Simvastatin protects against long-lasting behavioral and morphological consequences of neonatal hypoxic/ischemic brain injury

被引:94
作者
Balduini, W [1 ]
De Angelis, V [1 ]
Mazzoni, E [1 ]
Cimino, M [1 ]
机构
[1] Univ Urbino, Ist Farmacol & Farmacognosia, I-61029 Urbino, Italy
关键词
cerebral ischemia; HMG-CoA reductase inhibitors; neuroprotection; newborn; rats;
D O I
10.1161/hs0901.094287
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Background and Purpose-Recent studies suggest that statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) not only reduce the incidence of stroke by lowering cholesterol levels but may also exert neuroprotective effects via a mechanism not related to their lipid-lowering effect. Despite the growing body of evidence, however, the neuroprotective effect of statins in stroke is still controversial. Herein, we studied whether a prophylactic administration of simvastatin (Sim) provides significant protection against brain damage, and we sought to determine its long-lasting behavioral consequences in a neonatal model of hypoxia/ischemia. Methods-Newborn male rats were injected daily from postnatal days 1 to 7 with activated Sim (20 mg/kg) or an equivalent volume of vehicle. On postnatal day 7, the rats were subjected to ligation of the right common carotid artery, followed by 3 hours of hypoxia or by sham operation. The neuroprotective effect of Sim was evaluated after the rats had achieved adulthood by using a battery of behavioral tests and histological analysis. Results-Sim-treated ischemic rats performed the circular water maze, the radial arm maze, and the multiple-choice water maze significantly better than did vehicle-treated ischemic rats. Furthermore, in contrast to the ischemic rats, hypoxia/ischemia-injured rats pretreated with Sim were not hyperactive at weaning and showed less behavioral asymmetry. Consistently, it was found that brain damage was significantly attenuated. Conclusions-These findings indicate that prophylactic administration of statins may provide a potential neuroprotective strategy leading to an improvement in functional outcome in ischemic stroke. However, toxicity concern must be addressed before these agents can be directed to the asphyxiated fetus or newborn.
引用
收藏
页码:2185 / 2191
页数:7
相关论文
共 28 条
[1]   Long-lasting behavioral alterations following a hypoxic/ischemic brain injury in neonatal rats [J].
Balduini, W ;
De Angelis, V ;
Mazzoni, E ;
Cimino, M .
BRAIN RESEARCH, 2000, 859 (02) :318-325
[2]   Stroke, statins, and cholesterol - A meta-analysis of randomized, placebo-controlled, double-blind trials with HMG-CoA reductase inhibitors [J].
Blauw, GJ ;
Lagaay, AM ;
Smelt, AHM ;
Westendorp, RGJ .
STROKE, 1997, 28 (05) :946-950
[3]   Time-dependent reorganization of brain circuitry underlying long-term memory storage [J].
Bontempi, B ;
Laurent-Demir, C ;
Destrade, C ;
Jaffard, R .
NATURE, 1999, 400 (6745) :671-675
[4]   COMPARATIVE ASPECTS OF THE BRAIN GROWTH SPURT [J].
DOBBING, J ;
SANDS, J .
EARLY HUMAN DEVELOPMENT, 1979, 3 (01) :79-83
[5]  
Duval D, 2000, STROKE, V31, P989
[6]   Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase [J].
Endres, M ;
Laufs, U ;
Huang, ZH ;
Nakamura, T ;
Huang, P ;
Moskowitz, MA ;
Liao, JK .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (15) :8880-8885
[7]   Enhanced expression of interleukin (IL)-1 and IL-6 messenger RNA and bioactive protein after hypoxia-ischemia in neonatal rats [J].
Hagberg, H ;
Gilland, E ;
Bona, E ;
Hanson, LA ;
HahnZoric, M ;
Blennow, M ;
Holst, M ;
McRae, A ;
Soder, O .
PEDIATRIC RESEARCH, 1996, 40 (04) :603-609
[8]   LOVASTATIN INDUCES GROWTH-INHIBITION AND APOPTOSIS IN HUMAN-MALIGNANT GLIOMA-CELLS [J].
JONES, KD ;
COULDWELL, WT ;
HINTON, DR ;
SU, YH ;
HE, SK ;
ANKER, L ;
LAW, RE .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1994, 205 (03) :1681-1687
[9]   The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. [J].
Kureishi, Y ;
Luo, ZY ;
Shiojima, I ;
Bialik, A ;
Fulton, D ;
Lefer, DJ ;
Sessa, WC ;
Walsh, K .
NATURE MEDICINE, 2000, 6 (09) :1004-1010
[10]   Neuroprotection mediated by changes in the endothelial actin cytoskeleton [J].
Laufs, U ;
Endres, M ;
Stagliano, N ;
Amin-Hanjani, S ;
Chui, DS ;
Yang, SX ;
Simoncini, T ;
Yamada, M ;
Rabkin, E ;
Allen, PG ;
Huang, PL ;
Böhm, M ;
Schoen, FJ ;
Moskowitz, MA ;
Liao, JK .
JOURNAL OF CLINICAL INVESTIGATION, 2000, 106 (01) :15-24