Effect of ADAMTS-13 on cerebrovascular microthrombosis and neuronal injury after experimental subarachnoid hemorrhage.
BACKGROUND
Microthrombosis and reactive inflammation contribute to neuronal injury after subarachnoid hemorrhage (SAH). ADAMTS-13 cleaves von Willebrand factor multimers, and inhibits thrombus formation and, seemingly, inflammatory reactions.


OBJECTIVE
To investigate the effect of ADAMTS-13 in experimental SAH.


METHODS
A total of 100 male C57/BL6 mice were randomly assigned to four groups: sham (n = 15), SAH (n = 27), vehicle (n = 25), and ADAMTS-13 (n = 23; 100 μL per 10 g of body weight of 100 μg of ADAMTS-13 per 1 mL of 0.9% NaCl; 20 min after SAH). Neurologic performance was assessed on days 1 and 2 after SAH. Animals were killed on day 2. The amounts of subarachnoid blood, microthrombi, apoptosis and degenerative neurons were compared. The degree of neuronal inflammation and vasospasm was also compared. In five mice each (SAH and ADAMTS-13 groups), bleeding time was assessed 2 h after SAH.


RESULTS
Systemic administration of ADAMTS-13 achieved significant amelioration of microthrombosis and improvement in neurologic performance. ADAMTS-13 reduced the amount of apoptotic and degenerative neurons. A tendency for decreased neuronal inflammation was observed. ADAMTS-13 did not show any significant effect on vasospasm. The degree of systemic inflammation was not changed by ADAMTS-13 administration. ADAMTS-13 neither increased the amount of subarachnoid blood nor prolonged the bleeding time.


CONCLUSIONS
ADAMTS-13 may reduce neuronal injury after SAH by reducing microthrombosis formation and neuronal inflammation, thereby providing a new option for mitigating the severity of neuronal injury after SAH.
Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan; Institute of Aging and Brain Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan; Department of Neurosurgery, Kantonsspital Aarau, Aarau, Switzerland; Neurocritical Care Unit, Department of Neurosurgery, University Hospital Zurich, Zurich, Switzerland.
C
C
Muroi
M
M
Fujioka
K
K
Mishima
K
K
Irie
Y
Y
Fujimura
T
T
Nakano
J
J
Fandino
E
E
Keller
K
K
Iwasaki
M
M
Fujiwara
D051722:ADAM Proteins / Q000627:therapeutic use*; D000071120:ADAMTS13 Protein; D000818:Animals; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006470:Hemorrhage; D006801:Humans; D007249:Inflammation; D020767:Intracranial Thrombosis / Q000097:blood / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D011994:Recombinant Proteins / Q000627:therapeutic use; D013345:Subarachnoid Hemorrhage / Q000097:blood / Q000628:therapy*; D013997:Time Factors; D014841:von Willebrand Factor / Q000378:metabolism
D011994:Recombinant Proteins; D014841:von Willebrand Factor; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human
ADAMTS13, mouse; cerebral vasospasm; microcirculation; subarachnoid hemorrhage; thrombosis