Mechanism And Strategy Of Oxidative Stress Inhibits IGF-I's Neuroprotection

BackgroundCerebral hypoxia-ischemia remains a leading cause of severe brain damage that occursin as many as 0.1-0.2% of term or near -term infants (Gradesâ…¡&â…¢brain injuries), amongwhom approximately 20% die and up to 40% of the survivors often suffer devastatingdisabilities, such as cerebral palsy, mental retardation, and epilepsy. Because of highmortality and poor prognosis, hypoxic-ischemic damage in neonatal brains continues to bea major medical emergency for newborn patients. To damage in neonatal brains continuesto be a major medical emergency for newborn patients. To date, no effective clinicaltreatment is available to mitigate brain damage and improve the prognosis and well beingof these children. Previously, the cascade of neuropathological events that leads to neuronaldamage was best revealed in a rat model of neonatal hypoxia-ischemia. Hypoxia-ischemiaresults in neuronal death that has different patterns and forms in young rats than those seenin adult rats. Young neurons die of necrosis at the early stage of recovery and of delayedapoptosis, whereas adult neurons die of necrosis. This difference is mainly due to theup-regulation of NMDA receptors and increased Caspase 3 activity in young brains that areundergoing programmed cell death. These two factors make young neurons particularlyvulnerable to hypoxia-ischemia. From the onset of oxygen and nutrient deprivation, acascade of pathological events are initiated, such as glutamate excitotoxicity, caspaseactivation, and activation of nitric oxide synthase. Without intervention, young neurons will eventually die and the animals, if they survive, will develop impaired somatosensoryfunction and lateralized memory loss in adult life.Insulin-like growth factorâ… (IGF-â… ) is a pleiotrophic factor essential for the development ofthe mammalian nervous system. IGF-â… and its receptor are expressed at the highest levelsduring the peak of neuronal differentiation. Through activating its receptors on all braincells, IGF-â… promotes neuronal survival and differentiation as well as oligodendrogenesis,and myelination. Studies of IGF-â… transgenic or gene deletion mice have clearly shown thatthe IGF system plays a key role in neuronal survival and neuro- and oligodendrogenesis invivo, which is also supported by its effects in a variety of animal models of brain injury andneuronal degeneration, in day 7 rat pups and fetal sheep, intraventricular infusion of IGF-â… soon after hypoxia-ischemia provided a certain degree of neuroprotection. However, severalconcerns prevented IGF-â… from being further tested in a clinical trial: (1). In awell-established neonatal hypoxia-ischemia rat model, even intraventricular infusion ofhigh doses of IGF-â… immediately following hypoxia-ischemia only reduced brain damageby 40% when evaluated 3 days later; (2). The therapeutic effects of delayed IGF-â… treatmentfollowing hypoxia-ischemia (after 6 hours) are unknown; and (3). The long-term effects ofIGF-â… treatment on brain and behavior development have not been evaluated. Our recentstudies answered these concerns and strongly support IGF-â… as a potential effectivetreatment for HIE patients. Subcutaneous administration of IGF-â… at 24 and 48 hours ofrecovery significantly reduced hypoxia-ischemia induced injury to immature rat brains andimproved their memory and cognitive behavior development evaluated 2 months later.However, this new evidence raised this question: why is immediate IGF-â… â… treatmentfollowing hypoxia-ischemia less effective than delayed treatment?Oxidative damage plays a major role in ischemia/reperfusion induced brain injuries,such as HIE. Compared to the adult brain, the neonatal brain is exceedingly vulnerable tooxidative stress due to high levels of free iron, lower levels of glutathione peroxidase, and aconcomitant accumulation of hydrogen peroxide (H₂O₂). Besides its own neurotoxicity, high levels of H₂O₂ likely induce neuronal resistance to IGF-â… by (1) inhibiting IGF-â… signaling, as recently shown in cerebellar granule neurons, and (2) decreasing IGF-â… treatment following hypoxia-ischemia is less effective than delayed treatment. Immediatelyfollowing hypoxia-ischemia, ROS rapidly accumulates and induces neuronal IGF-â… resistance which deprives neurons of this trophic factor for their maturation and survival.The survival of immature neurons is further compromised by a decline in IGF-â… calculatinglevels and neuronal IGF-â… expression following hypoxia-ischemia. It is not surprising thatantioxidants alone had only limited efficacy in clinical trials, because young neurons stilllack essential trophic support even though ROS levels are lowered.Thus, we expect to find a way to resolve this problem. Because of hypoxia-ischemia,oxidative stress induces neuronal cells IGF-â… resistance. Theoretically speaking, we need anantioxidant and IGF-â… in neuroprotection. Firstly, antioxidant scavenges accumulated ROS,in order to remove neuron cell in oxidant stress and to recover its sensitiveness to theneuronal trophic support of IGF-1. Then IGF-1 can exert its protective functions andtrophic effect. Sodiumpyruvate is just an reagent of this kind. It has the followingcharacteristics: 1. No by-effects. It will not damage cell. 2. It can easily enter cells andfunctions both in internal cell and external cell. 3. With excellent antioxidant functions, itcan scavenge ROS and remove the oxidative stress following hypoxia-ischemia. 4. Itcollaborates with IGF-1 and recovers the reactivity of IGF-1. It can also increase theprotective function of IGF-1 to hypoxia-ischemia. Applying IGF-1 or sodiumpyruvatealone in clinic does not achieve satisfactory results. However, sodiumpyruvate'scollaboration with IGF-1 resolves this problem. It sheds lights on the curation ofhypoxia-ischemia.Objective:Despite advances in our knowledge of neuronal injury, effective clinical treatments forHIE in newborns are still lacking. IGF-â… reduces hypoxic-ischemic brain injuries in animal models of HIE, but in a time-dependent manner. Our preliminary data demonstrated that thelower rate of therapeutic efficacy in the early phase of recovery may result from oxidativestress induced neuronal IGF-â… resistance. We will (1) investigate potential mechanisms ofthe oxidative stress induced neuronal IGF-â… resistance; and (2) determine whether restoringneuronal sensitivity to IGF-â… will increase its therapeutic efficacy in the treatment ofhypoxia-ischemia induced injury to immature brains.Conclusions:1. Oxidative stress activated P38 blocks the IGF-1/Akt signaling pathway, which will inturn attenuate Akt's inhibition on FOXO3. Moreover, oxidative stress will also activatethe JNK2 signaling pathway, which will induce FOXO3 activation. As a result, thesetwo signaling pathways work together to induce the neuronal apoptosis.2. Oxidative stress also activates P53, which suppresses IGF-â… receptor gene expression.This is an important mechanisms of oxidative stress induced neuronal IGF-â… resistance.3. Under oxidative stress status, sodium pymvate scavenges ROS effectively and restoresneuronal sensitivity to IGF-1. Combined with IGF-â… will improve IGF-â… 'sneuroprotective function.