132,309 research outputs found
D-aspartate: an atypical amino acid with neuromodulatory activity in mammals
No full textWithin the pool of endogenous amino acids, serine and aspartate are the only two residues occurring at significant concentrations in free D-form in mammalian tissues. D-Serine (D-Ser) is mainly localized in the forebrain structures of the CNS throughout embryonic development and postnatal phase. Compelling evidence demonstrates that D-Ser has a functional role as an endogenous co-agonist at N-methyl-D-aspartate receptors (NMDARs) and shows its beneficial involvement in psychiatric disorders including schizophrenia. On the other hand, knowledge concerning the role of free D-Asp in mammals has so far been less extensive. D-Asp occurs in the brain as well as in peripheral tissues including the endocrine glands. In endocrine glands, D-Asp levels increase during the postnatal period in concomitance with their functional maturation. The involvement of D-Asp in the regulation of the synthesis and/or release of different hormones has been clearly demonstrated. However, its biological significance in the brain is still obscure. D-Asp appears with a peculiar temporal pattern of localization, being abundant during embryonic development and strongly decreasing after birth. This phenomenon is the result of the postnatal onset of D-Asp oxidase (DDO) expression, the only known enzyme that strictly controls the endogenous levels of D-Asp. The pharmacological affinity of D-Asp for the glutamate site of NMDARs has raised the intriguing question whether this D-amino acid may have some in vivo influence on responses mediated by this subclass of glutamate receptors. In order to unveil the physiological function of D-Asp and of its metabolizing enzyme, genetic and pharmacological approaches have been recently developed. It has now become possible to generate animal models with abnormally elevated levels of D-Asp in adulthood based on the targeted deletion of the Ddo gene and on the oral administration of D-Asp. These animal models have thus highlighted that D-Asp has a neuromodulatory role at NMDARs in brain areas where they regulate crucial nervous functions. Indeed, abnormally high D-Asp levels in the hippocampus are able to strongly enhance NMDAR-dependent LTP and, in turn, to facilitate spatial memory of mice. Moreover, in both mutant and treated animals, this deregulated D-Asp content completely suppresses striatal LTD, most likely via overactivation of NMDARs. The later synaptic plasticity alteration resembles that produced by chronic administration of haloperidol and is probably the neurobiological substrate responsible for the attenuation of prepulse inhibition deficits induced by amphetamine and MK-801 in Ddo knockout and D-Asp-treated mice. These in vitro and in vivo findings, together with others reported in this review, support a neuromodulatory action for D-Asp at glutamatergic synapses. In addition, they suggest that this D-amino acid may play a potential beneficial role in conditions related to a pathological hypofunctioning of NMDARs in the mammalian brain
D-aspartate: an atypical amino acid with neuromodulatory activity in mammals.
No full textWithin the pool of endogenous amino acids, serine and aspartate are the only two residues occurring at significant concentrations in free D-form in mammalian tissues. D-Serine (D-Ser) is mainly localized in the forebrain structures of the CNS throughout embryonic development and postnatal phase. Compelling evidence demonstrates that D-Ser has a functional role as an endogenous co-agonist at N-methyl-D-aspartate receptors (NMDARs) and shows its beneficial involvement in psychiatric disorders including schizophrenia. On the other hand, knowledge concerning the role of free D-Asp in mammals has so far been less extensive. D-Asp occurs in the brain as well as in peripheral tissues including the endocrine glands. In endocrine glands, D-Asp levels increase during the postnatal period in concomitance with their functional maturation. The involvement of D-Asp in the regulation of the synthesis and/or release of different hormones has been clearly demonstrated. However, its biological significance in the brain is still obscure. D-Asp appears with a peculiar temporal pattern of localization, being abundant during embryonic development and strongly decreasing after birth. This phenomenon is the result of the postnatal onset of D-Asp oxidase (DDO) expression, the only known enzyme that strictly controls the endogenous levels of D-Asp. The pharmacological affinity of D-Asp for the glutamate site of NMDARs has raised the intriguing question whether this D-amino acid may have some in vivo influence on responses mediated by this subclass of glutamate receptors. In order to unveil the physiological function of D-Asp and of its metabolizing enzyme, genetic and pharmacological approaches have been recently developed. It has now become possible to generate animal models with abnormally elevated levels of D-Asp in adulthood based on the targeted deletion of the Ddo gene and on the oral administration of D-Asp. These animal models have thus highlighted that D-Asp has a neuromodulatory role at NMDARs in brain areas where they regulate crucial nervous functions. Indeed, abnormally high D-Asp levels in the hippocampus are able to strongly enhance NMDAR-dependent LTP and, in turn, to facilitate spatial memory of mice. Moreover, in both mutant and treated animals, this deregulated D-Asp content completely suppresses striatal LTD, most likely via overactivation of NMDARs. The later synaptic plasticity alteration resembles that produced by chronic administration of haloperidol and is probably the neurobiological substrate responsible for the attenuation of prepulse inhibition deficits induced by amphetamine and MK-801 in Ddo knockout and D-Asp-treated mice. These in vitro and in vivo findings, together with others reported in this review, support a neuromodulatory action for D-Asp at glutamatergic synapses. In addition, they suggest that this D-amino acid may play a potential beneficial role in conditions related to a pathological hypofunctioning of NMDARs in the mammalian brain
d-Aspartate: An endogenous NMDA receptor agonist enriched in the developing brain with potential involvement in schizophrenia
No full textFree d-aspartate and d-serine occur at substantial levels in the mammalian brain. d-Serine is a physiological endogenous co-agonist for synaptic N-Methyl d-Aspartate (NMDA) receptors (NMDARs), and is involved in the pathophysiology of schizophrenia. Much less is known about the biological meaning of d-aspartate. d-Aspartate is present at high levels in the embryo brain and strongly decreases at post-natal phases. Temporal reduction of d-aspartate levels depends on the post-natal onset of d-aspartate oxidase (DDO), an enzyme able to selectively catabolize this d-amino acid. Pharmacological evidence indicates that d-aspartate binds to and activates NMDARs. Characterization of genetic and pharmacological mouse models with abnormally higher levels of d-aspartate has evidenced that increased d-aspartate enhances hippocampal NMDAR-dependent synaptic plasticity, dendritic morphology and spatial memory. In line with the hypothesis of a hypofunction of NMDARs in the pathogenesis of schizophrenia, it has been shown that increased d-aspartate levels also improve brain connectivity, produce corticostriatal adaptations resembling those observed after chronic haloperidol treatment, and protects against prepulse inhibition deficits and abnormal circuits activation induced by psychotomimetic drugs. In healthy humans, genetic variation predicting reduced expression of DDO in post-mortem prefrontal cortex is associated with greater prefrontal gray matter and activity during working memory. On the other side, evaluation of d-aspartate content in post-mortem patients with schizophrenia has shown a significant reduction of this d-amino acid in the prefrontal cortex and striatum. Generation of mouse models with reduced embryonic levels of d-aspartate may disclose unprecedented role for d-aspartate in developmental brain processes associated with vulnerability to psychotic-like symptoms
Bimodal effect of D-aspartate on brain aging processes: insights from animal models.
No full text"Nowadays it is widely recognized that D-amino acids are present in bacteria as well as in eukaryotes, including mammals. In particular, free D-serine and D-aspartate are found in the brain of mammals. Notably, D-aspartate occurs at substantial levels in the embryo brain to then consistently decrease at post-natal phases. Temporal regulation of D-aspartate content depends on the post-natal onset of D-aspartate oxidase expression, the only known enzyme able to catabolize this D-amino acid. Pharmacological evidence indicates that D-aspartate binds and activates NMDA receptors (NMDARs). To decipher the physiological function of D-aspartate in mammals, in the last years, genetic and pharmacological mouse models with abnormally higher levels of this D-amino acid have been generated. Overall, these animal models have pointed out a significant neuromodulatory role for D-aspartate in the regulation of NMDAR-dependent functions. Indeed, increased content of D-aspartate are able to increase hippocampal NMDAR-dependent long-term potentiation (LTP) and spatial memory of adult mice. However, if exposure to elevated levels of D-Asp lasts for the entire lifetime of mice, enhancement of synaptic plasticity turns into a dramatic worsening, thus triggering an acceleration of the NMDAR-dependent aging processes in the hippocampus. Nonetheless, administration of D-Asp to old mice can restore the physiological age-related decay of hippocampal NMDA-related LTP. Besides its effect on hippocampus-dependent processes in mouse models, different points of evidence are indicating, today, a potential role for D-Asp in neurologic and psychiatric disorders associated with aberrant signalling of NMDARs.
Thyroid Hormones and D-Aspartic Acid, D-Aspartate Oxidase, D-Aspartate Racemase, H2O2, and ROS in Rats and Mice
No full textTotal concentrations of thyroid hormones T(3) and T(4), and of their free forms, FT(3) and FT(4), D-aspartic acid (D-Asp), D-aspartate oxidase (D-AspO), D-aspartate racemase, H(2)O(2), and ROS (reactive oxygen species) were determined in rats and mice. T(3) and T(4) were 1 and 50 ng/ml, respectively, in serum, and 750 and 40000 ng/g, respectively, in thyroid. Concentrations of the free forms FT(3) and FT(4) were ca. 250 times lower than their respective total concentrations. The endogenous content of D-Asp in thyroid gland was ca. 100 nmol/g tissue, whereas the activity of D-AspO was ca. 80 units/mg thyroid, and that of D-aspartate racemase was ca. 15 units/mg thyroid. H(2)O(2) Concentration in rat and mouse thyroid gland was ca. 290 pmol/g thyroid, and the concentration of ROS was ca. 10 pmol/DCF/min/mg protein. H(2)O(2) is essential for the iodination of the tyrosyl residues to produce mono- and diiodotyrosine that are the precursors for the synthesis of T(3) and T(4). Production of H(2)O(2) in thyroid glands occurs by oxidation of endogenous D-Asp by D-AspO (D-Asp+O(2)+H(2)O-->alpha-oxaloacetate+NH(3)+H(2)O(2)). D-Aspartate racemase catalyzes the in vivo production of D-Asp from L-Asp. Thus, interaction of endogenous D-Asp, D-AspO, and D-aspartate racemase in thyroid gland constitutes an additional biochemical pathway for the production of H(2)O(2) and consequently for the synthesis of thyroid hormones
I collemboli in studi ecotossicologici e valutazione del rischio ambientale
No full textL’Ecotossicologia studia gli effetti dei contaminanti sugli organismi con l'obiettivo finale di salvaguardare la struttura e il funzionamento degli ecosistemi. La valutazione del rischio ambientale per il suolo è generalmente basata sui risultati di test di tossicità eseguiti in laboratorio utilizzando invertebrati, ma solo pochi animali, tra cui Folsomia candida (Collembola: Hexapoda), vengono utilizzati come organismi test in linee guida internazionali standardizzate. Tra queste ISO 11267 descrive un metodo standardizzato che si basa sulla determinazione degli effetti subletali di suoli contaminati su F. candida. I collemboli sono un gruppo di invertebrati del suolo abbondante e ben studiato che svolge un importante ruolo ecologico. Sono ottimi bioindicatori perché hanno caratteristiche anatomiche, fisiologiche ed ecologiche ben conosciute e sono sensibili ai contaminanti presenti nel suolo (concimi, ammendanti, pesticidi, metalli). In particolare, F. candida è ideale per vari esperimenti di laboratorio poiché ha caratteristiche che lo rendono facilmente allevabile. Recentemente, alcuni Autori mettono in discussione le linee guida esistenti e affermano che dovrebbero essere migliorate anche al fine di poterle applicare ai nuovi contaminanti e, nel caso di contaminanti prodotti in quantità ridotte, potrebbe essere necessario ridurre la quantità di suolo e di conseguenza il numero di collemboli.
Uno degli obiettivi del mio lavoro è quello di verificare se le linee guida ISO 11267 possono essere sempre considerate "standard" e in particolare, se il test di tossicità può essere utilizzato per contaminanti che alterano le proprietà del suolo come pH e se il risultato di test di tossicità può essere influenzato dall’uso di diversi suoli standard. I contaminanti utilizzati per questo studio sono stati a) digestati, residuo organico della digestione anaerobica di rifiuti agro-industriali e urbani per la produzione di biogas, che possono essere utilizzati in agricoltura ad es. come fertilizzanti e b) cadmio.
In esperimenti in cui il digestato è stato aggiunto al suolo artificiale standard (suolo OECD), i valori di pH del suolo sono aumentati e ho dimostrato che gli effetti negativi sulla riproduzione di F. candida sono attribuibili soprattutto all'aumento del pH che agisce principalmente sulla oogenesi. Quindi F. candida non risulterebbe adatto a saggiare contaminanti che modificano il pH del suolo. Per verificare se i risultati dei test di tossicità sono influenzati dall’uso, come substrato, di suoli diversi, ho usato due tipi di contaminanti (cadmio e digestato) aggiunti separatamente a due suoli standard: il suolo artificiale OECD e il suolo naturale LUFA entrambi previsti dalle linee guida (ISO 11267). Nelle prove in cui è stato utilizzato il cadmio, il test di tossicità ha dato gli stessi risultati per entrambi i suoli a cui è stato aggiunto. Al contrario, in esperimenti in cui è stato utilizzato il digestato, il test di tossicità ha dato risultati opposti per i due tipi di suolo. In prospettiva di una valutazione del rischio ambientale, per un potenziale uso come fertilizzante, il digestato non è risultato tossico nel test in cui è stato usato il suolo OECD, invece si è rivelato tossico nel test in cui è stato usato LUFA. Il mio studio mette in discussione i risultati dei test standardizzati di tossicità e mette in evidenza le difficoltà nella loro interpretazione. Inoltre, un altro scopo del mio studio è la miniaturizzazione dei test di tossicità dimezzando la quantità di suolo (OECD e LUFA) e il numero di collemboli per poter testare contaminanti disponibili in quantità ridotte. Il dimezzamento del numero di animali non sembrerebbe influenzare il risultato del test mentre il dimezzamento della quantità di suolo potrebbe influenzarlo.Ecotoxicology studies the effects of contaminants on organisms in the environment, with the final aim to protect the structure and functioning of ecosystems. The risk assessment of contaminants to soil ecosystems is generally based on the results of toxicity tests in the laboratory evaluated using many group of soil invertebrates, but only few are used as test organisms in international standard guidelines, amongst these is Folsomia candida (Collembola: Hexapoda). Collembola are abundant in the soil, well-investigated, play an important ecological role and are considered excellent bio-indicators because for their sensitivity to contaminants in the soil (eg. fertilizers, soil improvers, pesticides, heavy metals). In particular, F. candida is ideal organism for various laboratory experiments: indeed the short life cycle, the rapid growth, the parthenogenetic reproduction make rearing easy. The ISO guidelines 11267 (1999; 2014) describe a standardized method that is based on the determination of sublethal effects of contaminated soils on F. candida.
In the 2014 guidelines, in addition to artificial standard soil (OECD soil), standard natural soil (eg. LUFA soil) and reference soil were considered as substrates for the toxicity tests. Recently, some Authors affirm that existing guidelines might need to be improved mainly in order to apply them to new contaminants and in the case of contaminants produced in very small quantities might need to be reduced the amount of soil and consequently the number of springtails. One of the aims of my work is to investigate whether the protocol ISO 11267 can always be considered as "standard" and in particular, whether this toxicity test can be used for contaminants that alters soil properties such as pH and whether the outcome of toxicity tests can be affected by use of different standard soils.
The contaminants used for this study are: i) digestates, the residual organic material of anaerobic digestion of agro-industrial and urban wastes for the biogas production and that can be used in agriculture as soil improver, and ii) cadmium, a natural contaminant widely distributed in the environment due to human industrial activities. In experiments where digestate was added to OECD soil, the soil pH values increased and a negative effects of digestate was detected on the survival and reproduction of F. candida. The decrease of the number of offspring was attributed mainly to the increase of pH values. So F. candida would not be suitable to assay contaminants that modify the soil pH. The data obtained in this study allow to attribute the decrease of the offspring at a negative effect on oogenesis. To investigate whether the results of toxicity tests were affected by type of soil (OECD and LUFA) I have used two different types of contaminants (a digestate and a metal, cadmium) added separately to the two soils. In tests in which the cadmium has been used, the toxicity test gave the same results for both soils to which was added. On the contrary, in experiments in which the digestate has been used, the toxicity test gave opposite results for the two soils. From the perspective of the environmental risk assessment, for a potential use as fertilizer, digestate showed no toxicity in tests with the OECD soil, whereas it has proved toxic when tested using LUFA soil. My study contests deeply the results of toxicity tests standardized and highlights the difficulty of their interpretation. Furthermore, another aim of my work was the miniaturization of test systems halving the amount of soil (OECD and LUFA soil) and the number of springtails using cadmium as contaminant. The halving of the number of animals does not seem to influence the outcome of the test while the halving of the amount of soil could influence it
New insights on the influence of free d-aspartate metabolism in the mammalian brain during prenatal and postnatal life
No full textFree d-aspartate is abundant in the mammalian embryonic brain. However, following the postnatal onset of the catabolic d-aspartate oxidase (DDO) activity, cerebral d-aspartate levels drastically decrease, remaining constantly low throughout life. d-Aspartate stimulates both glutamatergic NMDA receptors (NMDARs) and metabotropic Glu5 receptors. In rodents, short-term d-aspartate exposure increases spine density and synaptic plasticity, and improves cognition. Conversely, persistently high d-Asp levels produce NMDAR-dependent neurotoxic effects, leading to precocious neuroinflammation and cell death. These pieces of evidence highlight the dichotomous impact of d-aspartate signaling on NMDAR-dependent processes and, in turn, unveil a neuroprotective role for DDO in preventing the detrimental effects of excessive d-aspartate stimulation during aging. Here, we will focus on the in vivo influence of altered d-aspartate metabolism on the modulation of glutamatergic functions and its involvement in translational studies. Finally, preliminary data on the role of embryonic d-aspartate in the mouse brain will also be reviewed
Renewal properties of the d = 1 Ising model
No full textWe consider the d = 1 Ising model with Kac potentials at inverse temperature β > 1 where the mean field predicts a phase transition with two possible equilibrium magnetizations ± mβ, mβ > 0. We show that when the Kac scaling parameter γ is sufficiently small, typical spin configurations are described (via a coarse graining) by an infinite sequence of successive plus and minus intervals where the empirical magnetization is "close" to mβ, and respectively, - mβ. We prove that the corresponding marginal of the unique DLR measure is a renewal process
New insights on the role of free D-aspartate in the mammalian brain
No full textFree D-aspartate (D-Asp) occurs in substantial amounts in the brain at the embryonic phase and in the first few postnatal days, and strongly decreases in adulthood. Temporal reduction of D-Asp levels depends on the postnatal onset of D-aspartate oxidase (DDO) activity, the only enzyme able to selectively degrade this D-amino acid. Several results indicate that D-Asp binds and activates N-methyl-D-aspartate receptors (NMDARs). Accordingly, recent studies have demonstrated that deregulated, higher levels of D-Asp, in knockout mice for Ddo gene and in D-Asp-treated mice, modulate hippocampal NMDAR-dependent long-term potentiation (LTP) and spatial memory. Moreover, similarly to D-serine, administration of D-Asp to old mice is able to rescue the physiological age-related decay of hippocampal LTP. In agreement with a neuromodulatory action of D-Asp on NMDARs, increased levels of this D-amino acid completely suppress long-term depression at corticostriatal synapses and attenuate the prepulse inhibition deficits produced in mice by the psychotomimetic drugs, amphetamine and MK-801. Based on the evidence which points to the ability of D-Asp to act as an endogenous agonist on NMDARs and considering the abundance of D-Asp during prenatal and early life, future studies will be crucial to address the effect of this molecule in the developmental processes of the brain controlled by the activation of NMDARs
- …
