Suramin-induced reversal of chronic cerebral vasospasm in experimental subarachnoid hemorrhage.
OBJECTIVE
The naphthylsulfonate derivative suramin is an inhibitor of growth factor receptors (receptor tyrosine kinases) and G protein-coupled P2Y receptors. Both types of these receptors are suspected of being involved in cerebral vasospasm after subarachnoid hemorrhage (SAH). In the current study, the authors examined the therapeutic effects of suramin and a selective P2X-receptor antagonist, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), in the reversal of vasospasm in an established canine double-hemorrhage model.


METHODS
Twenty-four dogs underwent double blood injection into the cisterna magna, with injections given on Days 0 and 2. The dogs were divided randomly into three groups (six animals in each group) to be treated from Days 2 through 6 with the vehicle dimethyl sulfoxide, suramin, or PPADS. An additional group of six dogs received double blood injection without any treatment and served as an SAH control group. The animals were killed on Day 7. Angiography was performed on Day 0 before blood injection and again on Day 7 before the animals were killed. After the death of the animals, the basilar arteries (BAs) were collected for morphological studies and determination of tyrosine kinase expression, and the bloody cerebrospinal fluid (CSF) produced by the hemorrhages was collected for measurement of oxyhemoglobin and adenosine triphosphate (ATP). In the SAH control group, the mean diameter of the BAs on Day 7 was 46.23 +/- 6.32% of the value on Day 0 (which served as a reference of 100%). In the DMSO-treated group, the mean residual diameter of the BA was 47.77 +/- 0.8% on Day 7 compared with the value on Day 0. Suramin, but not PPADS, increased the residual diameter to 74.02 +/- 4.24% on Day 7. On Day 7 the level of ATP in the CSF was decreased and the level of oxyhemoglobin was increased, compared with values measured on Day 0. Suramin, but not PPADS, reduced tyrosine phosphorylation in the spastic BAs.


CONCLUSIONS
By reducing tyrosine kinase activity, suramin may be useful in the treatment of cerebral vasospasm.
Department of Neurosurgery, University of Mississippi Medical Center, Jackson, USA.
Hitoshi
H
Kimura
Toshinari
T
Meguro
Ahmed
A
Badr
John H
JH
Zhang
D000255:Adenosine Triphosphate / Q000134:cerebrospinal fluid; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002908:Chronic Disease; D004285:Dogs; D005260:Female; D008297:Male; D010108:Oxyhemoglobins / Q000134:cerebrospinal fluid; D010766:Phosphorylation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D013498:Suramin / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism
D000970:Antineoplastic Agents; D010108:Oxyhemoglobins; D010975:Platelet Aggregation Inhibitors; D018048:Receptors, Purinergic P2; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D014443:Tyrosine; D011732:Pyridoxal Phosphate; D013498:Suramin; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases