Adrenerginen neuroni säätelee keskiaivojen dopaminijärjestelmään

http://www.ncbi.nlm.nih.gov/pubmed/26820641

C A  Mejias Aponte:  Adrenergisten projektioiden spesifisyys ja vaikutus  keskiaivojen dopamiinijärjestelmään. 

LÄHDE:  Brain Res. 2016 Jun 15;1641(Pt B):258-73. doi: 10.1016/j.brainres.2016.01.036. Epub 2016 Jan 26.

Specificity and impact of adrenergic projections to the midbrain dopamine system. Mejias-Aponte CA¹.

Tiivistelmä, (Abstract)

DOPAMIINI  on biogeeninen amini, neuromodulaattori, joka säätelee  erilaisissa aivopiireissä, jotka osallistuvat kognitiivisiin funktioihin, motoriikan koordinaatioon ja emootioihin.  Jos  dopamiinijärjestelmässa on  säätelyvikaa, se heijastuu moniin neurologisiin ja psykiatrisiin häiriöihin kuten parkinsonin tauti ja eri aineitten väärinkäyttö.

• Dopamine (DA) is a neuromodulator that regulates different brain circuits involved in cognitive functions, motor coordination, and emotions. Dysregulation of DA is associated with many neurological and psychiatric disorders such as Parkinson's disease and substance abuse.

Monista tutkimuslinjoista  on saatu osoitusta  siitä, että sentraalinen adrenerginen systeemi säätelee  keskiaivojen dopamiinijärjestelmää. 

•  Several lines of research have shown that the midbrain DA system is regulated by the central adrenergic system. 

 Tässä  katsaukseesa keskiönä on  adrenergiset vuorovaikutukset keskiaivojen dopamiinineuronien kanssa. keskustellaan nykyisestä neuroanatomiasta, mukaan luetttuna  adrenergisen  hermotuksen alkukohdat, synpsien tyypit ja adrenoseptorien  esiintyminen. Pohditaan myös dopamiinisolujen aktiivisuuden adrenergistä säätelyä ja hermonvälittäjäaineen vapautumista.

• This review focuses on adrenergic interactions with midbrain DA neurons. It discusses the current neuroanatomy including source of adrenergic innervation, type of synapses, and adrenoceptors expression. It also discusses adrenergic regulation of DA cell activity and neurotransmitter release.

 Lopuksi  tehsään katsaus useisiin neurologisiin ja psykiatrisiin häiriöihin, joissa  adrenergisen järjestelmän muutokset  ovat liittyneet keskiaivojen  dopamiinijärjestelmän  säätelyhäiriöön.  Tämä artikkeli  on osa  spesiaaliaiheesta  otsikolla  Noradrenerginen järjestelmä.

•  Finally, it reviews several neurological and psychiatric disorders where changes in adrenergic system are associated with dysregulation of the midbrain DA system. This article is part of a Special Issue entitled SI: Noradrenergic System. Copyright © 2016 Elsevier B.V. All rights reserved.

KEYWORDS:

Addiction; Anatomy; Dopamine; Norepinephrine; Physiology; Prefrontal cortex

Dopamiinin synteesistä ajatus

Jos tuntee  aineenvaihdunta kartan jossa aminohaposta fenylalaniinista äsin muodostuu dopamiinia, käsittää että dopamiinin muodostumisen vaje on vain signaali siitä että noradrenaliinia ja adrenaliiniakaan ei voi muodostua  riittäviä määriä. tästä näkökohdasta katsoin tänään kirjastossa, mikä on  sympaattisen hermoston tilanne parkinsonin taudissa.  loppusanana neuropatologisessa kappaleessa oli tämä: Anatomisten löytöjen listasta  pitäisi olla ilmiselvää, että vaikka  parkinsonin taudin neurokemiallisen patologian  biokemiallisia  merkkejä onkin  dopamiinista tyhjä  Corpus striatum, niin tässä taudissa on  tapahtunut haitallisia muutoksia laajassa neuronijoukossa: kaikissa dopaminergisissä, noradrenergisissä, serotonergisissä ja kolinergisissä neuroneissa. Ainoastaan hypotalamuksen dopaminergiset  neuronit ovat  jostain syystä säästyneet.

Kirjoitan tämän lauseen engalnniksi:
"From the list given it should be apparent that, although the biochemical hallmark of the neurochemical pathology of Parkinson disease is depletion of dopamine in the Corpus Striatum, neuronal populations affected in the disease are all of dopaminergic, noradrenergic, serotonergic and cholinergic types. 
Hypothalamic dopaminergic neurons are however spared".

(Mazzuk MM,  Saper CB. Preservation of hypothalamic dopaminergic neurons in Parkinson disease. Ann neur 1985; 15: 552-555.

Artikkeli, jota katselin tänään biomedisiinisessä kirjastossa, oli vuodelta  2002. Katsoin  kappaletta 11 ja 20.
Kirjotitajat: Jean Pintar HUBBLE, M.D., Carolyn Weeks, B.S:
 Autonomic Nervous System Dysfunction . Ohio University, Columbus, USA.
 (Artikkeli kuuluu amerikkalaiseen kirjaan: Parkinson disease. Diagnosis and Clinical Management 2002).

Mitenkähän nykyterapia ottaa huomioon aivojen ilmeisen  systeemisen sairauden tässä  taudissa jonka kapean spektrin motorista komponenttia lähinnä  on totuttu sympotomaattisesti  hoitamaan. 

Kuitenkin  dopamiinihermot ovat yhdellä alueella  (hypotalamuksessa)  säilyneet systeemiseltä degeneraatiolta jostain  syystä.

Onkohan parkinsonismin taudin  kokonaiskäsityksessä jotain paradigman  laajentamista vaativaa.  Sitä paitsi jos  oireisto on vähemmän motoriikan aluetta  siirretään  diagnostiikka mentaalisiin ryhmiin vaikka kyse on ehkä samasta  systeemitaudista.  Aminohappoaineenvaihdunnat jotka ovat  mukana: fenylalaniini, tyrosiini, tryptofaani, metioniini, seriini. tuon ylläolevan luettelon perusteella - ainakin.
oksidatiivinen stressi on havaittu . raudan  sijoittautuminen toxisesti, ei -ferritiinitavalla.

Syväaivon valon aistiminen -synkronisointi vuorokauden aikoihin

http://www.ncbi.nlm.nih.gov/pubmed/11962759

Histol Histopathol. 2002 Apr;17(2):555-90.

Nonvisual photoreceptors of the deep brain, pineal organs and retina.

Vigh B¹, Manzano MJ, Zádori A, Frank CL, Lukáts A, Röhlich P, Szél A, Dávid C.

Abstract

The role of the nonvisual photoreception is to synchronise periodic functions of living organisms to the environmental light periods in order to help survival of various species in different biotopes. In vertebrates, the so-called deep brain (septal and hypothalamic) photoreceptors, the pineal organs (pineal- and parapineal organs, frontal- and parietal eye) and the retina (of the "lateral" eye) are involved in the light-based entrain of endogenous circadian clocks present in various organs.

 In humans, photoperiodicity was studied in connection with sleep disturbances in shift work, seasonal depression, and in jet-lag of transmeridional travellers. In the present review, experimental and molecular aspects are discussed, focusing on the histological and histochemical basis of the function of nonvisual photoreceptors.

 We also offer a view about functional changes of these photoreceptors during pre- and postnatal development as well as about its possible evolution. Our scope in some points is different from the generally accepted views on the nonvisual photoreceptive systems. The deep brain photoreceptors are hypothalamic and septal nuclei of the periventricular cerebrospinal fluid (CSF)-contacting neuronal system. Already present in the lancelet and representing the most ancient type of vertebrate nerve cells ("protoneurons"), CSF-contacting neurons are sensory-type cells sitting in the wall of the brain ventricles that send a ciliated dendritic process into the CSF. Various opsins and other members of the phototransduction cascade have been demonstrated in telencephalic and hypothalamic groups of these neurons.

 In all species examined so far, deep brain photoreceptors play a role in the circadian and circannual regulation of periodic functions. Mainly called pineal "glands" in the last decades, the pineal organs actually represent a differentiated form of encephalic photoreceptors. Supposed to be intra- and extracranially outgrown groups of deep brain photoreceptors, pineal organs also contain neurons and glial elements. Extracranial pineal organs of submammalians are cone-dominated photoreceptors sensitive to different wavelengths of light, while intracranial pineal organs predominantly contain rod-like photoreceptor cells and thus scotopic light receptors. Vitamin B-based light-sensitive cryptochromes localized immunocytochemically in some pineal cells may take part in both the photoreception and the pacemaker function of the pineal organ. In spite of expressing phototransduction cascade molecules and forming outer segment-like cilia in some species, the mammalian pineal is considered by most of the authors as a light-insensitive organ. Expression of phototransduction cascade molecules, predominantly in young animals, is a photoreceptor-like characteristic of pinealocytes in higher vertebrates that may contribute to a light-percepting task in the perinatal entrainment of rhythmic functions.

 In adult mammals, adrenergic nerves--mediating daily fluctuation of sympathetic activity rather than retinal light information as generally supposed--may sustain circadian periodicity already entrained by light perinatally. Altogether three phases were supposed to exist in pineal entrainment of internal pacemakers: an embryological synchronization by light and in viviparous vertebrates by maternal effects (1); a light-based, postnatal entrainment (2); and in adults, a maintenance of periodicity by daily sympathetic rhythm of the hypothalamus. In addition to its visual function, the lateral eye retina performs a nonvisual task. Nonvisual retinal light perception primarily entrains genetically-determined periodicity, such as rod-cone dominance, EEG rhythms or retinomotor movements. It also influences the suprachiasmatic nucleus (SCN) , the primary pacemaker of the brain. As neither rods nor cones seem to represent the nonvisual retinal photoreceptors, the presence of additional photoreceptors has been supposed. Cryptochrome 1, a photosensitive molecule identified in retinal nerve cells and in a subpopulation of retinal photoreceptors, is a good candidate for the nonvisual photoreceptor molecule as well as for a member of pacemaker molecules in the retina. When comparing various visual and nonvisual photoreceptors, transitory, "semi visual" (directional) light-perceptive cells can be detected among them, such as those in the parietal eye of reptiles. Measuring diffuse light intensity of the environment, semivisual photoreceptors also possess some directional light perceptive capacity aided by complementary lens-like structures, and screening pigment cells. Semivisual photoreception in aquatic animals may serve for identifying environmental areas of suitable illumination, or in poikilotermic terrestrial species for measuring direct solar irradiation for thermoregulation. As directional photoreceptors were identified among nonvisual light perceptive cells in the lancelet, but eyes are lacking, an early appearance of semivisual function, prior to a visual one (nonvisual --> semivisual --> visual?) in the vertebrate evolution was supposed.

PMID:

11962759

[PubMed - indexed for MEDLINE]

• 
  

Keramidi ja THC?

http://www.ncbi.nlm.nih.gov/pubmed/16624285
  In summary, results presented here show that CB2 receptor activation signals apoptosis via a ceramide-dependent stimulation of the mitochondrial intrinsic pathway.

Sfingomyeliini ja THC?

http://www.ncbi.nlm.nih.gov/pubmed/11306675

Mol Pharmacol. 2001 May;59(5):955-9.

The CB(1) cannabinoid receptor of astrocytes is coupled to sphingomyelin hydrolysis through the adaptor protein fan.

Sánchez C¹, Rueda D, Ségui B, Galve-Roperh I, Levade T, Guzmán M.

Abstract

Cannabinoids exert most of their effects through the CB(1) receptor. This G protein-coupled receptor signals inhibition of adenylyl cyclase, modulation of ion channels, and stimulation of mitogen- and stress-activated protein kinases. In this article, we report that Delta(9)-tetrahydrocannabinol (THC), the major active component of marijuana, induces sphingomyelin hydrolysis in primary astrocytes but not in other cells expressing the CB(1) receptor, such as primary neurons, U373 MG astrocytoma cells, and Chinese hamster ovary cells transfected with the CB(1) receptor cDNA. THC-evoked sphingomyelin breakdown in astrocytes was also exerted by the endogenous cannabinoid anandamide and the synthetic cannabinoid HU-210 and was prevented by the selective CB(1) antagonist SR141716. By contrast, the effect of THC was not blocked by pertussis toxin, pointing to a lack of involvement of G(i/o) proteins. A role for the adaptor protein FAN in CB(1) receptor-coupled sphingomyelin breakdown is supported by two observations: 1) coimmunoprecipitation experiments show that the binding of FAN to the CB(1) receptor is enhanced by THC and prevented by SR141716; 2) cells expressing a dominant-negative form of FAN are refractory to THC-induced sphingomyelin breakdown. This is the first report showing that a G-protein-coupled receptor induces sphingomyelin hydrolysis through FAN and that the CB(1) cannabinoid receptor may signal independently of G(i/o) proteins.

Mitokondria ja THC?

http://www.ncbi.nlm.nih.gov/pubmed/12533310
uncoupling of electron transport- elektroninsiirtoketjun poiskytkeytymä 

Am J Physiol Lung Cell Mol Physiol. 2003 Feb;284(2):L298-306. Epub 2002 Oct 25.

Delta 9-tetrahydrocannabinol disrupts mitochondrial function and cell energetics.

Sarafian TA¹, Kouyoumjian S, Khoshaghideh F, Tashkin DP, Roth MD.

Abstract

We have observed rapid and extensive depletion of cellular energy stores by Delta(9)-tetrahydrocannabinol (THC) in the pulmonary transformed cell line A549. ATP levels declined dose dependently with an IC(50) of 7.5 microg/ml of THC after 24-h exposure. Cell death was observed only at concentrations >10 microg/ml. Studies using JC-1, a fluorescent probe for mitochondrial membrane potential, revealed diminished mitochondrial function at THC concentrations as low as 0.5 microg/ml. At concentrations of 2.5 or 10 microg/ml of THC, a decrease in mitochondrial membrane potential was observed as early as 1 h after THC exposure. Mitochondrial function remained diminished for at least 30 h after THC exposure. Flow cytometry studies on cells exposed to particulate smoke extracts indicate that JC-1 red fluorescence was fivefold lower in cells exposed to marijuana smoke extract relative to cells exposed to tobacco smoke extract. Comparison with a variety of mitochondrial inhibitors demonstrates that THC produced effects similar to that of carbonyl cyanide p-trifluoromethoxyphenylhydrazone, suggesting uncoupling of electron transport. Loss of red JC-1 fluorescence by THC was suppressed by cyclosporin A, suggesting mediation by the mitochondrial permeability transition pore. This disruption of mitochondrial function was sustained for at least 24 h after removal of THC by extensive washing. These results suggest that exposure of the bronchopulmonary epithelium to THC may have important health and physiological consequences.

Akuutit dissosiatiiviset oireet huumevaikutuksesta

 Sekavuustiloja verrataan  jakomielisyyteen ja  ketamiinivaikutukseen, joita ne muistuttavat.

Psychiatry Res. 2015 Aug 30;228(3):907-12. doi: 10.1016/j.psychres.2015.04.028. Epub 2015 Apr 30.

MDMA, cannabis, and cocaine produce acute dissociative symptoms.

van Heugten-Van der Kloet D¹, Giesbrecht T², van Wel J², Bosker WM², Kuypers KP², Theunissen EL², Spronk DB³, Jan Verkes R³, Merckelbach H², Ramaekers JG².

Author information

Abstract

Some drugs of abuse may produce dissociative symptoms, but this aspect has been understudied. We explored the dissociative potential of three recreational drugs (3,4-methylenedioxymethamphetamine (MDMA), cannabis, and cocaine) during intoxication and compared their effects to literature reports of dissociative states in various samples. Two placebo-controlled studies were conducted. In Study 1 (N=16), participants received single doses of 25, 50, and 100 mg of MDMA, and placebo. In Study 2 (N=21), cannabis (THC 300 µg/kg), cocaine (HCl 300 mg), and placebo were administered. Dissociative symptoms as measured with the Clinician-Administered Dissociative States Scale (CADSS) significantly increased under the influence of MDMA and cannabis. To a lesser extent, this was also true for cocaine. Dissociative symptoms following MDMA and cannabis largely exceeded those observed in schizophrenia patients, were comparable with those observed in Special Forces soldiers undergoing survival training, but were lower compared with ketamine-induced dissociation. Cocaine produced dissociative symptoms that were comparable with those observed in schizophrenia patients, but markedly less than those in Special Forces soldiers and ketamine users. Thus, MDMA and cannabis can produce dissociative symptoms that resemble dissociative pathology. The study of drug induced dissociation is important, because it may shed light on the mechanisms involved in dissociative psychopathology.

Fosfatidyyliseriini ja THC?

Toxicol Appl Pharmacol. 2001 Aug 1;174(3):264-72.

Tapahtuu muuttuminen solutuholaadussa apoptoottisesta tiestä  nekroottiseen.

Marijuana smoke and Delta(9)-tetrahydrocannabinol promote necrotic cell death but inhibit Fas-mediated apoptosis.

Sarafian TA¹, Tashkin DP, Roth MD.

Abstract

Marijuana smoke shares many components in common with tobacco smoke except for the presence of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the psychotropic compound found only in Cannibis sativa. Delta(9)-THC has been shown to potentiate smoke-induced oxidative stress and necrotic cell death. In the present study, our objective was to determine the effects of Delta(9)-THC on the balance between Fas-induced apoptosis and necrosis in A549 lung tumor cells. We found that Fas-induced activation of caspase-3 was inhibited by whole smoke from both tobacco and marijuana cigarettes. Gas-phase smoke, which generates high levels of intracellular reactive oxygen species, had no effect on caspase-3 activity. However, particulate-phase smoke (tar) was a potent inhibitor of Fas-induced caspase-3 activity, with marijuana tar being more potent than either tobacco or placebo marijuana tar (lacking Delta(9)-THC). Delta(9)-THC also inhibited Fas-induced caspase-3 activity in A549 cells. In contrast, no inhibition was observed when Delta(9)-THC was incubated with activated caspase-3 enzyme, suggesting that Delta(9)-THC acts on the cell pathway(s) leading to caspase-3 activation and not directly on enzyme function. Flow cytometry was used to measure the percentage of cells undergoing apoptosis (staining for annexin V) versus necrosis (staining for propidium iodide) and confirmed that both marijuana tar extract and synthetic Delta(9)-THC inhibit Fas-induced apoptosis while promoting necrosis. These observations suggest that the Delta(9)-THC contained in marijuana smoke disrupts elements of the apoptotic pathway, thereby shifting the balance between apoptotic and necrotic cell death. This shift may affect both the carcinogenic and immunologic consequences of marijuana smoke exposure.

Fosfatidyyli-inositidi ja THC?

Tästä hakusanasta tulen alueelle TRPV1 jonikanava, jota (PIP  ja  PIP2 säätelee.(inhiboiden ) (PIP3 ei vaikuta) ja THC vaikuttaa  aktivoiden käsittääkseni.  Tästä  jonikanavasta, joka  havainnoi pH.ta ja  liikalämpövaikutusta, en ole aiemmin  ollut tietoinen.
TRPV1  kanavasta on tuoretta  tietoa 2016.

TRPV1provided by HGNC

Official Full Name

transient receptor potential cation channel subfamily V member 1provided by HGNC

http://www.ncbi.nlm.nih.gov/gene/7442

Capsaicin, the main pungent ingredient in hot chili peppers, elicits a sensation of burning pain by selectively activating sensory neurons that convey information about noxious stimuli to the central nervous system. The protein encoded by this gene is a receptor for capsaicin and is a non-selective cation channel that is structurally related to members of the TRP family of ion channels.
 This receptor is also activated by increases in temperature in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo.
 Four transcript variants encoding the same protein, but with different 5' UTR sequence, have been described for this gene. [provided by RefSeq, Jul 2008]

Related articles in PubMed

1. Expression and diagnosis of transient receptor potential vanilloid1 in urothelium of patients with overactive bladder. Zhang HY, et al. J Biol Regul Homeost Agents, 2015 Oct-Dec. PMID 26753651
2. TRPV1 on astrocytes rescues nigral dopamine neurons in Parkinson's disease via CNTF. Nam JH, et al. Brain, 2015 Dec. PMID 26490328,
3. Supraspinal Transient Receptor Potential Subfamily V Member 1 (TRPV1) in Pain and Psychiatric Disorders. Madasu MK, et al. Mod Trends Pharmacopsychiatri, 2015. PMID 26436415
4. Cannabinoid-based drugs targeting CB1 and TRPV1, the sympathetic nervous system, and arthritis. Lowin T, et al. Arthritis Res Ther, 2015 Sep 6. PMID 26343051, Free PMC Article
5. Interaction between the Linker, Pre-S1, and TRP Domains Determines Folding, Assembly, and Trafficking of TRPV Channels. Garcia-Elias A, et al. Structure, 2015 Aug 4. PMID 26146187

See all (268) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF

 

1. Studies indicate that crosstalk between cannabinoid receptor type 1 (CB1) and transient receptor potential vanilloid 1 (TRPV1) modulates pain and inflammation in arthritis.
2. Interaction between the linker, pre-S1, and TRP domains determines folding, assembly, and trafficking of TRPV1 and TRPV4 channels.
3. activation of astrocytic TRPV1 activates endogenous neuroprotective machinery in vivo and it is a novel therapeutic target for the treatment of Parkinson's disease
4. TRPV1 expression level, IL-4 level, and rs4790522 site mutation are the main risk factors inducing bronchial asthma in children
5. high expression of TRPV1 in urothelium of female overactive bladder(OAB) patients is closely correlated to OAB occurrence.
6. and TRPV1 have different sensitivities toward membrane phospholipids, such as PI(4)P, PI(4,5)P2, and AA, although they have common roles as proton sensors.  
7. This review focuses on the current knowledge of TRPV1 in improving VSMC function and attenuating hypertension. [review]
8. These findings suggested that the pathophysiology of heartburn sensation or esophageal hypersensitivity may be associated with the activation of PAR-2, TRPV1, and acid-sensing ion channels.
9. This study evaluated the presence of TRPV1 in human and canine mammary cancer cells and the role of TRPV1 in regulating cell proliferation.
10. Supraspinal/brain transient receptor potential subfamily V member 1 is known to modulate pain processing.

 (Kohta 3): Currently there is no neuroprotective or neurorestorative therapy for Parkinson's disease. Here we report that transient receptor potential vanilloid 1 (TRPV1) on astrocytes mediates endogenous production of ciliary neurotrophic factor (CNTF), which prevents the active degeneration of dopamine neurons and leads to behavioural recovery through CNTF receptor alpha (CNTFRα) on nigral dopamine neurons in both the MPP(+)-lesioned or adeno-associated virus α-synuclein rat models of Parkinson's disease. Western blot and immunohistochemical analysis of human post-mortem substantia nigra from Parkinson's disease suggests that this endogenous neuroprotective system (TRPV1 and CNTF on astrocytes, and CNTFRα on dopamine neurons) might have relevance to human Parkinson's disease. Our results suggest that activation of astrocytic TRPV1 activates endogenous neuroprotective machinery in vivo and that it is a novel therapeutic target for the treatment of Parkinson's disease.

(Kohta 6.)  Protons are released in pain-generating pathological conditions such as inflammation, ischemic stroke, infection, and cancer. During normal synaptic activities, protons are thought to play a role in neurotransmission processes. Acid-sensing ion channels (ASICs) are typical proton sensors in the central nervous system (CNS) and the peripheral nervous system (PNS). In addition to ASICs, capsaicin- and heat-activated transient receptor potential vanilloid 1 (TRPV1) channels can also mediate proton-mediated pain signaling. In spite of their importance in perception of pH fluctuations, the regulatory mechanisms of these proton-sensitive ion channels still need to be further investigated.

 Here, we compared regulation of ASICs and TRPV1 by membrane phosphoinositides, which are general cofactors of many receptors and ion channels. We observed that ASICs do not require membrane phosphatidylinositol 4-phosphate (PI(4)P) or phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) for their function. However, TRPV1 currents were inhibited by simultaneous breakdown of PI(4)P and PI(4,5)P2. By using a novel chimeric protein, CF-PTEN, that can specifically dephosphorylate at the D3 position of phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3), we also observed that neither ASICs nor TRPV1 activities were altered by depletion of PI(3,4,5)P3 in intact cells.

 Finally, we compared the effects of arachidonic acid (AA) on two proton-sensitive ion channels. We observed that AA potentiates the currents of both ASICs and TRPV1, but that they have different recovery aspects. In conclusion, ASICs and TRPV1 have different sensitivities toward membrane phospholipids, such as PI(4)P, PI(4,5)P2, and AA, although they have common roles as proton sensors. Further investigation about the complementary roles and respective contributions of ASICs and TRPV1 in proton-mediated signaling is necessary.

Aivofosfolipidi PE (fosfatidyletanoli eli kefaliini) ja THC ?

http://www.ncbi.nlm.nih.gov/pubmed/?term=phosphatidylethanol+and+THC

Biochem Pharmacol. 1994 Sep 15;48(6):1253-64.

Phospholipase participation in cannabinoid-induced release of free arachidonic acid.

Burstein S¹, Budrow J, Debatis M, Hunter SA, Subramanian A.

Abstract

The exposure of cells in culture to cannabinoids results in a rapid and significant mobilization of phospholipid bound arachidonic acid. In vivo, this effect has been observed as a rise in eicosanoid tissue levels that may account for some of the pharmacological actions of delta 9-tetrahydrocannabinol (THC), the major psychoactive cannabinoid. Fluoroaluminate pretreatment of mouse peritoneal cells potently reduced the cannabinoid response, while promoting arachidonate release on its own, consistent with earlier observations that this effect may be a receptor/G-protein-mediated process. Further support for receptor mediation was the demonstration of saturable, high-affinity cannabinoid binding in these cells. THC potency was reduced in the presence of ethanol, and was accompanied by significant increases in phosphatidylethanol (PdEt) levels, a unique product of phospholipase D (PLD) activity.
THC-dependent arachidonate release was reduced partially in similar amounts by either propranolol or wortmannin, further implicating PLD as a mediator of THC action. A central role for diacylglyceride (DAG), a secondary product of PLD metabolism, in this THC-induced process, both as a source of arachidonate and as a stimulator of protein kinase C (PKC), is supported by the data in this report. Cells exposed to phorbol ester for 18 hr prior to THC challenge became less responsive, indicating a possible role for PKC. The involvement of PKC further suggests participation by phospholipase A2 (PLA2) whose activity may be regulated by the former. Treatment of cells with interleukin-1 alpha, an agent known to elevate PLA2 levels, caused an increase in the THC response, supporting a role for this enzyme in the release reaction. Direct evidence, by immunoblotting, for the activation and phosphorylation of PLA2 by THC was also obtained. In summary, the evidence presented in this report indicates that THC-induced arachidonic acid release occurs through a series of events that are consistent with a receptor-mediated process involving the stimulation of one or more phospholipases.

PMID:

7945419

[PubMed - indexed for MEDLINE]

Arakidonilan villi viidakko!

On ilmeistä, että jos nykyaikana on n-6/n-3 essentiellien rasvahappolinjojen kanta-aineiden (linoli/linoleenihappo) suhde  täysin  paisunut 20:1  ja ylikin verrattuna siihen, mitä se on aiemmin ollut 1:1, niin mahdollisuudetkin arakidonihappojohdannaisten,  kuten lipoksiinien ym,  ylivaltaan on   rajaton. Ei ole odotettavissa mitään rauhoittumista  rasvakudoksen kuten aivon ja myeliinin ja muun rasvakudoksen tulehduksiin ennenkuin  tuo suhde oikaistaan.

Sitten jälleen omega-3 linjan EPA, DPA ja DHA voisivat  järkevässä suhteessa  n6- linjan   aggressiivisiin voimavaikuttajiin    tasapainottaa niitä arakidonihappojärjestelmän  eikosanoidien kärhien  temmellystä. Ei tarvitse  alkaa  sen epätasapainon takia käyttämään  tekosyyllä kannabista  hermotulehdusta vastaan.  endokannabinoidien  fysiologisesa järejstelmässä. Ehkä  astma- ja allergialääkkeiden ja antihistamiinienkin tarvetta saataisiin rajautumaan ja ehkä tulehduksellisiin neurodegeneraatioihinkin tulisi jotain vaikutusta. Pitäisihän aivojen saada päärasvahapokseen kehkeytettyä sitä DHA.ta  eikä valiutuisi  strategisiin neuronaalisiin  siajinteihin   sen alternatiivimuotoja  n6-linjasta. tai muita tehtävään tehottomia rasvahappoja.
 Endokannabinoidit ovat  se verkosto, joka muodostaa integraatiota ja  isolaatiota vahvojen vaikuttajamolekyylien  ja niiden substraattien  logistiikalle.  Kannabis  aineenvaihduntaan kelpaamattomana  jätetuotteena jää kertymään tähän järjestelmään  kuin esteinä  metabolisella turvaverkolle ja  vuosien aikana haittaa  hermosolufunktiota, myeliinin ja asetylkokliinin  de novo muodostusta ja  hermosolujen uusiutumista.

 http://www.ncbi.nlm.nih.gov/pubmed/26546723

DHA ja endokannabinoidi systeemi

 PubMed haku anta 19 vastausta , josita tuoreimmat otan sitaattina 25.5. 2016. 

Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways.

Dyall SC, Mandhair HK, Fincham RE, Kerr DM, Roche M, Molina-Holgado F.

Neuropharmacology. 2016 Apr 1;107:387-395. doi: 10.1016/j.neuropharm.2016.03.055. [Epub ahead of print]

Emerging evidence suggests a complex interplay between the endocannabinoid system, omega-3 fatty acids and the immune system in the promotion of brain self-repair. However, it is unknown if all omega-3 fatty acids elicit similar effects on adult neurogenesis and if such effects are mediated or regulated by interactions with the endocannabinoid system. This study investigated the effects of DHA and EPA on neural stem cell (NSC) fate and the role of the endocannabinoid signalling pathways in these effects.

 EPA, but not DHA, significantly increased proliferation of NSCs compared to controls, an effect associated with enhanced levels of the endocannabinoid 2-arachidonylglycerol (2-AG) and p-p38 MAPK, effects attenuated by pre-treatment with CB1 (AM251) or CB2 (AM630) receptor antagonists.

 

 Furthermore, in NSCs derived from IL-1β deficient mice, EPA significantly decreased proliferation and p-p38 MAPK levels compared to controls, suggesting a key role for IL-1β signalling in the effects observed. Although DHA similarly increased 2-AG levels in wild-type NSCs, there was no concomitant increase in proliferation or p-p38 MAPK activity.

 

 In addition, in NSCs from IL-1β deficient mice, DHA significantly increased proliferation without effects on p-P38 MAPK, suggesting effects of DHA are mediated via alternative signalling pathways. 

These results provide crucial new insights into the divergent effects of EPA and DHA in regulating NSC proliferation and the pathways involved, and highlight the therapeutic potential of their interplay with endocannabinoid signalling in brain repair.

 

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An Increase in the Omega-6/Omega-3 Fatty Acid Ratio Increases the Risk for Obesity.

Simopoulos AP.

Nutrients. 2016 Mar 2;8(3). pii: E128. doi: 10.3390/nu8030128. Review.

In the past three decades, total fat and saturated fat intake as a percentage of total calories has continuously decreased in Western diets, while the intake of omega-6 fatty acid increased and the omega-3 fatty acid decreased, resulting in a large increase in the omega-6/omega-3 ratio from 1:1 during evolution to 20:1 today or even higher. This change in the composition of fatty acids parallels a significant increase in the prevalence of overweight and obesity. Experimental studies have suggested that omega-6 and omega-3 fatty acids elicit divergent effects on body fat gain through mechanisms of adipogenesis, browning of adipose tissue, lipid homeostasis, brain-gut-adipose tissue axis, and most importantly systemic inflammation. Prospective studies clearly show an increase in the risk of obesity as the level of omega-6 fatty acids and the omega-6/omega-3 ratio increase in red blood cell (RBC) membrane phospholipids, whereas high omega-3 RBC membrane phospholipids decrease the risk of obesity. Recent studies in humans show that in addition to absolute amounts of omega-6 and omega-3 fatty acid intake, the omega-6/omega-3 ratio plays an important role in increasing the development of obesity via both AA eicosanoid metabolites and hyperactivity of the cannabinoid system, which can be reversed with increased intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). A balanced omega-6/omega-3 ratio is important for health and in the prevention and management of obesity. 

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Select item 268129193.

Potential Biomarkers for Depression Associated with Coronary Artery Disease: A Critical Review.

Adibfar A, Saleem M, Lanctot KL, Herrmann N.

Curr Mol Med. 2016;16(2):137-64.

Adibfar A, Saleem M, Lanctot KL¹, Herrmann N.

Depression, the most common mood disorder, is a leading contributor to the global burden of disease affecting more than 120 million individuals worldwide. Various pathophysiological processes underlie depression; this complexity renders it difficult to identify clinically useful diagnostic and prognostic markers, as well as treatment options. The current state of knowledge driving the management and treatment of depression remains incomplete, which underscores the need for further insight into pathways relevant to depression. Exploring co-morbid conditions, such as coronary artery disease, may be useful to further elucidate the etiopathology of depression. The present review therefore systematically identifies and critically evaluates relevant markers of depression as assessed in a high-risk population, namely patients with coronary artery disease. Biomarkers related to hypothalamicpituitary- adrenal axis dysregulation, inflammation, endothelial dysfunction, platelet activation and aggregation, serotonin activity, sympathetic nervous system activation, thyroid function, structural and morphological brain abnormalities, genetic variation, lipid metabolism, one-carbon metabolism, endocannabinoid signalling irregularities, and vitamin D deficiency are reviewed. Markers exhibiting the most consistent associations with depression include tumour necrosis factor-α, flow-mediated dilation, endothelin-1, endothelial progenitor cells, brain-derived neurotrophic factor, and docosahexaenoic acid. Further investigating the mechanisms underlying those markers and exploring novel pathways, such as oxidative stress, will extend the current state of knowledge and potentially lead to the identification of novel therapeutic targets.

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Select item 262194144.

Dietary DHA reduces downstream endocannabinoid and inflammatory gene expression and epididymal fat mass while improving aspects of glucose use in muscle in C57BL/6J mice.

Kim J, Carlson ME, Kuchel GA, Newman JW, Watkins BA.

Int J Obes (Lond). 2016 Jan;40(1):129-37. doi: 10.1038/ijo.2015.135. Epub 2015 Jul 29.

 

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Fatty Acid modulation of the endocannabinoid system and the effect on food intake and metabolism.

Naughton SS, Mathai ML, Hryciw DH, McAinch AJ.

Int J Endocrinol. 2013;2013:361895. doi: 10.1155/2013/361895. Epub 2013 May 26.

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 Endocannabinoids and their G-protein coupled receptors (GPCR) are a current research focus in the area of obesity due to the system's role in food intake and glucose and lipid metabolism.

 Importantly, overweight and obese individuals often have higher circulating levels of the arachidonic acid-derived endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) and an altered pattern of receptor expression. Consequently, this leads to an increase in orexigenic stimuli, changes in fatty acid synthesis, insulin sensitivity, and glucose utilisation, with preferential energy storage in adipose tissue

. As endocannabinoids are products of dietary fats, modification of dietary intake may modulate their levels, with eicosapentaenoic and docosahexaenoic acid based endocannabinoids being able to displace arachidonic acid from cell membranes, reducing AEA and 2-AG production. Similarly, oleoyl ethanolamide, a product of oleic acid, induces satiety, decreases circulating fatty acid concentrations, increases the capacity for β -oxidation, and is capable of inhibiting the action of AEA and 2-AG in adipose tissue. Thus, understanding how dietary fats alter endocannabinoid system activity is a pertinent area of research due to public health messages promoting a shift towards plant-derived fats, which are rich sources of AEA and 2-AG precursor fatty acids, possibly encouraging excessive energy intake and weight gain.

 

Select item 230882596.

N-Acyl amines of docosahexaenoic acid and other n-3 polyunsatured fatty acids - from fishy endocannabinoids to potential leads.

Meijerink J, Balvers M, Witkamp R.

Br J Pharmacol. 2013 Jun;169(4):772-83. doi: 10.1111/bph.12030. Review.

N-3 Long-chain polyunsaturated fatty acids (n-3 LC-PUFAs), in particular α-linolenic acid (18:3n-3), eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) are receiving much attention because of their presumed beneficial health effects. To explain these, a variety of mechanisms have been proposed, but their interactions with the endocannabinoid system have received relatively little attention so far. However, it has already been shown some time ago that consumption of n-3 LC-PUFAs not only affects the synthesis of prototypic endocannabinoids like anandamide but also stimulates the formation of specific n-3 LC-PUFA-derived conjugates with ethanolamine, dopamine, serotonin or other amines. Some of these fatty amides show overlapping biological activities with those of typical endocannabinoids, whereas others possess distinct and sometimes largely unknown receptor affinities and other properties. The ethanolamine and dopamine conjugates of DHA have been the most investigated thus far. These mediators may provide promising new leads to the field of inflammatory and neurological disorders and for other pharmacological applications, including their use as carrier molecules for neurotransmitters to target the brain. Furthermore, combinations of n-3 LC-PUFA-derived fatty acid amides, their precursors and FAAH inhibitors offer possibilities to optimise their effects in health and disease.Free PMC Article

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ANANDAMIDI -järjestelmä käyttää arakidonihappoa C20:4 omega 6 rakennemolekyyliksi.

http://alcalc.oxfordjournals.org/content/40/1/2

Miten kynureeni joutuu antranilaattitielle?

 KYN->ANA
https://en.wikipedia.org/wiki/Kynurenine_pathway

Kynurenine pathway

From Wikipedia, the free encyclopedia

The kynurenine pathway is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide (NAD+) from the degradation of the essential amino acid tryptophan. Disruption in the pathway is associated with certain genetic disorders.

The Kynurenine Pathway

Contents

• 1 Kynurenine Pathway Dysfunction
  • 1.1 Hydroxykynureninuria
  • 1.2 Acquired and inherited enzyme deficiencies
• 2 Research
  • 2.1 Aging
  • 2.2 Kynurenine/Tryptophan ratio
• 3 References

Kynurenine Pathway Dysfunction

Disorders affecting the kynurenine pathway may be primary (of genetic origin) or secondary (due to inflammatory conditions).

Hydroxykynureninuria      (3-HK- tie)

Also known as Kynureninase Deficiency, this extremely rare inherited disorder is caused by the defective enzyme "kynureninase" which leads to a block in the pathway from tryptophan to nicotinic acid. As a result, tryptophan is no longer a source of nicotinic acid and deficiency of the vitamin can develop. Both, B6-responsive and B6-unresponsive forms are known. Patients with this disorder excrete excessive amounts of xanthurenic acid (XA) , kynurenic acid (KYNA) , 3-hydroxykynurenine (3-HK) , and kynurenine (KYN)  after tryptophan (trp)  loading and are said to suffer from tachycardia, irregular breathing, arterial hypotension, cerebellar ataxia, developmental retardation, coma, renal tubular dysfunction, renal or metabolic acidosis, and even death. The only biochemical abnormality noted in affected patients was a massive hyperkynureninuria, seen only during periods of coma or after intravenous protein loading. This disturbance was temporarily corrected by large doses of vitamin B6. The activity of kynureninase in the liver was markedly reduced. The activity was appreciably restored by the addition of pyridoxal phosphate.^{[1][2][3][4][5]}

Acquired and inherited enzyme deficiencies

Downregulation of kynurenine-3-monooxygenase (KMO) can be caused by genetic polymorphisms, cytokines, or both.^[6][7] KMO deficiency leads to an accumulation of kynurenine (KYN)   and to a shift within the tryptophan metabolic pathway towards kynurenic acid (KYNA)  and anthranilic acid (ANA).^{[8][9][10][11][12][13]}
Deficiencies of one or more enzymes on the kynurenine pathway leads to an accumulation of intermediate metabolic products which can cause effects depending on their concentration, function and their inter-relation with other metabolic products.^[14]

 For example, Kynurenine 3-monooxygenase deficiency is associated with disorders of the brain (e.g. schizophrenia, tic disorders) and of the liver.^{[15] [16][17][18][19][20]} The mechanism behind this observation is typically a blockade or bottleneck situation at one or more enzymes on the kynurenine pathway due to the effects of Indolamine-2,3-Dioxygenase (IDO) and Tryptophan-2,3-Dioxygenase (TDO) and/or due to genetic polymorphisms afflicting the particular genes.^{[21][22][23][24]}
Dysfunctional states of distinct steps of the kynurenine pathway (e.g. kynurenine (KYN), kynurenic acid (KYNA), quinolinic acid (QUINA), anthranilic acid (ANA) , 3 -Hydroxykynurenine (3-HK) have been described for a number of disorders, e.g.:^[25]

• HIV dementia
• Tourette Syndrome
• Tic disorders
• Psychiatric disorders (e.g. Schizophrenia, major depression, anxiety disorders)
• Multiple sclerosis
• Huntington's disease
• Encephalopathies
• Lipid metabolism
• Liver fat metabolism
• Systemic lupus erythematosus
• Glutaric aciduria
• Vitamin B6 deficiency
• Eosinophilia-myalgia syndrome

Research

Research into roles of the kynurenine pathway in human physiology is ongoing.

Aging

Scientists are investigating the role of dysregulation of this pathway in aging and neurodegenerative diseases.^[26]

Kynurenine/Tryptophan ratio

Changes in the ratio of kynurenine  (KYN) versus tryptophan (TRP)  are reported for many diseases like e.g. arthritis, HIV/AIDS, neuropsychiatric disorders, cancer and inflammations.^[27][28][29] The ratio of Kynurenin/Tryptophan is also an indicator for the activity of Indolamine-2,3-Dioxygenase (IDO).^[30][31]
 Muistiin 23.5. 2016
vanhaan karttaani harperin kirjaan 1969 on tähän kartaan tullu lisää tuo antranilaatti (ANA) -nuoli. ANA-kertymä on tyypillsitä kroonsiessa migreenissä.
KYN on neuroprotektiivinen molekyyli sinänsä itse.

Tryptofaanista kynureenihappo-risteykseen, entä stten?

http://www.ncbi.nlm.nih.gov/pubmed/27130315

J Headache Pain. 2015 Dec;17(1):47. doi: 10.1186/s10194-016-0638-5. Epub 2016 Apr 29.

Altered kynurenine pathway metabolites in serum of chronic migraine patients.

Curto M^1,2, Lionetto L³, Negro A^4,5, Capi M³, Fazio F⁶, Giamberardino MA⁷, Simmaco M³, Nicoletti F^6,8, Martelletti P^4,5.

Author information

Abstract

BACKGROUND:

Activation of glutamate (Glu) receptors plays a key role in the pathophysiology of migraine. Both NMDA and metabotropic Glu receptors are activated or inhibited by metabolites of the kynurenine pathway, such as kynureninic acid (KYNA), quinolinic acid (QUINA), and xanthurenic acid (XA). In spite of the extensive research carried out on KYNA and other kynurenine metabolites in experimental models of migraine, no studies have ever been carried out in humans. Here, we measured all metabolites of the kynurenine pathway in the serum of patients affected by chronic migraine (CM) and age- and gender-matched healthy controls.

METHODS:

We assessed serum levels of tryptophan (Trp), L-kynurenine (KYN), KYNA, anthranilic acid (ANA), 3-hydroxyanthranilic acid (3-HANA), 3-hydroxykynirenine (3-HK), XA, QUINA, and 5-hydroxyindolacetic acid (5-HIAA) in 119 patients affected by CM (ICHD-3beta criteria) and 84 age-matched healthy subjects. Patients with psychiatric co-morbidities, systemic inflammatory, endocrine or neurological disorders, and mental retardation were excluded. Serum levels of all metabolites were assayed using liquid chromatography/tandem mass spectrometry (LC-MS/MS).

RESULTS:

LC-MS/MS analysis of kynurenine metabolites showed significant reductions in the levels of KYN (-32 %), KYNA (-25 %), 3-HK (-49 %), 3-HANA (-63 %), 5-HIAA (-36 %) and QUINA (-80 %) in the serum of the CM patients, as compared to healthy controls. Conversely, levels of Trp, ANA and XA were significantly increased in CM patients (+5 %, +339 % and +28 %, respectively).

CONCLUSIONS:

These findings suggest that in migraine KYN is unidirectionally metabolized into ANA (anthranilte) at expenses of KYNA and 3-HK. The reduction in the levels of KYNA, which behaves as a competitive antagonist of the glycine site of NMDA receptors, is consistent with the hypothesis that NMDA receptors are overactive in migraine. The increase in XA, a putative activator of Glu2 receptors, may represent a compensatory event aimed at reinforcing endogenous analgesic mechanisms. The large increase in the levels of ANA encourages research aimed at establishing whether ANA has any role in the regulation of nociceptive transmission.

KEYWORDS:

Chronic migraine; Glutamate; Kynurenine; Metabotropic Glu receptors; NMDA receptors; Pain

Ihmisen sepiateriini reduktaasi

https://en.wikipedia.org/wiki/Sepiapterin_reductase
Sepiapterin reductase (SPR)  is an enzyme that in humans is encoded by the SPR gene.^[1][2][3]
Tetrahydrobioteriinin (THB)  synteesissä tarvitava  entsyymi.

Function

Sepiapterin reductase (7,8-dihydrobiopterin:NADP⁺ oxidoreductase; EC 1.1.1.153) catalyzes the NADPH-dependent reduction of various carbonyl substances, including derivatives of pteridines, and belongs to a group of enzymes called aldo-keto reductases
. SPR plays an important role in the biosynthesis of tetrahydrobiopterin (BH4, THB) .
http://www.biopku.org/pdf/ponzone1.pdf

Sepiapterin reductase (SPR) catalyzes the chemical reaction
L-erythro-7,8-dihydrobiopterin + NADP+ sepiapterin + NADPH + H+
Thus, the two substrates of this enzyme are L-erythro-7,8-dihydrobiopterin and NADP⁺, whereas its three products are sepiapterin, NADPH, and a single hydrogen ion (H⁺).
This enzyme belongs to the family of oxidoreductases, to be specific, those acting on the CH-OH group of donor with NAD⁺ or NADP⁺ as acceptor. The systematic name of this enzyme class is 7,8-dihydrobiopterin:NADP⁺ oxidoreductase. This enzyme participates in folate biosynthesis.

Clinical significance

Sepiapterin reductase deficiency belongs to the rare diseases. The clinical phenotype can include progressive psychomotor retardation, altered tone, seizures, choreoathetosis, temperature instability, hypersalivation, microcephaly, and irritability.

Patients with sepiapterin reductase deficiency also manifest dystonia with diurnal variation, oculogyric crises, tremor, hypersomnolence, oculomotor apraxia, and weakness. ^[5]

 Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation and outcome of these diseases their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD).

(Tryptofaaniaineenvaihdunnan harhahtiestä  B6 vitamiinin puutteessa lisääntyvä xanthureenihappo (XA) esiintyy neuronissa ja estää  vahvasti sepiapteriinireduktaasia. tekemästä BH4 kehovitamiinia)  

THB Tetrahydrobiopteriini tärkeä koentsyymi neuronissa

https://en.wikipedia.org/wiki/Sepiapterin_reductase
Sepiapterin reductase (SPR)  is an enzyme that in humans is encoded by the SPR gene.^[1][2][3]
Tetrahydrobioteriinin (THB)  synteesissä tarvitava  entsyymi.

Function

Sepiapterin reductase (7,8-dihydrobiopterin:NADP⁺ oxidoreductase; EC 1.1.1.153) catalyzes the NADPH-dependent reduction of various carbonyl substances, including derivatives of pteridines, and belongs to a group of enzymes called aldo-keto reductases
. SPR plays an important role in the biosynthesis of tetrahydrobiopterin (BH4, THB) .
http://www.biopku.org/pdf/ponzone1.pdf

Sepiapterin reductase (SPR) catalyzes the chemical reaction
L-erythro-7,8-dihydrobiopterin + NADP+ sepiapterin + NADPH + H+
Thus, the two substrates of this enzyme are L-erythro-7,8-dihydrobiopterin and NADP⁺, whereas its three products are sepiapterin, NADPH, and a single hydrogen ion (H⁺).
This enzyme belongs to the family of oxidoreductases, to be specific, those acting on the CH-OH group of donor with NAD⁺ or NADP⁺ as acceptor. The systematic name of this enzyme class is 7,8-dihydrobiopterin:NADP⁺ oxidoreductase. This enzyme participates in folate biosynthesis.
http://www.biopku.org/pdf/ponzone1.pdf

Clinical significance

Sepiapterin reductase deficiency belongs to the rare diseases. The clinical phenotype can include progressive psychomotor retardation, altered tone, seizures, choreoathetosis, temperature instability, hypersalivation, microcephaly, and irritability.

Patients with sepiapterin reductase deficiency also manifest dystonia with diurnal variation, oculogyric crises, tremor, hypersomnolence, oculomotor apraxia, and weakness. ^[5]

 Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation and outcome of these diseases their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD).

(Tryptofaaniaineenvaihdunnan harhahtiestä  B6 vitamiinin puutteessa lisääntyvä xanthureenihappo (XA) esiintyy neuronissa ja estää  vahvasti sepiapteriinireduktaasia. tekemästä BH4 kehovitamiinia)  

Xantureenihappo neuronissa

http://www.ncbi.nlm.nih.gov/pubmed/27167083

Neuroscience. 2016 May 7. pii: S0306-4522(16)30145-2. doi: 10.1016/j.neuroscience.2016.05.006. [Epub ahead of print]

Xanthurenic acid is localized in neurons in the central nervous system.

Roussel G¹, Bessede A², Klein C³, Maitre M⁴, Mensah-Nyagan AG³.

Author information

Abstract

Kynurenine (KYN)  pathway metabolites (KPM) are thought to be synthesized mainly by non-neuronal cells in the mammalian brain. KPM are of particular interest because several studies demonstrated their implication in various disorders of the nervous system.

 Among KPM is xanthurenic acid (XA) deriving from the catabolism of 3-hydroxykynurenine. Based on its chemical structure, XA appears as a close analog of kynurenic acid (KYNA)  which has been extensively investigated and is considered as a potent neuroprotective compound.

Contrary to kynurenine acid, XA has received little attention and its role in the brain remains not elucidated.

We have previously described several characteristics of XA, suggesting its possible involvement in neurotransmission. XA is also proposed as a potential modulator at glutamatergic synapses.

 Here, we used a selective antibody against XA and various neuronal, glial and synaptic markers to show that XA is essentially localized in the soma and dendrites of brain neurons, but is absent from axonal compartments and terminal endings. Our results also reveal that XA-like immunoreactivity is not expressed by glial cells.

 To double-check our findings, we have also used another XA antibody obtained from a commercial source to confirm the neuronal expression of XA. Together, our results suggest that, differently to several other KPM produced by glial cells, XA exhibits a neuronal distribution in the mouse brain.
Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

KEYWORDS:

immunocytochemistry; kynurenine pathway; mouse brain; neuronal localization; xanthurenic acid


Xanthureenihappo  on vahva inhibiittori entsyymille sepiapteriinireduktaasi (SPR), jota tarvitaan  tetrahydrobiopteriinin  de novo synteesiin. 

Neurologisista taudeista: Kansallisia suuntalinjoja MS ja PD tautiin Ruotsissa

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Suomennsota 16.5. 2016 
  Helmikuun 1. pv 2016 Sosiaalihallitus esitti ensimmäiset kansalliset  suuntalinjat multippleista skleroosista (MS)  ja Parkinsonin taudista (PD). Näin suositukst  antavat kroonisesti sairaiden kohdata  enemmän   henkilökuntaa, joilla on hyvä kokemus näistä taudeista sekä edistyneestä terapiasta. 

Näitten tavallisimpien neurologisten tautien (MS ja PD)  hoidossa on tehty suuria edistysaskelia.  Uudet suuntalinjat kohottavat myös  tavoitteiden tasoa ja osaltaan avustavat, että kaikki lähes 40 000 potilasta  saavat tasaveroisesti hoitoa. 

Joka vuosi sairastuu noin 1000 henkilöä MS-tautiin, tavallisesti 20- 45 ikävuosina ja sen katsotaan olevan tavallisin neurologinen toimintakyvyn laskija, koska  se kohtaa nuoria aikuisia.  Ruotsissa potee MS-tautia noin 17 500 henkilöä ja heissä on kaksi kertaa enemmän naisia kuin miehiä. Hoito suuntaa lähinnä vahingollisten tulehdusten estämiseen, osittain mahdollisten  seuraamusten  lieventämisen. On useita  eri tyyppejä tehokkaita lääkkeitä.

• den 1 februari 2016 kl. 09:00 Pressmeddelande
• Socialstyrelsen har tagit fram de första nationella riktlinjerna för MS och Parkinsons sjukdom. Rekommendationerna ger fler kroniskt sjuka patienter tillgång till personal med stor erfarenhet av sjukdomarna och avancerad behandling.
• – Stora framsteg har gjorts i vården vid två av våra vanligaste neurologiska sjukdomar MS och Parkinson. De nya riktlinjerna innebär ytterligare en ambitionshöjning och bidrar till att skapa en mer jämlik vård för nära 40 000 patienter, säger Socialstyrelsens projektledare Per-Henrik Zingmark.
• Varje år insjuknar omkring 1000 personer i MS, vanligtvis i åldrarna 20 till 45 år. MS anses vara den vanligaste orsaken till neurologisk funktionsnedsättning på grund av sjukdom bland unga vuxna. I Sverige har omkring 17 500 personer MS, dubbelt så många kvinnor som män
• Behandlingen är dels inriktad på att förhindra uppkomsten av skadliga inflammationer, dels på att lindra konsekvenserna av olika symtom som kan följa med sjukdomen. Flera typer av effektiva läkemedel finns att tillgå.

Seuranta ja toistuvat kontrollit (Uppföljning och återkommande kontroller) 

 Jotta havaittaisiin MS  varhemmin tai tunnistettaisiin suuressa  MS-riskissä olevat  Sosiaalihallitus suosittelee neurologista asiantuntija-arviota, jos   MRI tutkimus antaa syytä epäilyyn. 

 Täten voidaan asettaa aiemmin  alkuun taudin kehittymistä  jarruttava lääkitys,  mikä voi vähentää tulevien toiminnanalenemisten astetta, sanoo neurologian profeesori Jan Lycke, MS-ohjelinjatyössä asiantuntija- puheenjohtaja.

Perusta sekä MS - että Parkinsonin taudin  hyvään hoitoon ja hoivaan on tautien kehittymisen ja aloitettujen hoitojenhoidon tehon keskeytymätön  seuranta.  Keskeistä suosituksissa  on  sen takia kontrollitoistot asiaan hyvin perehtyneellä lääkärillä  MS-taudissa vähintäin kerran vuodessa  ja Parkinsonin taudissa  vähäintäin kaksi kertaa vuodessa. 

• För att upptäcka MS tidigare, eller identifiera personer som löper hög risk att få MS, rekommenderar Socialstyrelsen en neurologisk expertbedömning om magnetröntgenkameraundersökningen ger anledning till misstanke. 

• – På så sätt kan läkemedel för att bromsa sjukdomens utveckling sättas in tidigare, vilket kan minska graden av framtida funktionsnedsättning, säger Jan Lycke, professor i neurologi och faktaordförande för MS i riktlinjearbetet.

• Grunden för en god vård och omsorg vid både MS och Parkinson är kontinuerlig uppföljning av sjukdomarnas utveckling och effekten av de behandlingar som har satts in. Centrala rekommendationer är därför återkommande kontroller med undersökning hos en läkare med betydande erfarenhet av sjukdomen minst en gång om året vid MS, och minst två gånger om året vid Parkinson.

Useamman tulee saada  edistyksellistä  Parkinson-hoitoa.  (Fler bör få avancerad Parkinsonbehandling)

 Ruotsissa on noin  18 000  Parkinsonin tautia potevaa. tyypillinen sairastumis-ikä on 65 vuotta.  Sairastuneissa on jonkin verran enemmän miehiä kuin naisia. taudille tyypillistä on liikkumisen vähentyminen.  

Kaikkein tehokkain varhaisen Parkinsonin-taudin aikana on dopamiiniin kohdistuva lääkeaine levo-dopa. Pitkälle edenneessä vaiheessa voi liikkuvuutta leimata  nopeat heittelyt  yliliikehdinnän   ja aivan liikkumiskyvyttömyyden välillä.  Kun vaikeudet ovat suuria, on kolme edistynyttä Parkinson-hoitoa, joista voi saada selvää  lievitystä. 

- On todennäköistä että useampi voisi saada hyötyä edistyneestä Parkinson-hoidosta ja sen käyttö  valtion  alueella  vaihtelee.Valinnan täsmällisyyden lisäämiseksi neurologian professori Per Odin, ( Parkinsonin taudin hoidon   suuntalinjaprojektin asiantuntija-puheenjohtaja) esittää työryhmän suositukset hoitokonferensseista ennen päätöksen tekoa ja konferensseissa myötävaikuttajina tulee olla niitä, joilla on tietoa ja kokemusta sekä erilaisista pumppumenetelmistä että  aivon syväelektrodistimuloinnista.

• Omkring 18 000 personer i landet har Parkinsons sjukdom. Den typiska åldern då sjukdomen uppträder är 65 år. Något fler män drabbas. Parkinson kännetecknas bland annat av minskad rörlighet.
• Den mest effektiva behandlingen under tidig Parkinson är det dopamininriktade läkemedlet levodopa. I framskridet skede kan rörligheten präglas av snabba kast mellan överrörlighet och oförmåga att röra sig alls. Vid stora svårigheter finns tre avancerade Parkinsonbehandlingar som kan ge markant lindring.
• – Sannolikt skulle fler ha nytta av avancerad Parkinsonbehandling, och användningen varierar i landet. För att öka precisionen i valet av behandling rekommenderar vi behandlingskonferenser inför beslutet, där personer medverkar som har kunskap och erfarenhet av både olika pumpmetoder och djupelektrodstimulering av hjärnan, säger Per Odin, professor i neurologi och faktaordförande för Parkinson i riktlinjearbetet.

Yhteistyötä elämänlaadun säilyttämiseksi (Samarbete för att behålla livskvalitet)

 Sekä MS että Parkinsonin tauti voivat vaikuttaa  monella tapaa elämään ja esimerkiksi vaikeuttaa työntekoa ja vapaa-ajan harrastuksia.  Tämän takia  on tärkeää, että monen spesifisen  alueen tiimi suunnittelee potilaan tarpeista käsin tavoitteet ja toimenpiteet.

 Kun useaa  ammattia edustavat  henkilöt tekevät yhteistyötä yhden potilaan suhteen,  voidaan luoda parempia mahdollisuuksia elämänlaadun ja aktiivisen osallistumiskyvyn säilyttämiseksi, sanoo Eva Månsson Lexell, medisiinisen tieteen tohtori ja jälleenkuntoutuksen suuntalinjatyön vastuunkantaja.

 Sosiaalihallitus suosittelee, että tiimiin kuuluu  lääkärin ja sairaanhoitajan lisäksi vähintäin kahden muun ammattialan edustajia, fysioterapeutti, työterapeutti, kuraattori, psykologi, logopedi, dietisti, uroterapeutti tai jonkin  toisen  alueen erikoislääkäri.

Lue myös  Sosiaalihallituksen herätteellinen artikkeli Dagens Medicin-lehdessä: "Nyt kohotamme MS- taudin ja Parkinsonin taudin hoidon tavoitetasoa"..

• Både MS och Parkinson kan påverka livet på många olika sätt och exempelvis medföra svårigheter att arbeta och utöva fritidsintressen. Därför är ett multidiciplinärt omhändertagande där team planerar mål och åtgärder utifrån patientens behov viktigt.

• – När personer med olika yrken samarbetar kring en patient kan det skapa bättre möjligheter att behålla livskvaliteten och förmågan att vara aktiv och delaktig, säger Eva Månsson Lexell, doktor i medicinsk vetenskap och ansvarig för frågor om rehabilitering i riktlinjearbetet.
 

• Socialstyrelsen rekommenderar att det i teamen förutom läkare och sjuksköterska finns minst två andra professioner representerade; fysioterapeut, arbetsterapeut, kurator, psykolog, logoped, dietist, uroterapeut eller annan specialistläkare.

Läs också Socialstyrelsens debattartikel i Dagens Medicin -”Nu höjer vi ambitionen för vård vid MS och Parkinson”.

Tosiasioita (Fakta)

 Multippeli skleroosi-taudissa imuunijärjestelmä hyökkää keskushermostojärjestelmässä ( aivossa ja selkäytimessä)  olevia alueita  ja  omaa hermokudosta kohtaan   aiheuttaen toistuvia tulehduksia.  Tästä seuraa havaittavia neurologisten funktioitten häiriöitä. Mikä kohta kehosta sitten ilmentää tautia riippuu siitä, missä kohdassa  keskushermostoa menossa oleva tulehdus milloinkin sijaitsee.

• Vid Multipel Skleros angriper immunsystemet den egna nervvävnaden och områden i hjärnan och ryggmärgen, det centrala nervsystemet, drabbas av återkommande inflammationer. Detta orsakar störningar av neurologiska funktioner. Vilken del av kroppen som berörs beror på var den aktuella inflammationen sitter.

 Parkinsonin tauti tuhoaa niitä hermosoluja, jotka tekevät  dopamiinimolekyyliä, signaaliainetta, joka  vaikuttaa eri aivosolujen välistä signalointia. Tauti johtaa siihen, että  aivojen (tahdon)  ohjaama kehon liikkeitten hallinta vaikeutuu.  Parkinsonin taudille on tyypillistä muun muassa vähentynyt liikkuvuus, lihasjäykkyys, vapinat ja tasapainohäiriöt.  Mutta  esiintyy myös iso joukko muita oireita, jotka eivät koske liikkumista

• Parkinsons sjukdom förstör nervceller som tillverkar dopamin, en signalsubstans som skickar signaler mellan hjärncellerna. Detta leder till att hjärnan får svårare att styra kroppens rörelser. Parkinson kännetecknas bland annat av minskad rörlighet, muskelstelhet, skakningar och balanssvårigheter, men det finns även ett stort antal andra icke-motoriska symtom.