Thrombin, a mediator of neurotoxicity and memory impairment.
Thrombin has been found in neuritic plaques in Alzheimer's disease (AD). Also, traumatic brain injury, where neurons are exposed to high thrombin levels, is associated with an increased incidence of AD. Our objective was to determine the effects of thrombin administered in vivo on cognitive function and neuropathology. Rats were trained using a radial eight-arm maze and then thrombin (25 or 100 nM, 0.25 microl/h, 28 days) or vehicle was delivered via intracerebroventricular infusion. Animals that received 100 nM thrombin demonstrated cognitive impairments including deficits in reference memory and an increase in task latency. Also, significant neuropathology was detected in these animals such as enlargement of cerebral ventricles, an increased number of TUNEL-positive cells, astrogliosis, and an increase in the immunoreactivity for phosphorylated neurofilament, and apolipoprotein-E fragments. Thrombin-induced changes in cognitive function and ventricular enlargement were inhibited by hirudin. These findings demonstrate that thrombin is a mediator of neurotoxicity and cognitive deficits and suggest that inhibition of thrombin may be a treatment strategy for AD- or head trauma-associated cognitive deficits.
Mhatre
Molina
M
Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK 73104, USA.
Nguyen
Albert
A
Kashani
Shabnam
S
Pham
Tracy
T
Adesina
Adekunle
A
Grammas
Paula
P
D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006490:Hemostatics / Q000633:toxicity*; D024764:Hirudin Therapy / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced* / Q000503:physiopathology; D009043:Motor Activity / Q000187:drug effects; D016900:Neurofilament Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D013917:Thrombin / Q000633:toxicity*
D001057:Apolipoproteins E; D005343:Fibrinolytic Agents; D005904:Glial Fibrillary Acidic Protein; D006490:Hemostatics; D016900:Neurofilament Proteins; D013917:Thrombin