doi: 10.1161/01.STR.0000014207.05597.D7
(Stroke. 2002;33:1085.)
© 2002 American Heart Association, Inc.
Original Contributions |
NAP, a Femtomolar-Acting Peptide, Protects the Brain Against Ischemic Injury by Reducing Apoptotic Death
From the Department of Neurology, Agnes Ginges Center for Human Neurogenetics, Hebrew University-Hadassah Medical School, University Hospital, Jerusalem, Israel (R.R.L., A.T., N.G., H.O.); Department of Neurological Sciences, University of Rome, La Sapienza, Italy (A.T.); Section on Developmental and Molecular Pharmacology, Laboratory of Developmental Neurobiology, National Institutes of Health, Bethesda, Md (D.E.B.); Department of Organic Chemistry, Weizmann Institute, Rehovot, Israel (M.F.); and Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel (E.G., J.R., I.G.).
Correspondence to R.R. Leker, MD, Department of Neurology, Hadassah University Hospital, Ein Kerem, PO Box 12000, Jerusalem 91120, Israel. E-mail leker{at}cc.huji.ac.il
Background and Purpose— We sought to determine the cerebroprotective potential of NAP, a synthetic octapeptide related to vasoactive intestinal peptide. Activity-dependent neuroprotective protein mediates some of the protective effects of vasoactive intestinal peptide. The neuroprotective NAP sequence is derived from activity-dependent neuroprotective protein.
Methods— Spontaneously hypertensive rats underwent permanent middle cerebral artery occlusion by craniotomy and electrocoagulation. After dose-response and time-course experiments, the animals were injected with NAP (3 µg/kg) or vehicle intravenously 1 hour after stroke onset. Another group of rats was injected with the D-amino acid isomer of NAP (D-NAP) and served as a negative control. Rats were examined for motor and behavioral deficits 24 hours to 30 days later, and infarct volumes were determined. The effect of NAP administration on apoptotic death was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and caspase-3 stainings.
Results— NAP significantly reduced motor disability and infarct volumes compared with vehicle or D-NAP when tested at 24 hours after stroke onset (9.67±1.4% versus 17.04±1.18% and 19.19±1.9% of hemispheric volume, respectively; P<0.05). NAP given 4 but not 6 hours after permanent middle cerebral artery occlusion still conferred significant neuroprotection (infarct volume 10.9±3.9% of hemispheric volume; P<0.05 versus vehicle). Long-term studies demonstrated that infarct volumes and disability scores remained significantly lower after 30 days in NAP-treated animals. NAP significantly reduced the number of apoptotic cells.
Conclusions— Our results indicate that the durable cerebroprotection by NAP involves antiapoptotic mechanisms.
Key Words: animal models • cerebral ischemia • neuropeptides • neuroprotection • vasoactive intestinal peptide • rats
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