Simvastatin Augments Myelination In Neonatal Rat Of Hypoxic-ischemic Brain Damage

Background and Purpose: Hypoxic-ischemic brain damage (HIBD) is the single most severe neural dosorders in perinatal period. It often leads to the death of neonates or induces long-term nervous dysfunction, including psychomotor retardation, epilepsy, cerebral palsy, cognitive deficit and so on. What the grey matter is more sensitive than white matter to hypoxic-ischemic injury is conventional idea in the past years. But evidence in recent years revealed that white matter is the most important target of the hypoxic-ischemic injury. Oligodendrocyte is major component of white matter and is also the cell for myelinization in central nervous system. Epidemiology and the experimental studies in recent years showed that both of the exitotoxicity and immuno-inflammatory processes including the activation of microglia and release of cytokines could damage the oligodendrocyte and cause dysmyelination. The immature oligodendrocyte is most sensitive to hypoxic-ischemic injury and cytokines. The consequent dysmyelination is a major cause of abnormal nerve impulse conduction, cerebral palsy, long-term mental deficits and learning disabilities in childhood.Stains are the potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the key enzyme in cholesterol synthesis. They are widely used in medical practice in therapy for hypercholesterolemia. But recent researches discovered that Statins have the neuroprotective effects and promote neurogenesis through non-cholesterol dependent pleiotropic effects. Our previous work also demonstrated that Simvastatin promote the regeneration of clamp injuried sciatic nerve in rats by inhibiting the inflammatory response. But up to now, there is no report about effect of Statins on myelinationin in developing brain after HIBD.So we choiced Simvastain, one of the Statins which can cross the blood brain barrier, and observed the effect of it on myelination of oligodendrocyte in neonatal rats of HIBD, and investigated the possible action of microglia responses to brain injury in it.Material and Methods: 7-day-old Sprague-Dawley rats were randomly divided into four groups : naive, sham-operated(Sham), hypoxia-ischemia (HI) and hypoxia-ischemia +Simvastatin (HI+Sim). Activated Simvastatin (20 mg/kg) were injected subcutaneously daily by prophylactic administration from postnatal day 1 to day 7 in HI+Sim animals. After animal model of HIBD were made, we observed the rate of body weight growth. Cryostat sections of the brain were stained with cresyl violet (Nissl staining) in order to observe the states of neuron loss of the brain tissue. And also the brain sections were stained with immunohistochemistry to observe the reaction of microglia with OX-42 and oligodendrocyte myelination with MBP at 3d and 7d after operation.Results: The rate of body weight growth in HI+Sim rats was much faster than HI ones 7d after HI (p<0.05). The numbers of neuron loss in HI+Sim rats was less than HI ones 3 and 7days after HI (p <0.05). The quantity of OX-42 positive microglia in cortex and hippocampus in HI animals was much more than Na?ve and Sham ones (p<0.01), and that of HI+Sim rats was less than HI ones. The density of MBP positive oligodendrocyte in internal capsule and external capsule in HI rats was lower than Na?ve and Sham ones (p<0.05) and HI+Sim rats was higher than HI ones (p<0.05).Conclusions: 1. Rate of body weight growth of neonate rats becomes slow after they experienced HIBD, Cerebral edema, necrosis and atrophy in ipsilateral and neuron loss and necrosis in ipsilateral cortex, hippocampus and thalamus occur. 2. Micoroglia in ipsilateral cortex, hippocampus and striatum are activated after HI displaying that the quantity increases and morphology changes. 3. Density of MBP positive oligodendrocyte becomes decrese in ipsilateral internal capsule and external capsule after HI. 4. Simvastatin can attenuate the slow body weight growth and neuron death after HI, inhibit the activation of microglia and promote myelinization of oligodendrocyte. Consequently Simvastatin can lessen the white matter injury and produce the neuroprotective and therapeutical effects to the neonatal rats of HIBD.