Kinase Signaling System
MAP Kinase Kinase 1
Brain damage
Pharmacology
Arginine
Neuroprotection
Rats
Sprague-Dawley
Thrombin
Developmental Neuroscience
medicine
Animals
cardiovascular diseases
Gliosis
Cycloheximide
Enzyme Inhibitors
491.17
Extracellular Signal-Regulated MAP Kinases
Cerebral Hemorrhage
Neurons
Protein Synthesis Inhibitors
Sulfonamides
TUNEL assay
biology
Cell Death
Kinase
apoptosis
JNK Mitogen-Activated Protein Kinases
Brain
intracerebral hemorrhage
nervous system diseases
Rats
medicine.anatomical_structure
Neuroprotective Agents
Neurology
Mitogen-activated protein kinase
Pipecolic Acids
Immunology
Nerve Degeneration
biology.protein
Neuroglia
Brain Damage
Chronic
Neuron
Microglia
medicine.symptom
Platelet Aggregation Inhibitors
medicine.drug
Zdroj: Experimental neurology. 206(1)
ISSN: 0014-4886
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: