Suchergebnisse

The University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI), in collaboration with the Food and Drug Administration (FDA), conducted research and outreach to solicit input from the public, including medical specialists, to better understand the use of certain bulk drug substances nominated for use in compounding by outsourcing facilities under section 503B of the Federal Food, Drug, and Cosmetic Act (the Act). In particular, we were interested in how drugs compounded with these bulk drug substances were used historically, and how they are currently used in clinical practice. The research will assist the FDA in its development of a list of bulk drug substances that outsourcing facilities can use in compounding under section 503B of the Act. Research for each bulk drug substance included a systematic literature review, interviews with medical experts and a survey of healthcare practitioners. Our findings for the nominated substance, monosodium glutamate, were summarized in this report. ; U.S. Food and Drug Administration Clinical use of bulk drug substances nominated for inclusion on the 503B Bulks List Grant number: 2U01FD005946

Glutamate excitotoxicity in the cochlea
Mark Rutherford, Associate Professor at Washington University School of Medicine, discusses the burden and causes of hearing dysfunction, as well as the possible solutions for mitigating glutamate excitotoxicity. The cochlea, the snail-shaped organ of the inner ear located deep in the skull, contains approximately 15,000 sound receptors called sensory 'hair cells' and approximately 50,000 nerve fibers sending sound information to the brain. Although that may seem like a lot, it is not compared to the approximately 100 billion neurons in the brain. These hair cells and nerve fibers are all we get for life, and they are gradually lost over time due to aging. Unfortunately, environmental factors accelerate cochlear decline over time. One of those environmental factors is loud sounds.Today, we live in an environment of sound at levels that far exceed those under which our species evolved, especially those of us with noisy occupations or recreational activities. For example, military personnel are particularly vulnerable to hearing loss, making hearing disorders (including tinnitus) the number one disability claim of the U.S. Veterans Administration.

Monosodium glutamate (MSG) is salt of sodium and glutamic acid. It is most commonly known as a flavouring enhancer in food processing, which provides umami taste that intensifies the meaty, savory flavor of food, as naturally occurring glutamate does in foods such as stews and meat soups. The amino acid glutamic acid it is naturally presents in food. Globally, commercial MSG's consumption is increasing, markable high in Asia. Likewise, its production has known improvements regarding both method and technical equipment. Although MSG's safety was evaluated by international organizations (EFSA, FDA) as safe and the limits were set up, there are studies concern about its side effects such as obesity, asthma, migraine headache, etc. The European Union classifies it as a food additive permitted in certain foods and subject to quantitative limits. The increase in commercially MSG use has raised the concern of both scientists and consumers about its safety. Therefore, due to a need of full comprehension about MSG, it is necessary to give more attention in studying it. Advantage in the development of analysis methods and technical equipments should be exploited to obtain higher accuracy result. This review provides a brief and general information about MSG with updates in its research.

Glutamate is the principal excitatory neurotransmitter in the central nervous system and its actions are related to the behavioral effects of psychostimulant drugs. In the last two decades, basic neuroscience research and preclinical studies with animal models are suggesting a critical role for glutamate transmission in drug reward, reinforcement, and relapse. Although most of the interest has been centered in post-synaptic glutamate receptors, the presynaptic synthesis of glutamate through brain glutaminases may also contribute to imbalances in glutamate homeostasis, a key feature of the glutamatergic hypothesis of addiction. Glutaminases are the main glutamate-producing enzymes in brain and dysregulation of their function have been associated with neurodegenerative diseases and neurological disorders; however, the possible implication of these enzymes in drug addiction remains largely unknown. This mini-review focuses on brain glutaminase isozymes and their alterations by in vivo exposure to drugs of abuse, which are discussed in the context of the glutamate homeostasis theory of addiction. Recent findings from mouse models have shown that drugs induce changes in the expression profiles of key glutamatergic transmission genes, although the molecular mechanisms that regulate drug-induced neuronal sensitization and behavioral plasticity are not clear. ; This work was financially supported by Grants RD12/0028/0013 (JM) and RD12/0028/0001 (FRF) of the RTA RETICS network from the Spanish Health Institute Carlos III, Grant SAF2015-64501-R from the Spanish Ministry of Economy and Competitivity (to JM and JMM) and Excellence Grant CVI-6656 (Regional Andalusian government) (to JM).

The neurotransmitter glutamate is the primary excitatory neurotransmitter in mammalian brain and is responsible for most corticocortical and corticofugal neurotransmission. Disturbances in glutamatergic function have been implicated in the pathophysiology of several neuropsychiatric disorders—including schizophrenia, drug abuse and addiction, autism, and depression—that were until recently poorly understood. Nevertheless, improvements in basic information regarding these disorders have yet to translate into Food and Drug Administration–approved treatments. Barriers to translation include the need not only for improved compounds but also for improved biomarkers sensitive to both structural and functional target engagement and for improved translational models. Overcoming these barriers will require unique collaborative arrangements between pharma, government, and academia. Here, we review a recent Institute of Medicine–sponsored meeting, highlighting advances in glutamatergic theories of neuropsychiatric illness as well as remaining barriers to treatment development.

The neurotransmitter glutamate is the primary excitatory neurotransmitter in mammalian brain and is responsible for most corticocortical and corticofugal neurotransmission. Disturbances in glutamatergic function have been implicated in the pathophysiology of several neuropsychiatric disorders—including schizophrenia, drug abuse and addiction, autism, and depression—that were until recently poorly understood. Nevertheless, improvements in basic information regarding these disorders have yet to translate into Food and Drug Administration–approved treatments. Barriers to translation include the need not only for improved compounds but also for improved biomarkers sensitive to both structural and functional target engagement and for improved translational models. Overcoming these barriers will require unique collaborative arrangements between pharma, government, and academia. Here, we review a recent Institute of Medicine–sponsored meeting, highlighting advances in glutamatergic theories of neuropsychiatric illness as well as remaining barriers to treatment development. ; National Institute of Mental Health (U.S.) (grant R37MH49334) ; National Institute of Mental Health (U.S.) (Intramural Research Program) ; National Institute of Mental Health (U.S.) (R01DA03383) ; National Institute of Mental Health (U.S.) (P50MH086385) ; National Institutes of Health (U.S.) ; FRAXA Research Foundation ; Howard Hughes Medical Institute ; Simons Foundation

Hypothalamic astrocytes can respond to metabolic signals, such as leptin and insulin, to modulate adjacent neuronal circuits and systemic metabolism. Ghrelin regulates appetite, adiposity and glucose metabolism, but little is known regarding the response of astrocytes to this orexigenic hormone. We have used both in vivo and in vitro approaches to demonstrate that acylated ghrelin (acyl-ghrelin) rapidly stimulates glutamate transporter expression and glutamate uptake by astrocytes. Moreover, acyl-ghrelin rapidly reduces glucose transporter (GLUT) 2 levels and glucose uptake by these glial cells. Glutamine synthetase and lactate dehydrogenase decrease, while glycogen phosphorylase and lactate transporters increase in response to acyl-ghrelin, suggesting a change in glutamate and glucose metabolism, as well as glycogen storage by astrocytes. These effects are partially mediated through ghrelin receptor 1A (GHSR-1A) as astrocytes do not respond equally to desacyl-ghrelin, an isoform that does not activate GHSR-1A. Moreover, primary astrocyte cultures from GHSR-1A knock-out mice do not change glutamate transporter or GLUT2 levels in response to acyl-ghrelin. Our results indicate that acyl-ghrelin may mediate part of its metabolic actions through modulation of hypothalamic astrocytes and that this effect could involve astrocyte mediated changes in local glucose and glutamate metabolism that alter the signals/nutrients reaching neighboring neurons. ; This work was funded by grants from Fondo de Investigación Sanitaria (PI100747; PI1302195), Ministerio de Ciencia e Innovación (BFU2011–27492; BFU2014-51836-C2-2-R) and Fondos FEDER, Centro de Investigación Biomédica en Red Fisiopatología de Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, and Fundación de Endocrinología y Nutrición. SD was funded by the Swedish Research Council (Vetenskapsrådet grant 2012– 1758), Läkarutbildningsavtalet Göteborg grant at Sahlgrenska Hospital (ALFGBG-138741, The European Union Seventh Framework Programme under Grant Agreement 607310, Nudge-it)

Glial cells perform critical functions that alter the metabolism and activity of neurons, and there is increasing interest in their role in appetite and energy balance. Leptin, a key regulator of appetite and metabolism, has previously been reported to influence glial structural proteins and morphology. Here, we demonstrate that metabolic status and leptin also modify astrocyte-specific glutamate and glucose transporters, indicating that metabolic signals influence synaptic efficacy and glucose uptake and, ultimately, neuronal function. We found that basal and glucose-stimulated electrical activity of hypothalamic proopiomelanocortin (POMC) neurons in mice were altered in the offspring of mothers fed a high-fat diet. In adulthood, increased body weight and fasting also altered the expression of glucose and glutamate transporters. These results demonstrate that whole-organism metabolism alters hypothalamic glial cell activity and suggest that these cells play an important role in the pathology of obesity ; This work was supported by grants from the Spanish Government (FIS PI100747, BFU2011-27492, and CIBER de Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain). E. Fuente-Martín is supported by a postdoctoral fellowship from CIBERobn. T.L. Horvath was supported by NIH grants DK080000 and DK006850 and an ADA Fellowship grant