leptin and Hypoxia-Ischemia--Brain

The most common injury of preterm infants is periventricular leukomalacia (PVL) and to date there is still no safe and effective treatment. In our previous studies, leptin has been found to have neuroprotective effects on the preterm ischemia-hypoxia brain damage model rats in animal behavior. To gain insight into the neuroprotective mechanisms of leptin on preterm brain damage model rats, we constructed a comparative peptidomic profiling of hippocampal tissue between leptin-treated after model and preterm ischemia-hypoxia brain damage model rats using a stable isobaric labeling strategy involving tandem mass tag reagents, followed by nano liquid chromatography tandem mass spectrometry. 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 ischemia-hypoxia brain damage model with leptin treatment induced peptides changes in hippocampus, and these peptides, 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. These may advance our current understanding of the mechanism of leptin's neuroprotective effect on preterm brain damage and may be involved in the etiology of preterm brain damage. Meanwhile, we found that repression of ILK signaling pathway plays a significant role in neuroprotection of leptin. A better understanding of the role of ILK signaling pathway in neuroprotective mechanisms will help scientists and researchers to develop selective, safe and efficacious drug for therapy against human nervous system disorders.

Topics: Animals; Animals, Newborn; Brain; Carotid Artery, Common; Cytoskeletal Proteins; Disease Models, Animal; Elastin; Hippocampus; Homeodomain Proteins; Hypoxia-Ischemia, Brain; Leptin; Leukomalacia, Periventricular; Ligation; Microtubule-Associated Proteins; Myosins; Neuropeptides; Neuroprotective Agents; Peptides; Protein Serine-Threonine Kinases; Rats; Signal Transduction

Hypoxic ischemic encephalopathy (HIE) is a serious condition which results in neonatal morbidity and mortality. Early prediction of HIE especially in the first six hours of birth leads to early treatment with better prognosis.. The aim of this study was to compare the concentrations of leptin, adiponectin, and erythropoietin between normal neonates and those with HIE for the possible use of these markers for assessment of the degree of HIE and as markers for early prediction of HIE.. This study was carried out on 50 appropriate for gestational age (AGA) neonates with HIE born in Tanta University Hospital during the period from June 2016 to March 2018 (Group I). This study also included 50 appropriate for gestational age (AGA) normal neonates not suffering from any complications and matched with group I in age and sex as a control group (Group II). For all neonates in both groups, the following were done: Complete prenatal, natal, and postnatal history, assessment of APGAR score at 5 and 10 minutes, complete clinical examination with special account on clinical evidence of encephalopathy including hypotonia, abnormal oculomotor or pupillary movements, weak or absent suckling, apnea, hyperpnea, or seizures, measurement of cord blood gases and measurement of serum erythropoietin, leptin and adiponectin levels by ELISA immediately after birth.. There were no significant differences between Group I and Group II regarding gestational age, male to female ratio, mode of delivery, and weight while there were significant differences regarding Apgar score at 1 and 5 minutes with significantly lower Apgar score at 1 and 5 minutes in group I compared with Group II. There were significantly lower cord blood PH and adiponectin level and significantly higher cord blood Leptin and erythropoietin in group I compared with group II. There were significant differences between cord blood adiponectin, leptin, erythropoietin, and PH in different degrees of HIE with significantly lower cord blood adiponectin and PH and significantly higher cord blood leptin and erythropoietin in severe degree of hypoxia compared with moderate degree and in moderate degree compared with mild degree of hypoxia. There was a significant positive correlation between cord blood erythropoietin and leptin and a significant negative correlation between cord blood erythropoietin and both adiponectin and PH in studied neonates with hypoxia. ROC curve showed that EPO had the best sensitivity and specificity followed by leptin then adiponectin while the PH had the least sensitivity and specificity as early predictors of hypoxic neonates.. Neonates with HIE had lower cord blood PH and adiponectin levels and higher leptin and erythropoietin levels than normal healthy neonates at birth and during the early postnatal period. The significant differences between cord blood erythropoietin, leptin, and adiponectin between neonates with hypoxia compared with normal neonates may arouse our attention about the use of these markers in the cord blood as early predictors of neonatal HIE which can lead early treatment and subsequently better prognosis.

Topics: Adiponectin; Biomarkers; Erythropoietin; Female; Fetal Blood; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Leptin; Male; Pregnancy

The aim of this study was to investigate the possible neuroprotective and ameliorating effects of leptin treatment in hypoxic-ischemic injury induced neuronal cell death.. Experimental groups in the study were: sham-operated group, leptin treated hypoxia-ischemia group, and vehicle treated hypoxia-ischemia group. In hypoxia-ischemia group, left common carotid artery was ligated permanently on the seventh postnatal day. Two hours after the procedure, hypoxia (92% nitrogen and 8% oxygen) was applied for 2.5 h. Leptin treatment was injected (intraperitoneally; i.p.) as a single dose immediately after the hypoxia period. Neuronal cell death, neuronal density, and leptin levels were evaluated in both hemispheres 72 h after the hypoxic-ischemic insult.. Compared with the hypoxic-ischemia group, the mean leptin levels were higher in the brains of the sham group for both hemispheres. The leptin treatment significantly diminished the number of 'apoptotic cells' in the hippocampal CA1, CA2, CA3, and gyrus dentatus regions in both hemispheres. Leptin treatment significantly preserved the number of neurons in both hemispheres, when compared with the vehicle treated group.. We conclude that leptin treatment improves neuronal density and decreases apoptosis in the newborn rat with hypoxic-ischemic brain injury.

Topics: Animals; Animals, Newborn; Apoptosis; Drug Evaluation, Preclinical; Female; Hippocampus; Hypoxia-Ischemia, Brain; Leptin; Neuroprotective Agents; Pregnancy; Rats; Rats, Wistar

Hypoxia may result from hypoperfusion, as seen in the cardio-respiratory arrest. Subsequent to the acute neuronal damage, the delayed neuronal death ensues, and further neurons die within hours or days thereafter. An effective neuroprotective therapeutic agent should counteract one or, ideally, all well-established neuronal death pathways, i.e., excitotoxicity, oxidative stress and apoptosis. All these three mechanisms propagate through distinctive and mutual exclusive signal transduction pathway and contribute to the neuronal loss following the initial hypoxic-ischemic brain injury. Thus, the ideal therapeutic intervention against the hypoxic-ischemic neuronal injury should aim to prevent all three mechanisms of the neuronal death in a concerted effort. Recent studies demonstrated that intranasally administered leptin results in supra-physiological leptin levels at various regions of the brain (including hippocampus) within 30min of administration. We consider leptin to be an ideal neuroprotective agent, having targeted excitotoxicity (directly, by inhibiting AMDA and NMDA) oxidative stress (indirectly, by HIF1 mediation) and apoptosis (directly, by activating ERK 1/2 pathway) and hypothesize that intranasally administered leptin has neuroprotective effect against the neuronal hypoxic injury. If our hypothesis is confirmed, leptin administered before and/or soon after hypoxic injury, may be effective in minimizing the devastating sequelae of such event.

Topics: Administration, Intranasal; Animals; Apoptosis; Excitatory Amino Acids; Hippocampus; Humans; Hypoxia-Ischemia, Brain; Hypoxia, Brain; Leptin; MAP Kinase Signaling System; Models, Neurological; Neuroprotective Agents; Oxidative Stress

To investigate the effect of leptin on apoptosis of rat cerebral astrocytes with ischemia/ hypoxia injury and its mechanism.. The cerebral astrocytes with ischemic/hypoxia injury were induced in neonatal SD rats. The cellular viability of injury of astrocytes was detected by MTT assay. The apoptosis of astrocyte were detected with Annexin V-FITC kit. The effect of leptin on the expression of apoptosis factor bcl-2, bax, caspase-3 was detected by RT-PCR and Western blot.. Compared with the ischemia group, the cellular viability of leptin intervention group increased significantly (P < 0.01), while the astrocytes apoptosis of leptin intervention group decreased significantly (P < 0.01). The mRNA and protein expression level of antiapoptosis factor bcl-2 in leptin intervention group was much higher than that of ischemia group (P < 0.01), whereas the mRNA and protein expression of bax and caspase-3 was much lower than that of ischemia group (P < 0.01).. Leptin could significantly decrease the apoptosis of astrocytes with ischemia/hypoxia injury, and it i relevant to the increase of bcl-2 expression and the decrease of bax caspase-3 expression level.

Topics: Animals; Animals, Newborn; Apoptosis; Astrocytes; bcl-2-Associated X Protein; Brain; Caspase 3; Hypoxia-Ischemia, Brain; Leptin; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Reperfusion Injury; RNA, Messenger

Fetal or early postnatal stressors may predispose infants to develop diabetes, metabolic syndrome, or stroke. We hypothesized that postnatal stress will predispose animals to develop metabolic syndrome and impair the physiologic response to hypoxic-ischemic brain injury. We characterized the short- and long-term physiologic responses to postnatal stress by examining corticosterone (CS), glucose metabolism, and brain injury in neonatal and adult rats exposed to hypoxia-ischemia (H-I). Rat pups were divided into three levels of postnatal stress from postnatal day (P) 3 to P7. All rats underwent unilateral brain injury on either P7 or P134. We measured brain injury, growth, blood pressure, urine/plasma CS, plasma leptin, insulin, and glucose before and after H-I. Postnatal stress increased neonatal CS production, exacerbated neonatal white matter injury, and was associated with adult hyperglycemia after H-I despite increased insulin production. There were no group differences in adult weight, blood pressure, or leptin. Postnatal stress exacerbated brain injury and produced adult hyperglycemia, triggered after hypoxia exposure, consistent with the hypotheses that neonates exposed to early stress are more vulnerable to hypoxia and may be predisposed to develop metabolic syndrome in adulthood. Prolonged maternal separation produced more hyperglycemia than did brief daily handling.

Topics: Animals; Animals, Newborn; Blood Glucose; Blood Pressure; Body Weight; Brain Injuries; Corticosterone; Female; Humans; Hyperglycemia; Hypoxia-Ischemia, Brain; Insulin; Leptin; Pregnancy; Rats; Rats, Sprague-Dawley; Stress, Physiological