Neuroprotective effect of SolCD39, a novel platelet aggregation inhibitor, on transient middle cerebral artery occlusion in rats.
OBJECTIVE
SolCD39 is a soluble form of recombinant human ecto-ATP/ADPase (NTPDase1) and represents a new class of antithrombotic agents. SolCD39 blocks and reverses platelet activation, preventing recruitment of additional platelets into a growing thrombus. The purpose of this study was to examine the effect of solCD39 on neurological deficit, infarct size, and extent of edema after transient middle cerebral artery occlusion (MCAO) in rats.


METHODS
Physiologically controlled Sprague-Dawley rats underwent 2-hour MCAO by retrograde insertion of an intraluminal suture coated with poly-l-lysine. The agent (solCD39) was administered intravenously before MCAO or at 1-hour or 3-hour recirculation. Other groups received vehicle (Tris-buffered saline) or human albumin (as a "positive" neuroprotective control; 25%, 0.5% of body weight) at 1-hour recirculation. Neurological status was evaluated during occlusion (at 60 minutes) and daily for 3 days after MCAO. Brains were perfusion-fixed at 72 hours, and infarct volumes and brain swelling were determined.


RESULTS
Pretreatment with solCD39 significantly improved the neurological score at 72 hours compared with the vehicle group (4.4+/-0.6 versus 7.6+/-0.6, respectively; P=0.008). Cortical infarct areas were significantly reduced at multiple levels by pretreatment with solCD39. Total striatal infarct area was also significantly reduced compared with vehicle by both solCD39 pretreatment (48% mean reduction) and solCD39 treatment at 3-hour recirculation (51% mean reduction). Treatment with SolCD39 significantly reduced total infarct volume (corrected for brain swelling) by an average of 71% to 72% when administered either before ischemia or at 3 hours of recirculation compared with vehicle. Treatment with albumin significantly reduced neurological score and total, cortical, and subcortical infarction at multiple levels, as expected.


CONCLUSIONS
Treatment with SolCD39, administered either before or at 3 hours after MCAO, improves neurological score and reduces infarct size compared with vehicle. A pharmacological agent of this type appears to have potential for the treatment of focal ischemic stroke.
Belayev
Ludmila
L
Cerebral Vascular Disease Research Center, Department of Neurology (D4-5), University of Miami School of Medicine, PO Box 016960, Miami, FL 33101, USA. lbelayev@stroke.med.miami.edu
Khoutorova
Larissa
L
Deisher
Theresa A
TA
Belayev
Andrey
A
Busto
Raul
R
Zhang
Yongbo
Y
Zhao
Weizhao
W
Ginsberg
Myron D
MD
D000251:Adenosine Triphosphatases / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD / Q000494:pharmacology*; D001081:Apyrase; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D001929:Brain Edema / Q000209:etiology / Q000473:pathology; D002544:Cerebral Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy*; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D012709:Serum Albumin / Q000494:pharmacology; D013997:Time Factors
D015703:Antigens, CD; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010975:Platelet Aggregation Inhibitors; D012709:Serum Albumin; D000251:Adenosine Triphosphatases; D001081:Apyrase; C067869:CD39 antigen