Biomarkers Of Brain Damage Research Articles

Antipsychotics and Risk of Neuroleptic Malignant Syndrome Among A Sample of Egyptian Psychiatric Patients: Role of Alpha-synuclein as A Biomarker for Brain Damage

Antipsychotics and Risk of Neuroleptic Malignant Syndrome Among A Sample of Egyptian Psychiatric Patients: Role of Alpha-synuclein as A Biomarker for Brain Damage

Neuron-specific enolase in cerebrospinal fluid as a biomarker of brain damage in infants with hypoxic-ischemic encephalopathy.

Neuron-specific enolase in cerebrospinal fluid as a biomarker of brain damage in infants with hypoxic-ischemic encephalopathy.

Prediction of Outcome After Endovascular Embolectomy in Anterior Circulation Stroke Using Biomarkers

Stroke is a major public health problem that can cause a long-term disability or death due to brain damage. Serious stroke is frequently caused by a large vessel occlusion in the anterior circulation, which should be treated by endovascular embolectomy if possible. In this study, we investigated the use of the brain damage biomarkers tau, NFL, NSE, GFAp, and S100B to understand the progression of nervous tissue damage and their relationship to outcome in such stroke after endovascular treatment. Blood samples were taken from 90 patients pre-treatment and 2 h, 24 h, 48 h, 72 h and 3 months after endovascular treatment. Stroke-related neurological deficit was estimated using the National Institute of Health Stroke Scale (NIHSS) at admission and at 24 h. Neurological outcome was evaluated at 3 months. After stroke, tau, NFL, GFAp and S100B increased in a time dependent manner, while NSE remained constant over time. At 3 months, tau and GFAp levels were back to normal whereas NFL was still high. Tau, NFL and GFAp correlated well to outcome, as well as to infarct volume and NIHSS at 24 h. The best time for prediction of poor outcome was different for each biomarker. However, the combination of NIHSS at 24 h with either tau, NFL or GFAp at 48 h gave the best prediction. The use of biomarkers in the early setting after endovascular treatment of stroke will lead to a simplified and standardized way to estimate the nervous tissue damage and possibly complement the clinical judgement in foreseeing the need of rehabilitation measures.

Higher Concentration of Plasma Glial Fibrillary Acidic Protein in Wilson Disease Patients with Neurological Manifestations.

ABSTRACTBackgroundWilson disease is a rare, disabling, neurological genetic disease. Biomarkers of brain damage are less well developed.ObjectiveThe aim of this study was to evaluate the utility of plasma glial fibrillary acidic protein as a biomarker for neurological involvement in patients with Wilson disease.MethodsThis prospective cross‐observational study compared plasma glial fibrillary acidic protein concentration among different subtypes of patients with Wilson disease and healthy control subjects. Plasma glial fibrillary acidic protein levels were measured in 94 patients and 25 healthy control subjects. Patients were divided into two subtypes: patients with neurological manifestations (n = 74) or hepatic manifestations (n = 20).ResultsMedian levels of plasma glial fibrillary acidic protein were significantly elevated in patients with neurological manifestations (143.87 pg/mL) compared with those with hepatic manifestations (107.50 pg/mL) and healthy control subjects (86.85 pg/mL). Receiver operating characteristic curve revealed that a plasma glial fibrillary acidic protein cutoff value of 128.8 pg/mL provides sufficient sensitivity (80.0%) and specificity (63.5%) to differentiate patients with neurological manifestations from those with hepatic manifestations.ConclusionsPlasma glial fibrillary acidic protein may serve as a biomarker for distinguishing different subtypes of Wilson disease. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Biomarkers of Hypoxic-Ischemic Encephalopathy in Newborns

Biomarkers are particles that are released from target organs during tissue hypoxia injury. Recognizing biomarkers released from the damaged brain helps physicians determine the extent of tissue damage and the use of protective techniques in clinical treatment. Previous studies revealed that biomarkers such as brain-specific proteins (neuron-specific enolase (NSE), S100B, ubiquitincarboxy-terminal hydrolase-L1, total Tau) and cytokines, including IL-6, IL-1β, IL-10, IL-13, interferon-gamma, TNF alpha and brain-derived neurotrophic factor are useful in diagnosing hypoxic-ischemic encephalopathy (HIE) and predicting nerve growth outcomes. However, optimal sensitivity and specificity of these biomarkers have not been achieved, which has limited their clinical application. This review focuses on biomarkers such as lactate, LDH, NRBC, NSE, S100B, GFAP, CPK-BB, IL-6, NPBI, UCHL-1. More sensitive and accurate instruments such as brain imaging (such as brain MRI), brain function (such as NIRS, aEEG), and long-term neuroassay should be used in the future to confirm biomarkers of neonatal brain damage.

Glutamate biomarkers in comprehensive diagnostics of acute and chronic brain ischemia

The development and implementation of biomarkers of ischaemic brain damage at the pre-hospital and hospital stages, as well as during screening and regular medical examinations, are a priority in neurology. This review describes the role of NR2 peptide, a subunit of the NMDA ionotropic glutamate receptors, in the pathogenesis of cerebral ischemia. Experimental data are presented, showing that NR2 peptide expression increases in brain ischemia, its fragments passing through the blood-brain barrier and entering the bloodstream, thus stimulating the immune response and autoantibody production. Key studies are reviewed that have demonstrated the possibility of using glutamate receptors and their antibodies as potential biomarkers of acute and chronic cerebral ischemia. The sensitivity and specificity of NR2 peptide and NR2 antibodies in these studies averaged >90%. It has been shown that NR2A/B is the only marker with high negative and positive predictive value in people with suspected ischaemic stroke. Monitoring treatment effectiveness is another promising area of application for glutamate biomarkers. Previous studies have shown that the NR2 peptide and its antibodies are potential biomarkers of cerebral infarction, transient ischaemic attack, and chronic cerebral ischemia and may become important components in a successful and comprehensive approach to treatment, screening, and monitoring of disease outcomes.

Circulating MicroRNAs in Extracellular Vesicles as Potential Biomarkers of Alcohol-Induced Neuroinflammation in Adolescence: Gender Differences.

Current studies evidence the role of miRNAs in extracellular vesicles (EVs) as key regulators of pathological processes, including neuroinflammation and neurodegeneration. As EVs can cross the blood–brain barrier, and EV miRNAs are very stable in peripheral circulation, we evaluated the potential gender differences in inflammatory-regulated miRNAs levels in human and murine plasma EVs derived from alcohol-intoxicated female and male adolescents, and whether these miRNAs could be used as biomarkers of neuroinflammation. We demonstrated that while alcohol intoxication lowers anti-inflammatory miRNA (mir-146a-5p, mir-21-5p, mir-182-5p) levels in plasma EVs from human and mice female adolescents, these EV miRNAs increased in males. In mice brain cortices, ethanol treatment lowers mir-146a-5p and mir-21-5p levels, while triggering a higher expression of inflammatory target genes (Traf6, Stat3, and Camk2a) in adolescent female mice. These results indicate, for the first time, that female and male adolescents differ as regards the ethanol effects associated with the inflammatory-related plasma miRNAs EVs profile, and suggest that female adolescents are more vulnerable than males to the inflammatory effects of binge alcohol drinking. These findings also support the view that circulating miRNAs in EVs could be useful biomarkers for screening ethanol-induced neuroinflammation and brain damage in adolescence.

Biomarkers of Brain Damage Induced by Radiotherapy.

Radiotherapy remains currently a critical component for both primary and metastatic brain tumors either alone or in combination with surgery, chemotherapy, and molecularly targeted agents, while it could cause simultaneously normal brain tissue injury leading to serious health consequences, that is, development of cognitive impairments following cranial radiotherapy is considered as a critical clinical disadvantage especially for the whole brain radiotherapy. Biomarkers can help to detect the accurate physiology or conditions of patients with brain tumor and develop effective treatment procedures for these patients. In the near future, biomarkers will become one of the prime driving forces of cancer treatment. In this minireview, we analyze the documented work on the acute brain damage and late consequences induced by radiotherapy, identify the biomarkers, in particular, the predictive biomarkers for the damage, and summarize the biological significance of the biomarkers. It is expected that translation of these research advance to radiotherapy would assist stratifying patients for optimized treatment and improving therapeutic efficacy and the quality of life.

LOX-1 (Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1) Deletion Has Protective Effects on Stroke in the Genetic Background of Stroke-Prone Spontaneously Hypertensive Rat.

Background and Purpose- oxLDL (oxidized low-density lipoprotein) has been known for its potential to induce endothelial dysfunction and used as a major serological marker of oxidative stress. Recently, LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1), a lectin-like receptor for oxLDL, has attracted attention in studies of neuronal apoptosis and stroke. We aim to investigate the impact of LOX-1-deficiency on spontaneous hypertension-related brain damage in the present study. Methods- We generated a LOX-1 deficient strain on the genetic background of stroke-prone spontaneously hypertensive rat (SHRSP), an animal model of severe hypertension and spontaneous stroke. In this new disease model with stroke-proneness, we monitored the occurrence of brain abnormalities with and without salt loading by multiple procedures including T2 weighted magnetic resonance imaging and also explored circulatory miRNAs as diagnostic biomarkers for cerebral ischemic injury by microarray analysis. Results- Both T2 weighted magnetic resonance imaging abnormalities and physiological parameter changes could be detected at significantly delayed timing in LOX-1 knockout rats compared with wild-type SHRSP, in either case of normal rat chow and salt loading (P<0.005 in all instances; n=11-20 for SHRSP and n=13-23 for LOX-1 knockout rats). There were no significant differences in the form of magnetic resonance imaging findings between the strains. A number of miRNAs expressed in the normal rat plasma, including rno-miR-150-5p and rno-miR-320-3p, showed significant changes after spontaneous brain damage in SHRSP, whereas the corresponding changes were modest or almost unnoticeable in LOX-1 knockout rats. There appeared to be the lessening of correlation of postischemic miRNA alterations between the injured brain tissue and plasma in LOX-1 knockout rats. Conclusions- Our data show that deficiency of LOX-1 has a protective effect on spontaneous brain damage in a newly generated LOX-1-deficient strain of SHRSP. Further, our analysis of miRNAs as biomarkers for ischemic brain damage supports a potential involvement of LOX-1 in blood brain barrier disruption after cerebral ischemia. Visual Overview- An online visual overview is available for this article.

Holistic approach of the care of the infant with hypoxic-ischaemic encephalopathy in Spain

IntroductionThere is not much information about the care of infants with hypoxic-ischaemic encephalopathy (HIE) treated with therapeutic hypothermia (TH) in Spain. This includes whether protocols are routinely used, the type of neuro-monitoring performed, and how information on the neurological prognosis is presented to families. The answers to these would allow to detect and implement areas of improvement. MethodA cross-sectional analysis was performed on the responses to structured questionnaires sent to all the Spanish neonatal units that were performing TH in June 2015. Questions were divided into 5 sections: (1) the availability of protocols and technological resources, (2) the use of neuro-monitoring tools, (3) the knowledge and training of the professionals; (4) the prognostic information given to the parents; and (5) the discharge report and the follow-up plan. ResultsMost centres (95%) use servo controlled whole-body cooling methods and have specific management protocols. Sedation is used in 70% of centres, and in 68% of them the onset of enteral feeding is delayed until the end of the cooling period. Amplitude-integrated electroencephalography monitoring is used in more than 80% of the centres, although only in 50% are nurses able to interpret it. Cerebral oxygen saturation is not often monitored (16%). As regards diagnostic-prognostic studies, neuroimaging is universal, but brain damage biomarkers are hardly used (29%). Prognostic information is offered within the first 72 posnatal hours in 21% of the centres, and is given without the presence of the nurse in 70% of the centres. Follow-up is performed by a neuro-paediatrician (84%), with an uneven duration between centres. ConclusionsThe care of infants with HIE treated with TH in Spain is generally adequate, although there are areas for improvement in neuromonitoring, sedation, prognostic information, teamwork, and duration of follow-up.

Mesenchymal stem cells combined with albendazole as a novel therapeutic approach for experimental neurotoxocariasis.

Neurotoxocariasis (NT) is a serious condition that has been linked to reduced cognitive function, behavioural alterations and neurodegenerative diseases. Unfortunately, the available drugs to treat toxocariasis are limited with unsatisfactory results, because of the initiation of treatment at late chronic stages after the occurrence of tissue damage and scars. Therefore, searching for a new therapy for this important disease is an urgent necessity. In this context, cytotherapy is a novel therapeutic approach for the treatment of many diseases and tissue damages through the introduction of new cells into the damaged sites. They exert therapeutic effects by their capability of renewal, differentiation into specialized cells, and being powerful immunomodulators. The most popular cell type utilized in cytotherapy is the mesenchymal stem cells (MSCs) type. In the current study, the efficacy of MSCs alone or combined with albendazole was evaluated against chronic brain insults induced by Toxocara canis infection in an experimental mouse model. Interestingly, MSCs combined with albendazole demonstrated a healing effect on brain inflammation, gliosis, apoptosis and significantly reduced brain damage biomarkers (S100B and GFAP) and T. canis DNA. Thus, MSCs would be protective against the development of subsequent neurodegenerative diseases with chronic NT.

Urinary metabolomics reveals kynurenine pathway perturbation in newborns with transposition of great arteries after surgical repair

IntroductionTransposition of the great arteries (TGA) is a cyanotic congenital heart defect that requires surgical correction, with the use of cardiopulmonary-bypass (CPB), usually within 3 weeks of life. The use of CPB in open heart surgery results in brain hypoperfusion and in a powerful systemic inflammatory response and oxidative stress.ObjectiveWe aimed to develop a novel untargeted metabolomics approach to detect early postoperative changes in metabolic profile following neonatal cardiac surgery.MethodsWe studied 14 TGA newborns with intact ventricular septum undergoing arterial switch operation with the use of CPB. Urine samples were collected preoperatively and at the end of the surgery and were analyzed using an untargeted metabolomics approach based on UHPLC-high resolution mass spectrometry.ResultsSince post surgery metabolic spectra were heavily contaminated by metabolites derived from administered drugs, we constructed a list of drugs used during surgery and their related metabolites retrieved from urine samples. This library was applied to our samples and 1255 drugs and drug metabolites were excluded from the analysis. Afterward, we detected over 39,000 unique compounds and 371 putatively annotated metabolites were different between pre and post-surgery samples. Among these metabolites, 13 were correctly annotated or identified. Metabolites linked to kynurenine pathway of tryptophan degradation displayed the highest fold change.ConclusionsThis is the first report on metabolic response to cardiac surgery in TGA newborns. We developed an experimental design that allowed the identification of perturbed metabolic pathways and potential biomarkers of brain damage, limiting drugs interference in the analysis.

Acute normobaric hypoxia does not affect the simultaneous exercise-induced increase in circulating BDNF and GDNF in young healthy men: A feasibility study.

Physical exercise has a neuromodulatory effect on the central nervous system (CNS) partially by modifying expression of neuropeptides produced and secreted by neurons and glial cells, among which the best examined are brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). Because both neurotrophins can cross the brain-blood barrier (BBB), their blood levels indirectly reflect their production in the CNS. Moreover, both neuropeptides are involved in modulation of dopaminergic and serotoninergic system function. Because limited information is available on the effects of exercise to volition exhaustion and acute hypoxia on CNS, BDNF and GDNF formation, the aims of the present study were to verify whether 1) acute exercise to exhaustion in addition to neurons also activates glial cells and 2) additional exposure to acute normobaric moderate hypoxia affects their function. In this feasibility study we measured blood concentrations of BDNF, GDNF, and neuropeptides considered as biomarkers of brain damage (bFGF, NGF, S100B, GFAP) in seven sedentary healthy young men who performed a graded exercise test to volitional exhaustion on a cycle ergometer under normoxic (N) and hypoxic conditions: 2,000 m (H2; FiO2 = 16.6%) and 3,000 m altitude (H3; FiO2 = 14.7%). In all conditions serum concentrations of both BDNF and GDNF increased immediately after cessation of exercise (p<0.01). There was no effect of condition or interaction (condition x time of measurement) and exercise on any of the brain damage biomarkers: bFGF, NGF, S100B, GFAP. Moreover, in N (0<0.01) and H3 (p<0.05) exercise caused elevated serum 5-HT concentration. The results suggest that a graded effort to volitional exhaustion in normoxia, as well as hypoxia, simultaneously activates both neurons and astrocytes. Considering that s100B, GFAP, bFGF, and NGF (produced mainly by astrocytes) are markers of brain damage, it can be assumed that a maximum effort in both conditions is safe for the CNS.

Therapeutic Hypothermia After Cardiac Arrest: Involvement of the Risk Pathway in Mitochondrial PTP-Mediated Neuroprotection.

Therapeutic hypothermia is neuroprotective after cardiac arrest (CA) via poorly understood mechanisms. It may prevent mitochondrial permeability transition pore (PTP) opening, an event which plays a pivotal role in ischemia-reperfusion injury. PTP is the main end-effector of the reperfusion injury salvage kinase (RISK) signaling pathway. We hypothesized that therapeutic hypothermia activates the RISK pathway, thereby preventing PTP opening and its deleterious neurological consequences after CA. Four groups of New Zealand White rabbits were subjected to 15 min of CA and 120 min of reperfusion: Control, HT (hypothermia at 32°-34°C), NIM (specific PTP inhibition with N-methyl-4-isoleucine-cyclosporine at the onset of reperfusion), and HT+NIM. A Sham group only underwent surgery. The following measurements were taken: pupillary reflexes and brain damage biomarkers (NSE and S100β), RISK pathway activation in brain cortex (total and phosphorylated forms of both protein kinase B [Akt] and extracellular signal-regulated kinase [ERK]) and PTP opening in isolated brain mitochondria. Therapeutic hypothermia and pharmacological PTP inhibition preserved the pupillary reflexes and prevented the increase in both NSE and S100β (P < 0.05 vs. controls). These two interventions also enhanced (P < 0.05 vs. controls) the phospho-Akt/Akt ratio to a similar extent while preventing a CA-induced increase in phospho-ERK/ERK ratio. This Akt activation in the HT and NIM groups was associated with an attenuation of CA-induced PTP opening. In this model, therapeutic hypothermia promoted the activation of the RISK signaling pathway via Akt and limited CA-induced brain injury by preventing PTP opening.

Impaired brain glucose metabolism in cirrhosis without overt hepatic encephalopathy: a retrospective 18F-FDG PET/CT study.

Objectives:There are subclinical neurologic deficits in cirrhotic patients without overt hepatic encephalopathy. We aimed to use 18F-fluorodeoxyglucose PET/computed tomography to explore the impaired brain glucose metabolism of subclinical hepatic encephalopathy in cirrhosis.Methods:Thirty-seven patients with hepatitis B virus-related cirrhosis without overt hepatic encephalopathy and 49 controls were enrolled in the study. The patients’ Model for End-Stage Liver Disease scores were calculated. All participants underwent resting state 18F-fluorodeoxyglucose PET/computed tomography. Between-group comparisons of brain PET/computed tomography data were conducted with two-sample t-tests and multivariate tests with Statistical Parametric Mapping 8 software.Results:Most of the patients (30/37) had a Model for End-Stage Liver Disease score of less than 20. The patients and controls did not significantly differ in baseline characteristics, such as sex, age, plasma glucose level, smoking history or BMI, but they did significantly differ in blood uric acid level and serum levels of bilirubin, albumin, total protein, alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase (P < 0.0001). Relative to brain glucose metabolism in the controls, that in the patients involved both hyper- and hypometabolic regions (P < 0.001). The relative hypometabolic regions included the parietal, occipital and limbic lobes, and the hypermetabolic regions included the hippocampus, parahippocampal gyri, right basal ganglia and circumventricular organs.Conclusion:Patients with cirrhosis have characteristic patterns of brain glycometabolic impairment. 18F-fluorodeoxyglucose PET/computed tomography may serve as a preclinical biomarker for brain damage in cirrhosis.

The effect of post-stroke hyperglycaemia on the levels of brain damage and repair-related circulating biomarkers: the Glycaemia in Acute Stroke Study II.

The aim was to identify whether post-stroke hyperglycaemia (PSH) influences the levels of circulating biomarkers of brain damage and repair, and to explore whether these biomarkers mediate the effect of PSH on the ischaemic stroke (IS) outcome. This was a secondary analysis of the Glycaemia in Acute Stroke II study. Biomarkers of inflammation, prothrombotic activity, endothelial dysfunction, blood-brain barrier rupture, cell death and brain repair processes were analysed at 24-48h (baseline) and 72-96h (follow-up) after IS. The associations of the biomarkers and stroke outcome (modified Rankin Scale score at 3months) based on the presence of PSH were compared. A total of 174 patients participated in this sub-study. Brain-derived neurotrophic factor (BDNF) at admission was negatively correlated with glucose levels. PSH was associated with a trend toward higher levels of endothelial progenitor cells (EPCs) at baseline. The EPCs in the PSH group then decreased in the follow-up samples (-8.5±10.3) compared with the non-PSH group (4.7±7.33; P=0.024). However, neither BDNF nor EPC values had correlation with the 3-month outcome. Higher interleukin-6 at follow-up was associated with poor outcomes (modified Rankin Scale >2) independently of PSH. Post-stroke hyperglycaemia appears to be associated with a negative regulation of BDNF and a different reaction in EPC levels. However, neither BDNF nor EPCs showed significant mediation of the PSH association with IS outcome, and only higher interleukin-6 in the follow-up samples (72-96h) was related to poor outcomes, independently of PSH status. Further studies are needed to achieve definite conclusions.

Biomarkers of Cerebral Damage in Fatal Hypothermia: Preliminary Results.

The identification of hypothermia as the cause of death remains challenging in forensic pathology because of unspecific radiological, morphological, and biochemical results. Hyperemia, edema, and petechial hemorrhages within the cerebral parenchyma were described in cases of death by hypothermia. On the other hand, the effect of low temperatures in the brain has been speculated to cause local injuries on a cellular level with potential occurrences of necrosis and inflammation. In the study herein described, endocan, alkaline phosphatase, neuron-specific enolase, S100 protein subunit B, glial fibrillary acidic protein, and C-reactive protein were measured in postmortem serum from femoral blood and cerebrospinal fluid in a series of hypothermia fatalities and control cases. The combination of data collected failed to identify a specific biochemical profile for death by hypothermia in postmortem serum and/or the cerebrospinal fluid, thus suggesting that an alternative panel of brain damage biomarkers indicative of diffuse hypoxic brain injury needs to be defined in hypothermia fatalities.

The possible neuroprotective effects of melatonin in aluminum chloride-induced neurotoxicity via antioxidant pathway and Nrf2 signaling apart from metal chelation.

Aluminum (Al) had well-identified adverse influences on the nervous system mainly through the creation of reactive oxygen species (ROS). Melatonin works as an antioxidant through the inhibition of ROS and attenuating peroxidation of lipids. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a pivotal transcription factor which controls the transcription of antioxidant enzymes. This study was conducted to determine the potential neuroprophylactic impacts of melatonin in aluminum chloride (AlCl3)-initiated neurotoxicity including potential mechanism(s) of action and relevant signaling in rats. Thirty-six male rats were distributed into 4 groups: Control; AlCl3 (50mg/kg bwt, i.p, 3 times weekly for 3months); melatonin (5mg/kg bwt, i.p daily for 2weeks before AlCl3 and sustained for the next 3months); and melatonin with AlCl3. Neuronal alterations were histopathologically and biochemically evaluated. The neuronal antioxidant-related genes and relevant Nrf2 protein expression were determined by real-time PCR and Western blotting, respectively. The current data showed a substantial increase in brain damage biomarkers, acetylecholinesterase (AchE) activity, and malondialdehyde (MDA) content while the enzymatic antioxidant expression as glutathione-s-transferase (GST), catalase (CAT), and superoxide dismutase (SOD) were substantially attenuated in the aluminum-treated group, with cleared histopathological changes as inflammatory cell infiltration with neuronal degeneration. Supplementation of melatonin resulted in an obvious amelioration in all previous abnormal alteration observed in AlCl3-treated rats rather than increased Al burden and/or altered Fe and Cu homeostasis with upregulating both total and phosphorylated Nrf2 expression. Therefore, the study concluded that melatonin has a potential ability to be neuroprophylactic against Al-induced neurotoxic effect and oxidative damage in the rat brain through upregulating and instigating Nrf2 signaling apart from metal chelation.

Oxidative Stress as a Primary Risk Factor for Brain Damage in Preterm Newborns.

The risk of oxidative stress is high in preterm newborns. Room air exposure of an organism primed to develop in a hypoxic environment, lacking antioxidant defenses, and subjected to hyperoxia, hypoxia, and ischemia challenges the newborn with oxidative stress production. Free radicals can be generated by a multitude of other mechanisms, such as glutamate excitotoxicity, excess free iron, inflammation, and immune reactions. Free radical-induced damage caused by oxidative stress appears to be the major candidate for the pathogenesis of most of the complications of prematurity, brain being especially at risk, with short to long-term consequences. We review the role of free radical oxidative damage to the newborn brain and propose a mechanism of oxidative injury, taking into consideration the particular maturation-dependent vulnerability of the oligodendrocyte precursors. Prompted by our observation of an increase in plasma Adenosine concentrations significantly associated with brain white matter lesions in some premature infants, we discuss a possible bioenergetics hypothesis, correlated to the oxidative challenge of the premature infant. We aim at explaining both the oxidative stress generation and the mechanism promoting the myelination disturbances. Being white matter abnormalities among the most common lesions of prematurity, the use of Adenosine as a biomarker of brain damage appears promising in order to design neuroprotective strategies.

Newly validated biomarkers of brain damage may shed light into the role of oxidative stress in the pathophysiology of neurocognitive impairment in dietary restricted phenylketonuria patients.

Despite a strict dietary control, patient with hyperphenylalaninemia or phenylketonuria may show cognitive and/or behavioral disorders. These comorbid deficits are of great concern to patients, families, and health organizations. However, biomarkers capable of detecting initial stages of neurological damage are not commonly employed. The pathogenesis of phenylketonuria is complex in nature. Increasingly, the role of oxidative stress has gained acceptance and biomarkers reflecting oxidative damage to the brain and easily accessible in peripheral biofluids have been validated using mass spectrometry techniques. In the present review, the role of oxidative stress in the pathogenesis of phenylketonuria and hyperphenylalaninemia has been updated. Moreover, we report on newly validated brain-specific lipid peroxidation biomarkers and inform on their relevance in the detection and monitoring of neurological damage in phenylketonuric patients. In preliminary studies, a correlation between lipid peroxidation biomarkers and neurological dysfunction in patients with PKU was reported. However, there is a need of adequately powered trials to confirm the validity of these biomarkers for early detection of brain damage, initiation of treatment, and reliably monitor evolving disease both in phenylketonuria and hyperphenylalaninemia.