Nicotinamide as potential biomarker for Alzheimer's disease: A translational study based on metabolomics.

Introduction: The metabolic routes altered in Alzheimer's disease (AD) brain are poorly understood. As the metabolic pathways are evolutionarily conserved, the metabolic profiles carried out in animal models of AD could be directly translated into human studies. Methods: We performed untargeted Nuclear Magnetic Resonance metabolomics in hippocampus of McGill-R-Thy1-APP transgenic (Tg) rats, a model of AD-like cerebral amyloidosis and the translational potential of these findings was assessed by targeted Gas Chromatography-Electron Impact-Mass Spectrometry in plasma of participants in the German longitudinal cohort AgeCoDe. Results: In rat hippocampus 26 metabolites were identified. Of these 26 metabolites, nine showed differences between rat genotypes that were nominally significant. Two of them presented partial least square-discriminant analysis (PLS-DA) loadings with the larger absolute weights and the highest Variable Importance in Projection (VIP) scores and were specifically assigned to nicotinamide adenine dinucleotide (NAD) and nicotinamide (Nam). NAD levels were significantly decreased in Tg rat brains as compared to controls. In agreement with these results, plasma of AD patients showed significantly reduced levels of Nam in respect to cognitively normal participants. In addition, high plasma levels of Nam showed a 27% risk reduction of progressing to AD dementia within the following 2.5 years, this hazard ratio is lost afterwards. Discussion: To our knowledge, this is the first report showing that a decrease of Nam plasma levels is observed couple of years before conversion to AD, thereby suggesting its potential use as biomarker for AD progression.

Oleoylethanolamide and Palmitoylethanolamide Protect Cultured Cortical Neurons Against Hypoxia.

Introduction: Perinatal hypoxic-ischemic (HI) encephalopathy is defined as a neurological syndrome where the newborn suffers from acute ischemia and hypoxia during the perinatal period. New therapies are needed. The acylethanolamides, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), possess neuroprotective properties, and they could be effective against perinatal HI. These lipid mediators act through peroxisome proliferator-activated receptors subtype α (PPARα), or transient receptor potential vanilloid (TRPV), such as TRPV subtype 1 and 4. Materials and Methods: The objectives of this study were to discern: (1) the neuroprotective role of OEA and PEA in parietotemporal cortical neurons of newborn rats and mice subjected to hypoxia, and (2) the role of the receptors, PPARα, TRPV1, and TRPV4, in neuroprotective effects. Cell culture of cortical neurons and the lactate dehydrogenase assay was carried out. The role of receptors was discerned by using selective antagonist and agonist ligands, as well as knockout (KO) PPARα mice. Results: The findings indicate that OEA and PEA exert neuroprotective effects on cultured cortical neurons subjected to a hypoxic episode. These protective effects are not mediated by the receptors, PPARα, TRPV1, or TRPV4, because neither PPARα KO mice nor receptor ligands significantly modify OEA and PEA-induced effects. Blocking TRPV4 with RN1734 is neuroprotective per se, and cotreatment with OEA and PEA is able to enhance neuroprotective effects of the acylethanolamides. Since stimulating TRPV4 was devoid of effects on OEA and PEA-induced protective effects, effects of RN1734 cotreatment seem to be a consequence of additive actions. Conclusion: The lipid mediators, OEA and PEA, exert neuroprotective effects on cultured cortical neurons subjected to hypoxia. Coadministration of OEA or PEA, and the TRPV4 antagonist RN1734 is able to enhance neuroprotective effects. These in vitro results could be of utility for developing new therapeutic tools against perinatal HI.

Neuronal Damage Induced by Perinatal Asphyxia Is Attenuated by Postinjury Glutaredoxin-2 Administration.

The general disruption of redox signaling following an ischemia-reperfusion episode has been proposed as a crucial component in neuronal death and consequently brain damage. Thioredoxin (Trx) family proteins control redox reactions and ensure protein regulation via specific, oxidative posttranslational modifications as part of cellular signaling processes. Trx proteins function in the manifestation, progression, and recovery following hypoxic/ischemic damage. Here, we analyzed the neuroprotective effects of postinjury, exogenous administration of Grx2 and Trx1 in a neonatal hypoxia/ischemia model. P7 Sprague-Dawley rats were subjected to right common carotid ligation or sham surgery, followed by an exposure to nitrogen. 1 h later, animals were injected i.p. with saline solution, 10 mg/kg recombinant Grx2 or Trx1, and euthanized 72 h postinjury. Results showed that Grx2 administration, and to some extent Trx1, attenuated part of the neuronal damage associated with a perinatal hypoxic/ischemic damage, such as glutamate excitotoxicity, axonal integrity, and astrogliosis. Moreover, these treatments also prevented some of the consequences of the induced neural injury, such as the delay of neurobehavioral development. To our knowledge, this is the first study demonstrating neuroprotective effects of recombinant Trx proteins on the outcome of neonatal hypoxia/ischemia, implying clinical potential as neuroprotective agents that might counteract neonatal hypoxia/ischemia injury.

Moderate and severe perinatal asphyxia induces differential effects on cocaine sensitization in adult rats.

Perinatal asphyxia (PA) increases the likelihood of suffering from dopamine-related disorders, such as ADHD and schizophrenia. Since dopaminergic transmission plays a major role in cocaine sensitization, the purpose of this study was to determine whether PA could be associated with altered behavioral sensitization to cocaine. To this end, adult rats born vaginally (CTL), by caesarean section (C+), or by C+ with 15 min (PA15, moderate PA) or 19 min (PA19, severe PA) of global anoxia were repeatedly administered with cocaine (i.p., 15 mg/kg) and then challenged with cocaine (i.p., 15 mg/kg) after a 5-day withdrawal period. In addition, c-Fos, FosB/ΔFosB, DAT, and TH expression were assessed in dorsal (CPu) and ventral (NAcc) striatum. Results indicated that PA15 rats exhibited an increased locomotor sensitization to cocaine, while PA19 rats displayed an abnormal acquisition of locomotor sensitization and did not express a sensitized response to cocaine. c-Fos expression in NAcc, but not in CPu, was associated with these alterations in cocaine sensitization. FosB/ΔFosB expression was increased in all groups and regions after repeated cocaine administration, although it reached lower expression levels in PA19 rats. In CTL, C+, and PA15, but not in PA19 rats, the expression of TH in NAcc was reduced in groups repeatedly treated with cocaine, independently of the challenge test. Furthermore, this reduction was more pronounced in PA15 rats. DAT expression remained unaltered in all groups and regions studied. These results suggest that moderate PA may increase the vulnerability to drug abuse and in particular to cocaine addiction.

Paullinia cupana Mart. var. Sorbilis protects human dopaminergic neuroblastoma SH-SY5Y cell line against rotenone-induced cytotoxicity.

Paullinia cupana Mart. var. Sorbilis, commonly known as Guaraná, is a Brazilian plant frequently cited for its antioxidant properties and different pharmacological activities on the central nervous system. The potential beneficial uses of Guaraná in neurodegenerative disorders, such as in Parkinson's disease (PD), the pathogenesis of which is associated with mitochondrial dysfunction and oxidative stress, has not yet been assessed. Therefore, the main aim of the present study was to evaluate if an extract of commercial powdered seeds of Guaraná could protect human dopaminergic neuroblastoma SH-SY5Y cell line against rotenone-induced cytotoxicity. Two concentration of Guaraná dimethylsulfoxide extract (0.312 and 0.625 mg/mL) were added to SH-SY5Y cells treated with 300 nM rotenone for 48 h, and the cytoprotective effects were assessed by means of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, measuring lactate dehydrogenase (LDH) levels, and analyzing nuclear integrity with Hoechst33258 stain. Results showed that the addition of Guaraná extract significantly increased the cell viability of SH-SY5Y cells treated with rotenone, in a dose-dependent manner. On the other hand, LDH levels were significantly reduced by addition of 0.312 mg/mL of Guaraná, but unexpectedly, no changes were observed with the higher concentration. Moreover, chromatin condensation and nuclear fragmentation were significantly reduced by addition of any of both concentrations of the extract. The results obtained in this work could provide relevant information about the mechanisms underlying the degeneration of dopaminergic neurons in PD and precede in vivo experiments. Further studies are needed to investigate which active constituent is responsible for the cytoprotective effect produced by Paullinia cupana.

Estradiol therapy in adulthood reverses glial and neuronal alterations caused by perinatal asphyxia.

The capacity of the ovarian hormone 17beta-estradiol to prevent neurodegeneration has been characterized in several animal models of brain and spinal cord pathology. However, the potential reparative activity of the hormone under chronic neurodegenerative conditions has received less attention. In this study we have assessed the effect of estradiol therapy in adulthood on chronic glial and neuronal alterations caused by perinatal asphyxia (PA) in rats. Four-month-old male Sprague-Dawley rats submitted to PA just after delivery, and their control littermates, were injected for 3 consecutive days with 17beta estradiol or vehicle. Animals subjected to PA and treated with vehicle showed an increased astrogliosis, focal swelling and fragmented appearance of MAP-2 immunoreactive dendrites, decreased MAP-2 immunoreactivity and decreased phosphorylation of high and medium molecular weight neurofilaments in the hippocampus, compared to control animals. Estradiol therapy reversed these alterations. These findings indicate that estradiol is able to reduce, in adult animals, chronic reactive astrogliosis and neuronal alterations caused by an early developmental neurodegenerative event, suggesting that the hormone might induce reparative actions in the Central Nervous System (CNS).

Potenciales cerebrales relacionados con categorización lógica en humanos: estudio descriptivo y planteos experimentales / Brain potentiales associated with logic categorization in humans: descriptive study and experimental issues

El presente trabajo investiga desde un abordaje “biocomportamental” aspectos electroneurofisiológicos correlativos al aprendizaje de categorías lógicas en sujetos humanos sanos. Se empleó la técnica de potenciales relacionados a eventos (PREs) para registrar la actividad electrofisiológica de los sujetos durante la realización de una tarea de relaciones de equivalencia (Sidman, 1982). Como resultado, pudo observarse la siguiente sucesión temporal relacionada con los estímulos de comparación: un potencial visual temprano en la región occipital, luego un componente negativo en la región frontal y otro positivo tardío parietal. Finalmente, en sincronía con las respuestas, se obtuvo un componente negativo lateralizado en la región central. Se discute el significado funcional de los potenciales identificados, y se propone como planteo experimental examinar la correspondencia temporal de los distintos componentes PREs entre sí y con el tiempo de respuesta, como dispositivo experimental para el estudio de aspectos funcionales y estructurales del comportamiento complejo en humanos.