Endogenous Kynurenine Aminotransferases Inhibitor is Proposed to Act as “Glia Depressing Factor” (GDF)

The endogenous neuroinhibitory amino acid receptor antagonist kynurenic acid (KYNA) has been hypothetically linked to physiological processes and to the pathogenesis of several brain disorders. The aim of this study was to search KYNA metabolism i.e. KYNA levels and enzymes synthesising KYNA kynurenine aminotransferase I and II (KAT I and II) in the central nervous system (CNS) and in the peripheral nervous system. Within the investigated species we found a remarkably low KYNA content (3.4 nM) in piglet's serum compared to rat and human serum. Furthermore, in contrast to high KAT activity present in rat and human livers, a lack of KAT I and KAT II activity was found in piglet liver and other piglet peripheral organs. Therefore we attempted to find a reason for the absence of KYNA formation in piglet peripheral tissue and we researched to find if KYNA formation in rat liver homogenate (measured under standard assay conditions for KAT activity) can be influenced by the application of piglet tissue homogenates and other body fluids. KYNA formation in rat liver homogenate was investigated in the presence of piglet liver, piglet brain, rat brain and human brain homogenates, and also in the presence of cerebrospinal fluid (CSF) of the control and of Multiple Sclerosis patients. We found a significant and dose dependent reduction of rat liver KAT I and KAT II activities in the presence of piglet brain, piglet liver, and human brain, but not in the presence of rat brain homogenate. Interestingly, CSF of the human control subjects significantly lowered rat liver KAT I activity. Furthermore, the inhibitory effect of CSF of Multiple Sclerosis (MS) patients was significantly weaker when compared to the CSF of control subjects. Our data, for the first time, indicated the presence of active component(s)—depressing factor—in the body, which was able to block KYNA formation. Reduced KAT inhibitory effect by CSF of MS patients would suggest a lowered “depressing factor” level in CSF of MS patients and is possibly responsible for an enhancement of KYNA formation and for glia activation and gliosis in the CNS. Subsequently, two fractions obtained after centrifugation of CSF from patients with Neuroborreliosis showed a significantly different ability to block KAT I activity. The CSF-sediment fraction exerts a stronger inhibitory activity than the CSF-supernatant fraction, supporting further the presence of a depressing factor. For the first time, data revealed and demonstrated the ability of endogenous components to block KYNA's synthesis. We propose that a glia depressing factor (GDF), which is abundantly present in the body, might simultaneously control glia cell's KAT activity, respectively KYNA synthesis and also glia proliferation. The mechanism(s) of action, the composition and structure of this factor needs to be further elaborated.

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Biotransformation of Timosaponin BII into Seven Characteristic Metabolites by the Gut Microbiota

Molecules ◽

10.3390/molecules26133861 ◽

2021 ◽

Vol 26 (13) ◽

pp. 3861

Author(s):

Guo-Ming Dong ◽

Hang Yu ◽

Li-Bin Pan ◽

Shu-Rong Ma ◽

Hui Xu ◽

...

Keyword(s):

Gut Microbiota ◽

Rat Liver ◽

Pharmacological Activity ◽

Liver Homogenate ◽

Intestinal Flora ◽

Important Indicator ◽

Metabolic Characteristics ◽

Metabolic Behavior ◽

First Time ◽

Rat Liver Microsome

Timosaponin BII is one of the most abundant Anemarrhena saponins and is in a phase II clinical trial for the treatment of dementia. However, the pharmacological activity of timosaponin BII does not match its low bioavailability. In this study, we aimed to determine the effects of gut microbiota on timosaponin BII metabolism. We found that intestinal flora had a strong metabolic effect on timosaponin BII by HPLC-MS/MS. At the same time, seven potential metabolites (M1-M7) produced by rat intestinal flora were identified using HPLC/MS-Q-TOF. Among them, three structures identified are reported in gut microbiota for the first time. A comparison of rat liver homogenate and a rat liver microsome incubation system revealed that the metabolic behavior of timosaponin BII was unique to the gut microbiota system. Finally, a quantitative method for the three representative metabolites was established by HPLC-MS/MS, and the temporal relationship among the metabolites was initially clarified. In summary, it is suggested that the metabolic characteristics of gut microbiota may be an important indicator of the pharmacological activity of timosaponin BII, which can be applied to guide its application and clinical use in the future.

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BIOCHEMICAL STUDIES ON TOFRANIL

Canadian Journal of Biochemistry and Physiology ◽

10.1139/o61-055 ◽

1961 ◽

Vol 39 (3) ◽

pp. 551-558 ◽

Cited By ~ 17

Author(s):

P. N. Abadom ◽

K. Ahmed ◽

P. G. Scholefield

Keyword(s):

Rat Brain ◽

Rat Liver ◽

Brain Cortex ◽

Respiratory Activity ◽

Liver Mitochondria ◽

Brain Mitochondria ◽

Inhibitory Effect ◽

Rat Liver Mitochondria ◽

Brain Cortex Slices ◽

Cortex Slices

Tofranil inhibits the respiratory activity of rat brain cortex slices incubated in a glucose-containing medium. It also inhibits the uptake and incorporation of glycine-1-C14at concentrations which have only a slight inhibitory effect on the respiration of slices. Tofranil also inhibits oxidative phosphorylation in both rat liver and rat brain mitochondria but at higher concentrations respiration is greatly affected. Tofranil differs quantitatively from chlorpromazine in its greater inhibitory effect on the ATP–Pi32exchange reaction and its lesser effect on the cytochrome c oxidase activity of rat liver mitochondria.

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The history and scope of neuropsychiatry

Oxford Textbook of Neuropsychiatry ◽

10.1093/med/9780198757139.003.0001 ◽

2020 ◽

pp. 3-12

Author(s):

Michael Trimble

Keyword(s):

Twentieth Century ◽

Nervous System ◽

Human Brain ◽

Limbic System ◽

Historical Development ◽

The Body ◽

The Enlightenment ◽

Romantic Era ◽

The Brain

This chapter discusses the clinical necessity from which the intersection of neurology and psychiatry arose, exploring different eras and their associated intellectual milestones in order to understand the historical framework of contemporary neuropsychiatry. Identifying Hippocrates’ original acknowledgement of the relation of the human brain to epilepsy as a start point, the historical development of the field is traced. This encompasses Thomas Willis and his nascent descriptions of the limbic system, the philosophical and alchemical strides of the Enlightenment, and the motivations behind the Romantic era attempts to understand the brain. It then follows the growth of the field through the turn of the twentieth century, in spite of the prominence of psychoanalysis and the idea of the brainless mind, and finally the understanding of the ‘integrated action’ of the body and nervous system, which led to the integration of psychiatry and neurology, allowing for the first neuropsychiatric examinations of epilepsy.

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Characterization of a phenobarbital-inducible cytochrome P-450, NADPH-cytochrome P-450 reductase and reconstituted cytochrome P-450 mono-oxygenase system from rat brain. Evidence for constitutive presence in rat and human brain

Biochemical Journal ◽

10.1042/bj2880483 ◽

1992 ◽

Vol 288 (2) ◽

pp. 483-488 ◽

Cited By ~ 23

Author(s):

H K Anandatheerthavarada ◽

M R Boyd ◽

V Ravindranath

Keyword(s):

Human Brain ◽

Rat Brain ◽

Rat Liver ◽

Specific Content ◽

Nadph Cytochrome ◽

Apparent Homogeneity ◽

Brain Microsomes ◽

Molecular Masses ◽

Reconstituted System ◽

Cytochrome P 450

Cytochrome P-450 was purified to apparent homogeneity from the brain microsomes of phenobarbital-treated rats. The specific content of the purified P-450 was 12.7 nmol/mg of protein. NADPH-cytochrome P-450 reductase (reductase) was also purified to apparent homogeneity from brain microsomes. The specific content was 34.7 mumol of cytochrome c reduced/min per mg of protein. The reduced carbon monoxide spectrum of purified P-450 exhibited a peak at 450 nm. Both the P-450 and the reductase moved as single bands on SDS/PAGE. The molecular masses of the purified P-450 and the reductase were determined to be 53.3 and 72.0 kDa respectively. The purified brain P-450 cross-reacted with antibodies to rat liver P-450IIB1/IIB2 when examined by Western immunoblotting, but no immunological similarity was observed with rat liver P-450IA1/IA2 or P-450IIE1. Purified rat brain reductase cross-reacted with antibodies to rat liver reductase. Further, immunoblot experiments with untreated rat and human brain microsomes using antisera to the purified rat brain P-450 and reductase indicated that these forms of P-450 and NADPH-cytochrome P-450 reductase exist constitutively in rat and human brain. Purified rat brain P-450 was reconstituted with purified NADPH-cytochrome P-450 reductase, deoxycholate and dilauroyl glyceryl 3-phosphocholine. NADPH-dependent N-demethylation of aminopyrine and morphine was observed in the reconstituted system. The catalytic-centre activities were 80.25 and 38.2 nmol of formaldehyde formed/min per nmol of P-450 respectively. The reconstituted system had a comparatively lower catalytic-centre activity for 7-ethoxycoumarin O-de-ethylase (10.5 nmol of product formed/min per nmol of P-450).

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The Effect of α-Tocopheryl Succinate on Succinate Respiration in Rat Liver Mitochondria

Physiological Research ◽

10.33549/physiolres.933219 ◽

2015 ◽

pp. S609-S615 ◽

Cited By ~ 1

Author(s):

O. SOBOTKA ◽

Z. DRAHOTA ◽

O. KUČERA ◽

R. ENDLICHER ◽

H. RAUCHOVÁ ◽

...

Keyword(s):

Concentration Dependence ◽

Rat Liver ◽

Liver Homogenate ◽

Liver Mitochondria ◽

Inhibitory Effect ◽

Experimental Models ◽

Rat Liver Mitochondria ◽

Isolated Mitochondria ◽

Significant Inhibitory Effect ◽

Tocopheryl Succinate

We compared the effect of α-tocopheryl succinate (TOS) on succinate-dependent respiration in rat liver mitochondria, homogenate and permeabilized hepatocytes in both a coupled and uncoupled state. In isolated mitochondria, a significant inhibitory effect was observed at a concentration of 5 µM, in liver homogenate at 25 µM and in permeabilized hepatocytes at 50 µM. The inhibitory effect of TOS on succinate respiration in an uncoupled state was less pronounced than in a coupled state in all the experimental models tested. When the concentration dependence of the TOS inhibitory effect was tested, the most sensitive in both states were isolated mitochondria; the most resistant were permeabilized hepatocytes.

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THE CLINICAL CASES OF PALLISTER-KILLIANS’S SYNDROME IN A CHILD

Russian Pediatric Ophthalmology ◽

10.18821/1993-1859-2017-12-3-163-165 ◽

2017 ◽

Vol 12 (3) ◽

pp. 163-165

Author(s):

T. V Sudovskaya ◽

N. Sh Kokoeva ◽

Yu. A Bobrovskaya ◽

A. A Makarova

Keyword(s):

Nervous System ◽

Pathological Condition ◽

Mental Deficiency ◽

The Body ◽

Congenital Defects ◽

Palpebral Fissure ◽

Somatic Status ◽

Grade 3 ◽

Multiple Abnormalities ◽

First Time

This article was designed to report a clinical case of a rare syndromic disease - Pallister-Killians’s syndrome characterized by the signs of mental deficiency, abnormal features of cranial bones , congenitally reduced arterial pressure, multiple abnormalities of the facial features (including the eyes and the mouth cavity), ears, skeleton, the cardiovascular system, nervous system, and other systems of the body. The syndrome was described for the first time in 1977 by Philip Pallister and thereafter investigated in more detail by Maria Teschler-Nicola and Wolfgang Killian in 1981. In our case, the somatic status of a 3 month-old child presenting with this pathological condition was characterized by a large variety of congenital defects of the nervous system, including corpus collosum hypoxia, ischemic lesions of the brain tissue, bilateral subependymal pseudocysts, lenticulostriate agniopathies, and congenital heart failure. The pathological changes of the visual analyzer manifested themselves as unilateral grade 3 microphthalmos, sclerocornea, optic nerve disk coloboma, narrowing of the palpebral fissure, considerable decrease of the size of the conjunctival cavity in the absence of the appreciable alterations in the eye ball. Rehabilitation of the affected child with congenital microphthalmos included gradual ocular prosthetics and the treatment by the specialists of other medical professions.

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Comparison of the Position Sense of the Knee Joint in PatientsWith Multiple Sclerosis and Healthy Controls

Journal of Modern Rehabilitation ◽

10.18502/jmr.v13i1.2147 ◽

2019 ◽

Author(s):

Saina Aliabadi ◽

Roya Khanmohammadi ◽

Gholamrezareza Olyaei ◽

Nastaran Ghotbi ◽

Saeed Talebian ◽

...

Keyword(s):

Multiple Sclerosis ◽

Nervous System ◽

Knee Joint ◽

Healthy Subjects ◽

Position Sense ◽

The Body ◽

Control Group ◽

The Central Nervous System ◽

The Mean ◽

The Brain

Introduction: Position sense, one of the most accurate senses in the body, makes everyone aware of the state of the body in space. This sense is an essential ability in maintaining physical health and avoiding injury. Deficits in position sense cause balance impairments in people with mild Multiple Sclerosis (MS). Position sense requires instant and coordinated communication between the central nervous system and peripheral nervous system, while in patients with MS, communication between the brain and other parts of the body is disrupted. This study aims to compare the position sense of knee joint in people with MS and healthy subjects. Materials and Methods: Ten healthy subjects with the Mean±SD age of 27.6±3.71 years and 10 persons with MS disease and the Mean±SD age of 31.40±3.50 years participated in this study. For evaluating their position sense of knee joint, they flexed their knees (from 90 to 45 degrees) four times, and then a software calculated their repositioning errors. Results: No significant changes in repositioning errors (constant, variable, absolute) were observed in MS patients, and the control group (P˃0.05). Conclusion: The results indicate that mild MS disease cannot disturb the position sense of knee joint.

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THE EFFECT OF PODOPHYLLOTOXIN ON TISSUE METABOLISM AND ENZYME SYSTEMS

Journal of Experimental Medicine ◽

10.1084/jem.90.6.525 ◽

1949 ◽

Vol 90 (6) ◽

pp. 525-541 ◽

Cited By ~ 7

Author(s):

Zelma Baker Miller ◽

Clarke Davison ◽

Paul K. Smith

Keyword(s):

Lymph Nodes ◽

Rat Brain ◽

Rat Liver ◽

Chicken Embryo ◽

Rat Kidney ◽

Liver Homogenate ◽

Rabbit Kidney ◽

Toxic Dose ◽

Kidney Homogenate

Podophyllotoxin, 10–3M, inhibits the respiration in vitro of rat lymph nodes, thymus, kidney, tumor, spleen, liver, brain, testis, and chicken embryo. Lymph node and spleen respiration are most sensitive, and the degree of inhibition increases with time. The injection of podophyllotoxin into tumor-bearing mice (20 mg. per kg.) causes a dramatic reduction in the respiration of tumor slices. Within 6 hours, the respiration approaches zero. Inhibition is evident 2 hours after injection of the drug. Spleen respiration is reduced 50 per cent within 6 hours. Kidney and liver respirations remain within normal limits. Marked reductions in the respiration of spleen, lymph nodes, and thymus glands of normal rats are produced by the injection of 15 mg. per kg. Thymus gland is the most sensitive of these three tissues, and its respiration is reduced 66 per cent 24 hours after injection of the drug. The injection of 0.8 microgram podophyllotoxin into the yolk sac of chicken eggs bearing 5 day embryos has no effect on the respiration of the embryo within 8 hours, although this is a sufficiently toxic dose to kill 80 per cent of the embryos (within 24 hours). Kidney respiration in the presence of acetate, glucose, alanine, and glutamate is inhibited to approximately the same degree as in the absence of added substrate. Succinate and pyruvate oxidation by rat kidney slices appear to be less sensitive. Oxidation of acetate and butyrate by rabbit kidney homogenate is more sensitive to podophyllotoxin than oxidation by rabbit kidney homogenate without added substrate. Glucose oxidation by this preparation is not inhibited by 10–3M podophyllotoxin. The anaerobic glycolysis of chicken embryo, rat brain, and rat testis is stimulated by 10–5 and 10–6M podophyllotoxin, and is inhibited by 10–3M. The following enzymes are not inhibited by 10–3M podophyllotoxin: succinoxidase from pigeon breast muscle, choline, xanthine and tyrosine oxidase from rat liver homogenate, and leucine oxidase from Proteus vulgaris; alkaline and acid phosphatase from dog serum; adenosine triphosphatase from rat liver; choline esterase from rat brain homogenate; ribonucleodepolymerase from spleen mince and thymonucleodepolymerase from dog serum. High concentrations of podophyllotoxin do not influence the viscosity and degree of polymerization of thymonucleic acid.

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Recurring Migraines as the Presenting Symptom of Pediatric Multiple Sclerosis in a Teenage Girl: A Case Report

Journal of Pediatric Neurology ◽

10.1055/s-0039-1693482 ◽

2019 ◽

Vol 18 (05) ◽

pp. 263-266

Author(s):

James Bryan Meiling ◽

Priya Kaji Bui

Keyword(s):

Multiple Sclerosis ◽

Central Nervous System ◽

Nervous System ◽

Case Report ◽

The Body ◽

The Other ◽

Teenage Girl ◽

Pediatric Multiple Sclerosis ◽

The Central Nervous System ◽

Acute Attacks

AbstractMultiple sclerosis (MS) is a chronic disease of the central nervous system that leads to a progressive breakdown of the myelin sheath by self-harming autoantibodies. Both MS and migraines have a predilection for women as opposed to men. In addition, both can come across as acute attacks on the body that negatively affect the ability of an individual to function. Are they associative concurrent afflictions or is one the primary causality of the other? This case report represents a teenage girl who presented to her pediatrician with recurrent migraines, which led to a diagnosis of pediatric MS.

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