scholarly journals The diacylglycerol lipases: structure, regulation and roles in and beyond endocannabinoid signalling

2012 ◽  
Vol 367 (1607) ◽  
pp. 3264-3275 ◽  
Author(s):  
Melina Reisenberg ◽  
Praveen K. Singh ◽  
Gareth Williams ◽  
Patrick Doherty
Keyword(s):  
Dopaminergic Neurons ◽  
Cannabinoid Receptors ◽  
Homology Modelling ◽  
Detailed Examination ◽  
The Body ◽  
Adult Brain ◽  
And Migration ◽  
Regulatory Loop ◽  
Translational Mechanisms ◽  
The Brain

The diacylglycerol lipases (DAGLs) hydrolyse diacylglycerol to generate 2-arachidonoylglycerol (2-AG), the most abundant ligand for the CB 1 and CB 2 cannabinoid receptors in the body. DAGL-dependent endocannabinoid signalling regulates axonal growth and guidance during development, and is required for the generation and migration of new neurons in the adult brain. At developed synapses, 2-AG released from postsynaptic terminals acts back on presynaptic CB 1 receptors to inhibit the secretion of both excitatory and inhibitory neurotransmitters, with this DAGL-dependent synaptic plasticity operating throughout the nervous system. Importantly, the DAGLs have functions that do not involve cannabinoid receptors. For example, 2-AG is the precursor of arachidonic acid in a pathway that maintains the level of this essential lipid in the brain and other organs. This pathway also drives the cyclooxygenase-dependent generation of inflammatory prostaglandins in the brain, which has recently been implicated in the degeneration of dopaminergic neurons in Parkinson's disease. Remarkably, we still know very little about the mechanisms that regulate DAGL activity—however, key insights can be gleaned by homology modelling against other α/β hydrolases and from a detailed examination of published proteomic studies and other databases. These identify a regulatory loop with a highly conserved signature motif, as well as phosphorylation and palmitoylation as post-translational mechanisms likely to regulate function.

scholarly journals Vitamin C In Neuropsychiatry

2015 ◽  
Vol 16 (2) ◽  
pp. 157-161 ◽  
Author(s):  
Dragan M. Pavlović ◽  
Merdin Š. Markišić ◽  
Aleksandra M. Pavlović
Keyword(s):  
Ascorbic Acid ◽  
Vitamin C ◽  
The Body ◽  
Adult Brain ◽  
Normal Brain ◽  
Positive Effects ◽  
Normal Brain Function ◽  
High Concentrations ◽  
High Doses ◽  
The Brain

Abstract Vitamins are necessary factors in human development and normal brain function. Vitamin C is a hydrosoluble compound that humans cannot produce; therefore, we are completely dependent on food intake for vitamin C. Ascorbic acid is an important antioxidative agent and is present in high concentrations in neurons and is also crucial for collagen synthesis throughout the body. Ascorbic acid has a role in modulating many essential neurotransmitters, enables neurogenesis in adult brain and protects cells against infection. While SVCT1 enables the absorption of vitamin C in the intestine, SVCT2 is primarily located in the brain. Ascorbate deficiency is classically expressed as scurvy, which is lethal if not treated. However, subclinical deficiencies are probably much more frequent. Potential fields of vitamin C therapy are in neurodegenerative, cerebrovascular and affective diseases, cancer, brain trauma and others. For example, there is some data on its positive effects in Alzheimer’s disease. Various dosing regimes are used, but ascorbate is safe, even in high doses for protracted periods. Better designed studies are needed to elucidate all of the potential therapeutic roles of vitamin C.

scholarly journals Anatomical Differences between Children and Adults

2020 ◽  
Vol 8 (05) ◽  
pp. 355-359
Author(s):  
Rengin Kosif ◽  
Rabia Keçialan
Keyword(s):  
Subcutaneous Tissue ◽  
Vastus Lateralis ◽  
Rectus Femoris ◽  
The Body ◽  
Adult Brain ◽  
Skeletal Structure ◽  
School Age ◽  
Pediatric Drug ◽  
Gynecological Examination ◽  
The Brain

In this review,   anatomical differences between  child   and   adult   were   mentioned.   These differences are especially apparent in infancy and preschool term. When the child reaches the school age term, the differences begin to decrease gradually.  When the child reaches the age of 18, the child has the same characteristics as the adult. The main differences include skin, subcutaneous tissue, total amount of water in the body, muscles preferred in pharmaceutical applications,   external   ear   structure,   Eustachian   tube,   anatomy   of   the   eye,   bone   skeletal structure, spinal cord and brain, respiratory tract, digestive organs, cardiovascular system and urinary system. The differences especially between child and adult brain structure are striking. The brain tissue in the child is more sensitive, calvarium is thinner, subarachnoid space is narrower.   Morover;   the   differences   in   gynecological   examination   and   lumber   puncture practices   were   also   reviewed.  In   adults,   gluteal   muscles   are   used   in   intramuscular applications, while in infants, rectus femoris and vastus lateralis muscles are commonly used. These anatomical differences are important for the diagnosis and treatment of the doctors. Nurses should take these differences into account in pediatric drug applications in the clinic and in the care of children. Clinicians should know that children are not small adults.

scholarly journals In vivo imaging of the kinetics of microglial self-renewal and maturation in the adult visual cortex

2020 ◽  
Author(s):  
Monique S. Mendes ◽  
Jason Atlas ◽  
Zachary Brehm ◽  
Antonio Ladron-de-Guevara ◽  
Matthew N. McCall ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Visual Cortex ◽  
Adult Brain ◽  
Self Renewal ◽  
Two Photon ◽  
And Migration ◽  
The Mathematical Model ◽  
Kinetics Of ◽  
The Brain

AbstractMicroglia are the resident immune cells in the brain with the capacity to autonomously self-renew. Under basal conditions, microglial self-renewal appears to be slow and stochastic, although microglia have the ability to proliferate very rapidly following depletion or in response to injury. Because microglial self-renewal has largely been studied using static tools, the mechanisms and kinetics by which microglia renew and acquire mature characteristics in the adult brain are not well understood. Using chronic in vivo two-photon imaging in awake mice and PLX5622 (Colony stimulating factor 1 receptor (CSF1R) inhibitor) to deplete microglia, we set out to understand the dynamic self-organization and maturation of microglia following depletion in the visual cortex. We confirm that under basal conditions, cortical microglia show limited turnover and migration. Following depletion, however, microglial repopulation is remarkably rapid and is sustained by the dynamic division of the remaining microglia in a manner that is largely independent of signaling through the P2Y12 receptor. Mathematical modeling of microglial division demonstrates that the observed division rates can account for the rapid repopulation observed in vivo. Additionally, newly-born microglia resemble mature microglia, in terms of their morphology, dynamics and ability to respond to injury, within days of repopulation. Our work suggests that microglia rapidly self-renew locally, without the involvement of a special progenitor cell, and that newly born microglia do not recapitulate a slow developmental maturation but instead quickly take on mature roles in the nervous system.Graphical Abstract(a) Microglial dynamics during control condition. Cartoon depiction of the heterogenous microglia in the visual cortex equally spaced. (b) During the early stages of repopulation, microglia are irregularly spaced and sparse. (c) During the later stages of repopulation, the number of microglia and the spatial distribution return to baseline. (d-f) We then created and ran a mathematical model that sampled the number of microglia, (d) the persistent doublets, (e) the rapid divisions of microglia and (f) the secondary divisions of microglia during the peak of repopulation day 2-day 3. The mathematical model suggested that residual microglia can account for the rapid repopulation we observed in vivo.

scholarly journals Pericytes Across the Lifetime in the Central Nervous System

2021 ◽  
Vol 15 ◽  
Author(s):  
Hannah C. Bennett ◽  
Yongsoo Kim
Keyword(s):  
Review Article ◽  
Developmental Trajectory ◽  
Adult Brain ◽  
Normal Brain ◽  
Major Life ◽  
Perivascular Cell ◽  
Normal Brain Function ◽  
And Migration ◽  
And Function ◽  
The Brain

The pericyte is a perivascular cell type that encapsulates the microvasculature of the brain and spinal cord. Pericytes play a crucial role in the development and maintenance of the blood-brain barrier (BBB) and have a multitude of important functions in the brain. Recent evidence indicates that pericyte impairment has been implicated in neurovascular pathology associated with various human diseases such as diabetes mellitus, Alzheimer’s disease (AD), and stroke. Although the pericyte is essential for normal brain function, knowledge about its developmental trajectory and anatomical distribution is limited. This review article summarizes the scientific community’s current understanding of pericytes’ regional heterogeneity in the brain and their changes during major life stages. More specifically, this review article focuses on pericyte differentiation and migration during brain development, regional population differences in the adult brain, and changes during normal and pathological aging. Most of what is known about pericytes come from studies of the cerebral cortex and hippocampus. Therefore, we highlight the need to expand our understanding of pericyte distribution and function in the whole brain to better delineate this cell type’s role in the normal brain and pathological conditions.

scholarly journals Cholesterol Metabolism: A Potential Therapeutic Target in Glioblastoma

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 146 ◽  
Author(s):  
Fahim Ahmad ◽  
Qian Sun ◽  
Deven Patel ◽  
Jayne Stommel
Keyword(s):  
Brain Tumors ◽  
Cholesterol Synthesis ◽  
De Novo ◽  
Cholesterol Metabolism ◽  
Dietary Cholesterol ◽  
The Body ◽  
Adult Brain ◽  
Normal Brain ◽  
New Strategy ◽  
The Brain

Glioblastoma is a highly lethal adult brain tumor with no effective treatments. In this review, we discuss the potential to target cholesterol metabolism as a new strategy for treating glioblastomas. Twenty percent of cholesterol in the body is in the brain, yet the brain is unique among organs in that it has no access to dietary cholesterol and must synthesize it de novo. This suggests that therapies targeting cholesterol synthesis in brain tumors might render their effects without compromising cell viability in other organs. We will describe cholesterol synthesis and homeostatic feedback pathways in normal brain and brain tumors, as well as various strategies for targeting these pathways for therapeutic intervention.

scholarly journals A Brief Background on Cannabis: From Plant to Medical Indications

2019 ◽  
Vol 102 (2) ◽  
pp. 412-420 ◽  
Author(s):  
Linda E Klumpers ◽  
David L Thacker
Keyword(s):  
Cannabinoid Receptors ◽  
Endocannabinoid System ◽  
Good Evidence ◽  
The Body ◽  
Post Traumatic Stress ◽  
History Of ◽  
Post Traumatic ◽  
Loss Of Appetite ◽  
Medical Indications ◽  
The Brain

Abstract Cannabis has been used as a medicinal plant for thousands of years. As a result of centuries of breeding and selection, there are now over 700 varieties of cannabis that contain hundreds of compounds, including cannabinoids and terpenes. Cannabinoids are fatty compounds that are the main biological active constituents of cannabis. Terpenes are volatilecompounds that occur in many plants and have distinct odors. Cannabinoids exert their effect on the body by binding to receptors, specifically cannabinoid receptors types 1 and 2. These receptors, together with endogenous cannabinoids and the systems forsynthesis, transport, and degradation, are called the Endocannabinoid System. The two most prevalent and commonly known cannabinoids in the cannabis plantare delta-9-tetrahydrocannabinol (THC) and cannabidiol. The speed, strength, and type of effects of cannabis vary based on the route of administration. THC is rapidly distributed through the body to fattytissues like the brain and is metabolized by the cytochrome P450 system to 11-hydroxy-THC, which is also psychoactive. Cannabis and cannabinoids have been indicated for several medical conditions. There is evidence of efficacy in the symptomatic treatmentof nausea and vomiting, pain, insomnia, post-traumatic stress disorder, anxiety, loss of appetite, Tourette’s syndrome, and epilepsy. Cannabis hasalso been associated with treatment for glaucoma, Huntington’s Disease, Parkinson’s Disease, and dystonia, but thereis not good evidence tosupport its efficacy. Side effects of cannabis include psychosis and anxiety, which can be severe. Here, we provided a summary ofthe history of cannabis,its pharmacology, and its medical uses.

scholarly journals The biological significance of brain barrier mechanisms: help or hindrance in drug delivery to the central nervous system?

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 313 ◽  
Author(s):  
Norman R. Saunders ◽  
Mark D. Habgood ◽  
Kjeld Møllgård ◽  
Katarzyna M. Dziegielewska
Keyword(s):  
Blood Brain Barrier ◽  
Biological Significance ◽  
The Body ◽  
Adult Brain ◽  
Brain Barrier ◽  
Cellular Transport ◽  
Internal Environment ◽  
Blood Brain ◽  
Wide Range ◽  
The Brain

Barrier mechanisms in the brain are important for its normal functioning and development. Stability of the brain’s internal environment, particularly with respect to its ionic composition, is a prerequisite for the fundamental basis of its function, namely transmission of nerve impulses. In addition, the appropriate and controlled supply of a wide range of nutrients such as glucose, amino acids, monocarboxylates, and vitamins is also essential for normal development and function. These are all cellular functions across the interfaces that separate the brain from the rest of the internal environment of the body. An essential morphological component of all but one of the barriers is the presence of specialized intercellular tight junctions between the cells comprising the interface: endothelial cells in the blood-brain barrier itself, cells of the arachnoid membrane, choroid plexus epithelial cells, and tanycytes (specialized glial cells) in the circumventricular organs. In the ependyma lining the cerebral ventricles in the adult brain, the cells are joined by gap junctions, which are not restrictive for intercellular movement of molecules. But in the developing brain, the forerunners of these cells form the neuroepithelium, which restricts exchange of all but the smallest molecules between cerebrospinal fluid and brain interstitial fluid because of the presence of strap junctions between the cells. The intercellular junctions in all these interfaces are the physical basis for their barrier properties. In the blood-brain barrier proper, this is combined with a paucity of vesicular transport that is a characteristic of other vascular beds. Without such a diffusional restrain, the cellular transport mechanisms in the barrier interfaces would be ineffective. Superimposed on these physical structures are physiological mechanisms as the cells of the interfaces contain various metabolic transporters and efflux pumps, often ATP-binding cassette (ABC) transporters, that provide an important component of the barrier functions by either preventing entry of or expelling numerous molecules including toxins, drugs, and other xenobiotics.In this review, we summarize these influx and efflux mechanisms in normal developing and adult brain, as well as indicating their likely involvement in a wide range of neuropathologies.There have been extensive attempts to overcome the barrier mechanisms that prevent the entry of many drugs of therapeutic potential into the brain. We outline those that have been tried and discuss why they may so far have been largely unsuccessful. Currently, a promising approach appears to be focal, reversible disruption of the blood-brain barrier using focused ultrasound, but more work is required to evaluate the method before it can be tried in patients. Overall, our view is that much more fundamental knowledge of barrier mechanisms and development of new experimental methods will be required before drug targeting to the brain is likely to be a successful endeavor. In addition, such studies, if applied to brain pathologies such as stroke, trauma, or multiple sclerosis, will aid in defining the contribution of brain barrier pathology to these conditions, either causative or secondary.

Rate of cerebral ATP utilization in rats

1960 ◽  
Vol 198 (1) ◽  
pp. 213-216 ◽  
Author(s):  
Frederick E. Samson ◽  
William M. Balfour ◽  
Nancy A. Dahl
Keyword(s):  
Anaerobic Metabolism ◽  
Nerve Impulse ◽  
High Energy ◽  
The Body ◽  
Adult Brain ◽  
Energy Utilization ◽  
Neonatal Rat ◽  
High Energy Phosphate ◽  
The Brain ◽  
Aerobic And Anaerobic

The rate of adenosinetriphosphate (ATP) disappearance in the brain after inhibition of aerobic and anaerobic metabolism was investigated. It was found that the rate increases with increasing age in the neonatal rat and that the effect of lowering the body temperature, which slows the rate, is greater in the 21-day rat than in the newborn. Calculation from the data gives 0.5 µm/sec/gm as the rate of high-energy phosphate utilization in the 21-day rat, and 0.04 µm/sec/gm in the 1-day rat. This increase in the rate of energy utilization during neonatal maturation is compared with the capacity to generate ATP; the utilization increase is found to be six times that of the capacity to generate ATP. The Q10 of the high-energy phosphate utilization in the 21-day rat is 1.7 in the 37°–25°C range, but is 10. in the 25°–15°C range. It is concluded that the rate of high-energy phosphate utilization is closely related to the amount of neuronal activity and, further, that the energy cost per average nerve impulse probably is greater in the adult brain than in the neonatal brain.

Brain Fuel Utilization in the Developing Brain

2019 ◽  
Vol 75 (1) ◽  
pp. 8-18 ◽  
Author(s):  
Pascal Steiner
Keyword(s):  
Brain Development ◽  
Ketone Bodies ◽  
Brain Connectivity ◽  
Signal Transmission ◽  
Neuronal Cell ◽  
Building Blocks ◽  
The Body ◽  
Adult Brain ◽  
Acid Oxidation ◽  
The Brain

During pregnancy and infancy, the human brain is growing extremely fast; the brain volume increases significantly, reaching 36, 72, and 83% of the volume of adults at 2–4 weeks, 1 year, and 2 years of age, respectively, which is essential to establish the neuronal networks and capacity for the development of cognitive, motor, social, and emotional skills that will be continually refined throughout childhood and adulthood. Such dramatic changes in brain structure and function are associated with very large energetic demands exceeding by far those of other organs of the body. It has been estimated that during childhood the brain may account for up to 60% of the body basal energetic requirements. While the main source of energy for the adult brain is glucose, it appears that it is not sufficient to sustain the dramatic metabolic demands of the brain during its development. Recently, it has been proposed that this energetic challenge is solved by the ability of the brain to use ketone bodies (KBs), produced from fatty acid oxidation, as a complement source of energy. Here, we first describe the main cellular and physiological processes that drive brain development along time and how different brain metabolic pathways are engaged to support them. It has been assumed that the majority of energetic substrates are used to support neuronal activity and signal transmission. We discuss how glucose and KBs are metabolized to provide the carbon backbones used to synthesize lipids, nucleic acid, and cholesterol, which are indispensable building blocks of neuronal cell proliferation and are also used to establish and refine brain connectivity through synapse formation/elimination and myelination. We conclude that glucose and KBs are not only important to support the energy needs of the brain under development, but they are also essential substrates for the biosynthesis of macromolecules underlying structural brain growth and reorganization. We emphasize that glucose and fatty acids supporting the production of KBs are provided in complex food matrices, such as breast milk, and understanding how their availability impacts the brain will be key to promote adequate nutrition to support brain metabolism and, therefore, optimal brain development.

An evaluation of overnight fixation to facilitate neuropathological examination in Coroner's autopsies: our experience of over 200 cases

2012 ◽  
Vol 66 (1) ◽  
pp. 50-53 ◽  
Author(s):  
Ian Stuart Scott ◽  
Alastair Wray MacDonald
Keyword(s):  
Median Time ◽  
Histological Examination ◽  
Detailed Examination ◽  
Turnaround Time ◽  
The Body ◽  
Retrospective Audit ◽  
General Pathology ◽  
The Brain ◽  
Neuropathological Examination

AimsFollowing recent changes in Coroner's Rules, there has been a desire to examine brains at the time of autopsy, rather than after a prolonged period of immersion fixation. Examination of the fresh brain at postmortem can yield unsatisfactory results where detailed histological examination is required. We aim to provide a compromise, where detailed examination of the brain is possible, without the requirement for prolonged fixation, interference with funeral arrangements and delay in the Coronial process.MethodsA retrospective audit of over 200 neuropathology cases requested by HM Coroner for the East Riding of Yorkshire between 2007 and 2010 was performed. The cases consisted of full neuropathology autopsies (n=212) and brains referred by general pathology colleagues (n=26).ResultsOf the 238 brains examined, approximately half (n=109) of the brains were sectioned fresh in the mortuary. The remaining brains (n=129) were immersion fixed overnight in 20% formalin prior to cutting and sampling for histology (n=127). The median time for reporting was 31 days (range 1–167; n=101) for brains requiring histology. This equates to a median turnaround time of 1 month for a neuropathological autopsy requiring detailed histology. In all cases, the report was prepared and available to HM Coroner in advance of the Inquest.ConclusionsThis method provides reliable histological diagnoses in neuropathological autopsies and does not interfere with funeral arrangements for bereaved families following deaths falling under Coronial jurisdiction. In all cases, the body could be released to relatives, at Coroner's discretion, within two working days of the autopsy.

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