Simvastatin Protects Against Long-Lasting Behavioral and Morphological Consequences of Neonatal Hypoxic/Ischemic Brain Injury

Abstract

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. Key Words: cerebral ischemia Ⅲ HMG-CoA reductase inhibitors Ⅲ neuroprotection Ⅲ newborn Ⅲ rats I schemic stroke is one of the leading causes of permanent disabilities and death in the elderly. Stroke also commonly occurs in the perinatal period and can have severe consequences on motor, cognitive, and behavioral functions that span the infant's lifetime. The mechanisms of hypoxia/ischemia (HI)-induced brain damage, the behavioral outcome, and the effect of potential pharmacological treatments during development can be studied in 7-day-old rats subjected to unilateral carotid artery ligation and exposure to a hypoxic environment for 2 to 3 hours. [1][2][3][4] In terms of brain development, this age of the rat is similar to that of near-term human babies. 5 In a recent study, we characterized the long-lasting behavioral alterations occurring in this model of neonatal HI and found that these animals, when adults, show behavioral asymmetry and deficits in performing spatial learning tasks. 4 Therefore, these behavioral abnormalities can be used as an end point to evaluate the efficacy of potential pharmacological treatments that may improve the consequences of a perinatal HI insult.Recent clinical studies have reported ...

Autophagy in hypoxia-ischemia induced brain injury: Evidences and speculations

“…15 It should be noted that most neuroprotective treatments, including hypoxic preconditioning, 16 reduce inflammation, perhaps also as a consequence of the minor number of cells that undergo necrosis. Our study also showed that hypoxic preconditioning and simvastatin, which have neuroprotective effects in neonatal HI, [16][17][18] increased beclin 1 expression. 8 Increased beclin 1 expression, which correlated with the onset of protection, has been previously reported in an in vivo model of myocardial stunning, 19 and a recent paper that studied the role of autophagy in palmitate-induced beta cell death concluded, according to our hypothesis, that autophagy delays beta cell loss in type 2 diabetes.…”

Long-Term Functional and Protective Actions of Preconditioning With Hypoxia, Cobalt Chloride, and Desferrioxamine Against Hypoxic-Ischemic Injury in Neonatal Rats

“…HP and CoCl 2 preconditioning were able to reduce the extent of cortical injury and only HP reduced striatal damage. Although many treatments have been tested in the HI model at short term intervals, only a few have been examined and found to yield long-term functional outcomes (3,16,26,27). Using preconditioning with hypoxia and two hypoxia-mimetic compounds, CoCl 2 and DFX, we observed long-term protective actions of these treatment strategies.…”

“…Those genes affected include HIF-1 (9) and HIF-1 target genes: glucose transporters, glycolytic enzymes (10), erythropoietin and vascular endothelial growth factor (VEGF) (11). Numerous experimental studies have highlighted the need to examine long-term functional improvements in addition to histologic outcomes after HI injury in the neonate (3,15,16). Therefore, we have investigated whether preconditioning with hypoxia (HP), DFX and CoCl 2 has long lasting cytoprotective actions and thus improves both morphologic and behavioral endpoints 5 wk after an HI insult performed in postnatal day 7 rat pups.…”

Short-Term Administration of a New Free Radical Scavenger, Edaravone, Is More Effective Than its Long-Term Administration for the Treatment of Neonatal Hypoxic–Ischemic Encephalopathy

“…26 Because we did not perform qualitative histology to characterize the various cellular subtypes of the brain parenchyma, subtle injury to neuronal cells involved in behavioral learning cannot be excluded. 27 Future studies should include both morphological study and neurochemical studies, such as neurotrophic factors and neurotransmitters.…”