Treatment of focal cerebral ischemia with synthetic oligopeptide corresponding to lectin domain of selectin.
OBJECTIVE
Synthetic oligopeptides with amino acid sequences of the lectin domain of selectin block selectin-mediated cell adhesion in vitro, which may be applied to a therapeutic intervention to attenuate acute inflammatory reactions. To evaluate the efficacy of such treatment against ischemic brain injury, the effects of administering a selectin oligopeptide that selectively blocks selectin-mediated cell adhesion on histological outcome and on cerebral blood flow (CBF) were studied in models of rodent focal cerebral ischemia.


METHODS
Spontaneously hypertensive rats were anesthetized with halothane. Permanent focal cerebral ischemia was induced by tandem left middle cerebral artery (MCA) and common carotid artery (CCA) occlusion. Focal cerebral ischemia with partial reperfusion was introduced by reperfusing the CCA after 2 hours of tandem MCA/CCA occlusion. A synthetic oligopeptide (amino acid residues 23-30 from N terminal) of E-selectin was dissolved in physiological saline and was injected intravenously at a dosage of 2 mg/kg or 10 mg/kg before artery occlusion. Control animals received equivalent volumes of physiological saline or 10 mg/kg of synthetic oligopeptide with a scrambled amino acid sequence. Twenty-four hours after the occlusion, seven coronal brain slices were stained with 2,3,5-triphenyltetrazolium chloride, and the volume of ischemic injury was calculated. In a separate set of animals, regional CBF was monitored with laser-Doppler flowmetry at the dorsolateral cerebral cortex during 2-hour ischemia and 30 minutes after partial reperfusion.


RESULTS
The volume of ischemic injury did not differ among groups in permanent ischemia. In ischemia with partial reperfusion, 10 mg/kg selectin oligopeptide, but not the same dosage of scrambled oligopeptide, significantly reduced the volume of ischemic injury (95 +/- 13, 73 +/- 11, 55 +/- 6, and 111 +/- 14 mm3 for saline [n = 11]; 2 mg/kg [n = 10] and 10 mg/kg [n = 16] selectin oligopeptide and 10 mg/kg scrambled oligopeptide [n = 6], respectively; P < .01 by one-way ANOVA followed by the Tukey test). Laser-Doppler flowmetry demonstrated a larger increase in CBF after reperfusion of the CCA in the 10-mg/kg selectin oligopeptide group.


CONCLUSIONS
Our data demonstrate that administration of a synthetic oligopeptide corresponding to the lectin domain of selectin decreases the size of ischemic injury after transient, but not after permanent, focal cerebral ischemia as evaluated at 24 hours after onset of ischemia. These effects were associated with an improved CBF at the dorsolateral cerebral cortex after partial reperfusion.
Morikawa
E
E
Department of Neurosurgery, University of Tokyo Faculty of Medicine, Japan.
Zhang
S M
SM
Seko
Y
Y
Toyoda
T
T
Kirino
T
T
D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure; D001921:Brain / Q000473:pathology; D001929:Brain Edema / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002245:Carbon Dioxide / Q000097:blood; D002540:Cerebral Cortex / Q000098:blood supply; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D017078:Laser-Doppler Flowmetry; D037102:Lectins; D008297:Male; D010100:Oxygen / Q000097:blood; D010446:Peptide Fragments / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D015424:Reperfusion; D019087:Selectins / Q000737:chemistry* / Q000627:therapeutic use*
D037102:Lectins; D010446:Peptide Fragments; D019087:Selectins; D002245:Carbon Dioxide; D010100:Oxygen