| Leptin,an adipocytokine encoded by an obesity-associated gene expressed in adipose tissue,affects feeding behavior,thermogenesis and neuroendocrine status via leptin receptors distributed in the brain,particularly in the hypothalamus.Recently,studies have investigated the role of leptin in non-hypothalamic areas,including regions associated with learning and memory,and cognitive function.the neuroprotective effects of leptin on brain damage resulting from premature development remain unknown.Fetal weight increases markedly during the third trimester and >90% of fetal body fat is deposited during the last 10 weeks of gestation.Therefore,the development of adipose tissue in preterm infants may be delayed compared with in term infants,potentially resulting in leptin deficiency.Across 184 countries,the rate of preterm birth(<37 weeks gestation)ranges from 5 to18% of total births,with an estimated 15 million babies born preterm every year;this number is increasing annually.Complications arising from preterm birth are the leading cause of mortality among children under 5 years of age.A total of 75% of these babies may be saved with current,cost-effective treatments;however,numerous survivors endure lifelong disabilities,including learning disorders,and visual and hearing issues.According to the U.S.Centers for Disease Control and Prevention,very early preterm births(<32 weeks gestation)account for 16% of the total number of preterm births.It has been reported that ～10% of the preterm births with gestational ages <32 weeks and birth weights <1,500 g exhibit defects in locomotion,whereas～60% of infants possess neurocognitive disabilities and/or behavioral problems.The most common defect in preterm infants is periventricular leukomalacia(PVL)and the incidence of PVL in preterm infants has been reported to be >50%.At present,the mechanisms underlying premature brain damage are unclear,yet hypothermic,stem cell-associated and other types of therapeutic strategies have been reported;however,the majority of these applications lack efficacy.Therefore,it is important to develop novel,safe and effective treatment methods.In view of the trend in recent years the study of the biological effect research of leptin of the hypothalamus area,such as leptin on learning and memory,cognitive function and neural protection,through observation on neurobehavioral effects of leptin in premature brain white matter damage model rats,and analysis of the differential peptidomic profiles,we try to provide the theory basis for the treatment of premature infant brain white matter damage.The research was divided into the following three parts:1.Effects of leptin on neurocognitive and motor functions in juvenile rats in a preterm brain damage modelObjectives: In this part,the neuroprotective effects of leptin in a rat model of preterm brain white matter damage were investigated.Methods: Rats(2-days-old)were subjected to brain damage(ligation of the common carotid artery followed by exposure to 6% oxygen for 2 h)and treated with vehicle(control)or leptin.Spatial memory was analyzed in the present study using the Morris water maze test 19 days following ligation.Over the 24-day post-surgical observation period,capture-resistance test,forelimb suspension and open field tests were conducted to evaluate motor function and anxiety-associated behavior.Results: Treatment with leptin did not notably affect survival rate or body weight.Treatment with leptin increased the number of platform crossings in rats with premature brain damage in the Morris water maze test,which was used to assess spatial memory.Multivariate analysis revealed that leptin reduced the latency to finding the platform location,independent of gender and weight.In the capture-resistance,forelimb suspension and open field tests,there were no differences between animals administered leptin and the control groups.2.Peptidomics analysis of hippocampus tissue for recognization of putative bioactive peptide in preterm brain white matter damage model rats Objectives:To understand thoroughly the impact of peptide in differentiation and growth of the nervous system of preterm brain white matter damage model rats.Methods:We compared the peptide profile of hippocampus tissue between sham operation and preterm brain white matter damage model rats through a stable isobaric labeling strategy including tandem mass tag reagents,then by tandem mass spectrometry with nanometer liquid chromatography.Results: We recognized and measured 4164 peptides,262 of which were differential expressed in hippocampus tissue between sham and preterm brain white matter damage model rats;164 peptides were higher and 98 peptides were lower in preterm brain white matter damage model group.Through the Ingenuity Pathway Analysis,we discovered these peptide,related to ELN,PCLO,MYO15 a,MAP4 and MAP1 b,expressed differential with more significance in nervous system development and function.Meanwhile,the CDK5 signaling pathway was activated in the hippocampus of preterm infants with brain damage.3.Peptidomic analysis of hippocampal tissue for explore leptin neuroprotective effect on thepreterm brain white matter damage model ratsObjectives: To gain insight into the neuroprotective mechanisms of leptin on preterm brain damage model rats.Methods: we constructed a comparative peptidomic profiling of hippocampal tissue between leptin-treated after model and preterm brain white matter damage model rats using a stable isobaric labeling strategy involving tandem mass tag reagents,followed by nano liquid chromatography tandem mass spectrometry.Results: We identified and quantified 4164 peptides,238 of which were differential expressed in hippocampal tissue in the two groups;A total of 150 peptides were up regulated and 88 peptides were down regulated.These peptides were imported into the Ingenuity Pathway Analysis(IPA)and identified putative roles in nervous system development,function and diseases.We concluded that the preterm brain white matter damage model with leptin treatment induced peptide changes in hippocampus,and these peptide,especially for the peptides associated “microtubule-associated protein 1b(MAP1b),Elastin(Eln),Piccolo presynaptic cytomatrix protein(Pclo),Zinc finger homeobox 3(Zfhx3),Alpha-kinase 3(Alpk3)and Myosin XVA(Myo15a)”,could be candidate bio-active peptides and participate in neuroprotection of leptin.Meanwhile,we found that repression of ILK signaling pathway plays a significant role in neuroprotection of leptin.Conclusions:Collectively,the results of the present study suggested that leptin may alleviate spatial memory impairment resulting from premature brain damage,independent of gender or weight.Similar to the related differentially expressed peptides in the pathogenesis of brain injury in preterm,ELN,PCLO,MYO15 a,MAP4and MAP1 b,especially the differentially expressed peptides related to PCLO and MAP1 b,may be involved in the neuroprotective effect of leptin on brain injury in preterm.These peptide,related to ELN,PCLO,MYO15 a,MAP4 and MAP1 b,expressed differential with more significance in nervous system development and function.In addition,Akap13,Zfhx2,Zfhx3,H2 Afx,Col4a5 and apob-100 were also involved in the action process of leptin on the model.The CDK5 signaling pathway is activated in the hippocampus of preterm infants with brain damage,while the repression of ILK signaling pathway plays a significant role in neuroprotection of leptin. |
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