Leuco- methylthioninium kliinisissä kokeissa

http://www.hsc.nihr.ac.uk/topics/leuco-methylthioninium-for-alzheimers-disease/

D-penicillamiini

http://www.ncbi.nlm.nih.gov/pubmed/15661498 
Koska  D-penisillamiin voi estää kollageenin poikkisidosten muodostusta, sillä voisi olla merkitystä myös kelaattina Alz- taudissa estämässä  hankalia fibrillimuodostumia.  Löytyyhän tästä  artikkelikin: 


Eur J Pharm Biopharm. 2005 Feb;59(2):263-72. Novel D-penicillamine carrying nanoparticles for metal chelation therapy in Alzheimer's and other CNS diseases.

Cui Z, Lockman PR, Atwood CS, Hsu CH, Gupte A, Allen DD, Mumper RJ.

Source

Department of Pharmaceutical Sciences, Center for Pharmaceutical Science and Technology, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.

Abstract

Metal ions accumulate in the brain with aging and in several neurodegenerative diseases. Aside from the copper storage disease, Wilson's disease, recent attention has focused on the accumulation of zinc, copper and iron in the Alzheimer's disease (AD) brain and the accumulation of iron in Parkinson's disease. In particular, the parenchymal deposition of beta-amyloid (Abeta) and its interaction with metal ions has been postulated to play a role in the progression of AD. Thus, the strategy of lowering brain metal ions and targeting the interaction of Abeta peptide and metal ions through the administration of chelators has merit. Our recent finding that nanoparticle delivery systems can cross the blood-brain barrier has led us to investigate whether chelators delivered conjugated to nanoparticles could act to reverse metal ion induced protein precipitation. In the present studies, the Cu (I) chelator D-penicillamine was covalently conjugated to nanoparticles via a disulfide bond or a thioether bond. Nanoparticle-chelator conjugates were stable between pH 6-8 in aqueous suspension if stored at 4 degrees C, and did not aggregate when challenged with salts and serum. Release of D-penicillamine from the nanoparticles was achieved using reducing agents such as dithiothreitol (as a model for glutathione). Nanoparticles treated only under reducing conditions that released the conjugated D-penicillamine were able to effectively resolubilize copper-Abeta (1-42) aggregates. These results indicate that nanoparticles have potential to deliver D-penicillamine to the brain for the prevention of Abeta (1-42) accumulation, as well as to reduce metal ion accumulation in other CNS diseases.

Fysostigmiini

http://en.wikipedia.org/wiki/Physostigmine

Kuten tiedetään kolinerginen järjestelmä toimii eräänlaisena hermo ratojen johtokyvyn perusauraajana   siten että sen  vaihtovirtamainen  nopea asetylkoliini-- asetylkoliiniesteraasi- järjestelmä  normaalina tuottaa ihmisen järkevää kognitiota ja hyvää suorituskykyä.
 Jos  tuo hyvä järkevyys halutaan   täsmällisesti kolaroida pois- (kuitenkaan tappamatta  väestöä kuten tavallisilla hermokaasuilla  on tapana ), ja esim asetylkoliinin tehopitoisuutta vähennetään-   niin  vaikutus on typertävä, ihminen alkaa  töppäillä, hypistellä, nyppiä ja esim.  kiskoa vaatteitaan pois ja on toiminnaltaan deliriöösi, ajantajun kadottanut  eikä erota  vahvoista  hallusinaatioistaan   objektiivisia faktoja. - Sotilaille tuollainen  töppöily olisi  hyvin  "incapasitating", toimintakyvyn tehon äkkikatkaisija.  BZ kemiallinen ase  kuten sen sukuinen Agentti 15 ovat sitä sorttia.Tämän vuoden alkupuolella  huhuttiin että jotain  Agentti 15 kaltaista olisi  Syyriassakin olut, mutta  ilmeisesti  oli kyse pahempia tarkoittaneista  aineista.

Tuollaisen töppöilyyn on fysostigmiini vastalääke  . Sen yksi  nimi onkin "Antilirium " ( anti -delirium)  . Fysotigmiinillä on itsellään   yliannostusoreensa, joten  sen  antorajat ovat kapeat. Fysostigmiini saa kohotettua asetylkoliinin vaikuttavaa pitoisuutta estämällä  asetylkoliinia pilkkoutumasta.

NATO koodin BZ  aineille fysostigmiini on  aivan  spesifinen vasta-aine. sillä BZ aineet   ( asetylkoliinin kompetitiivisina estäjinä   postsynaptisissa ja postjunktionaalisissa muskariinireseptorikohdissa sekä aivoissa)  vähentävat asetylkoliinin efektiivistä  pitoisuutta noissa reseptorikohdissa.

Fysostigmiinin vaikutus asetylkoliiniesteraasiin on reversibeli, ohimenevä, palautuva, ( kun taas  organofosfaatti-hermokaasut  lamaavat  entsyymin pysyvästi). Fysostigmiini vahvistaa asetylkoliinin pitoisuutta sekä nikotiinireseptoreissa että muskariiniresptoreissa,  joten se vaikuttaa  aivoissakin lähimuistin ja    lihasfunktioissa kyseessä olevan hetken  tahdonalaisen toiminnan   paranemaa. 

 Sitaatti  Wikipediasta:

Clinical uses

Physostigmine is used to treat glaucoma, Alzheimer's disease and delayed gastric emptying. It has been shown to improve short term memory (Krus et al. 1968). Recently, it has begun to be used in the treatment of orthostatic hypotension.
Because it is a tertiary amine (and thus does not hydrogen bond, making it more hydrophobic), it can cross the blood–brain barrier, and physostigmine salicylate is used to treat the central nervous system effects of atropine, scopolamine and other anticholinergic drug overdoses.
Physostigmine is the antidote of choice for Datura stramonium poisoning. It is also an antidote for Atropa belladonna poisoning, the same as for atropine.^[4] It has been also used as an antidote for poisoning with GHB as well,^[5] but is poorly effective and often causes additional toxicity, so is not a recommended treatment.^[6]

Bioactivity

Physostigmine functions as an acetylcholinesterase inhibitor. Its mechanism is to prevent the hydrolysis of acetylcholine by acetylcholinesterase at the transmitted sites of acetylcholine. This inhibition enhances the effect of acetylcholine, making it useful for the treatment of cholinergic disorders and myasthenia gravis. More recently, physostigmine has been used to improve the memory of Alzheimer’s patients due to its potent anticholinesterase activity. However, the drug form of physostigmine, physostigmine salicylate, has poor bioavailability.
Physostigmine also has a miotic function, causing pupillary constriction. It is useful in treating mydriasis. Physostigmine also increases outflow of the aqueous humor in the eye, making it useful in the treatment of glaucoma.
Recently, physostigmine has been proposed as antidote for intoxication with gamma hydroxybutyrate (GHB, a potent sedative-hypnotic agent that can cause loss of consciousness, loss of muscle control, and death). Physostigmine may treat GHB by producing a nonspecific state of arousal. However, there is not enough scientific evidence to prove physostigmine properly treats GHB toxicity.
Physostigmine also has other proposed uses: it could reverse undesired side effects of benzodiazepines such as diazepam, alleviating anxiety and tension. Another proposed use of physostigmine is to reverse the effects of barbiturates (any of a group of barbituric acids derived for use as sedatives or hypnotics).

Side effects

An overdose can cause cholinergic syndrome.
Other side effects may include nausea, vomiting, diarrhea, anorexia, dizziness, headache, stomach pain, sweating, dyspepsia and seizures.^[7]

Metyltioniini tutkimuksissa

http://en.wikipedia.org/wiki/Methylthioninium_chloride
Metyltioniini eli metyleenisini on redusoiva ( pelkistävä) aine, jota käytetään terapeuttisesti joissain methemoglobinemiamuodoissa palauttamassa hemoglobiinin Ferrirautaa Hb-Fe+++  ferro-muotoon Hb-Fe++.
 On havaittu että  metyleenisini toimii myös  Tau-proteiinin aggrekaation estäjänä, jolloin  se on kiinnostava aine  mahdollisena  Alzheimerin taudin lääkekirjoon kuuluvana  uutena jäsenenä. Mahdollista edullista vaikutusta sillä lie myös Parkinsonin tautiin. Asiaa tutkitaan.

SITAATTI Wikipediasta:

Methylthioninium chloride

For other uses of the chemical compound methylthioninium chloride, see Methylene blue.

Methylthioninium chloride

Systematic (IUPAC) name
3,7-bis(Dimethylamino)-phenothiazin-5-ium chloride
Clinical data
Pregnancy cat.	?
Legal status	investigational
Routes	oral
Identifiers
CAS number	61-73-4
ATC code	None
PubChem	CID 6099
ChemSpider	5874
ChEBI	CHEBI:6872
ChEMBL	CHEMBL405110
Chemical data
Formula	C16H18ClN3S
Mol. mass	319.85 g/mol
SMILES[show]
InChI[show]
(what is this?)  (verify)

Methylthioninium chloride (INN, or methylene blue, proposed trade name Rember) is an investigational drug being developed by the University of Aberdeen and TauRx Therapeutics that has been shown in early clinical trials to be an inhibitor of Tau protein aggregation.^[1][2] The drug is of potential interest for the treatment of patients with Alzheimer's disease. Its development appears to be related to claim 7 of US 6953794 Inhibition of Tau-Tau Association. TauRx Therapeutics has suggested that the mechanism by which methylene blue might delay or reverse neurodegeneration in Alzheimer's disease is as an inhibitor of Tau protein aggregation. While methylene blue arguably has an effect on Tau aggregation, it also has an effect on mitochondrial function which is likely to play an important role. In vitro studies suggest that methylene blue might be an effective remedy for both Alzheimer's and Parkinson's disease by enhancing key mitochondrial biochemical pathways. It can disinhibit and increase complex IV, whose inhibition correlates with Alzheimer's disease. ^[3]

Contents

• 1 2008 clinical trial results
• 2 Phase III trial
• 3 See also
• 4 References
• 5 External links

...

AlJazeera kertoo eurooppalaisesta aivotutkimuksesta

http://www.aljazeera.com/news/europe/2013/10/scientists-closer-alzheimer-cure-201310109325971124.html
Tässä aivokuvassa näkyy AD taudissa  myelinisoidun valkean aineksen kato. 

Astrosyytin osuudesta aivohalvauksessa ,aivojen plastisuudessa ja neurogeneesissä. Uusi väitöskirja 2013

https://gupea.ub.gu.se/handle/2077/32390

Keywords:	astrocytes reactive gliosis stroke neurotrauma brain plasticity intermediate filaments nanofilaments GFAP vimentin neurogenesis neural stem/progenitor cell single-cell gene expression profiling
Abstract:	Astrocytes, one of the most abundant and heterogeneous cell types in the central nervous system, fulfill many important roles in the healthy and injured brain. This thesis investigates the role of astrocytes in the neurogenic niche and the astrocyte response in stroke and neurotrauma. Using gene expression profiling on a global level as well as on a single-cell level and applying it to disease and transgenic models in vivo and in vitro, we have addressed molecular bases of these responses and molecular signatures of the subpopulations of astrocytes. Following injury, stroke or neurodegenerative diseases, astrocytes upregulate intermediate filament (nanofilament) proteins glial fibrillary acidic protein and vimentin along with many other genes, in a process referred to as reactive gliosis. Results presented in this thesis show that mice with attenuated reactive gliosis developed larger infarct volumes following experimental brain ischemia, compared to controls, implying that reactive gliosis is neuroprotective. Using astrocyte and neurosphere co-cultures, we show that astrocytes inhibit neuronal differentiation through cell-cell contact via the Notch signaling pathway and that intermediate filaments are involved in this process. We found that even a very limited focal trauma triggers a distinct brain plasticity response both in the injured and contralesional hemisphere and that this response at least partly depends on activation of astrocytes. Finally, using single-cell gene expression profiling in vitro and in vivo, we show that the astrocyte population is highly heterogeneous, we attempt to define astrocyte subpopulations in molecular terms, and we demonstrate that astrocyte subpopulations respond differentially to a subtle neurotrauma both in the injured and contralesional hemisphere.

Aivoselkäydinneste (1)

Aineistoa suomennettavaksi:
1)  2007

Pflugers Arch. 2007 Apr;454(1):1-18. Epub 2006 Nov 21.

Water and solute secretion by the choroid plexus.

Praetorius J.

Source

The Water and Salt Research Center & Institute of Anatomy, University of Aarhus, Wilhelm Meyers Allé, 8000 Aarhus, Denmark. jp@ana.au.dk

Abstract

The cerebrospinal fluid (CSF) provides mechanical and chemical protection of the brain and spinal cord. This review focusses on the contribution of the choroid plexus epithelium to the water and salt homeostasis of the CSF, i.e. the secretory processes involved in CSF formation. The choroid plexus epithelium is situated in the ventricular system and is believed to be the major site of CSF production. Numerous studies have identified transport processes involved in this secretion, and recently, the underlying molecular background for some of the mechanisms have emerged. The nascent CSF consists mainly of NaCl and NaHCO(3), and the production rate is strictly coupled to the rate of Na(+) secretion. In contrast to other secreting epithelia, Na(+) is actively pumped across the luminal surface by the Na(+),K(+)-ATPase with possible contributions by other Na(+) transporters, e.g. the luminal Na(+),K(+),2Cl(-) cotransporter. The Cl(-) and HCO(3) (-) ions are likely transported by a luminal cAMP activated inward rectified anion conductance, although the responsible proteins have not been identified. Whereas Cl(-) most likely enters the cells through anion exchange, the functional as well as the molecular basis for the basolateral Na(+) entry are not yet well-defined. Water molecules follow across the epithelium mainly through the water channel, AQP1, driven by the created ionic gradient. In this article, the implications of the recent findings for the current model of CSF secretion are discussed. Finally, the clinical implications and the prospects of future advances in understanding CSF production are briefly outlined.

(2) 2001

Microsc Res Tech. 2001 Jan 1;52(1):49-59.

Mechanisms of CSF secretion by the choroid plexus.

Speake T, Whitwell C, Kajita H, Majid A, Brown PD.

Source

School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.

Abstract

The epithelial cells of the choroid plexus secrete cerebrospinal fluid (CSF), by a process that involves the movement of Na(+), Cl(-) and HCO(3)(-) from the blood to the ventricles of the brain. This creates the osmotic gradient, which drives the secretion of H(2)O. The unidirectional movement of the ions is achieved due to the polarity of the epithelium, i.e., the ion transport proteins in the blood-facing (basolateral) are different to those in the ventricular (apical) membranes. Saito and Wright (1983) proposed a model for secretion by the amphibian choroid plexus, in which secretion was dependent on activity of HCO(3)(-) channels in the apical membrane. The patch clamp method has now been used to study the ion channels expressed in rat choroid plexus. Two potassium channels have been observed that have a role in maintaining the membrane potential of the epithelial cell, and in regulating the transport of K(+) across the epithelium. An inward-rectifying anion channel has also been identified, which is closely related to ClC-2 channels, and has a significant HCO(3)(-) permeability. This channel is expressed in the apical membrane of the epithelium where it may play an important role in CSF secretion. A model of CSF secretion by the mammalian choroid plexus is proposed that accommodates these channels and other data on the expression of transport proteins in the choroid plexus.
Copyright 2001 Wiley-Liss, Inc.

(2) 2009 Kloridin jakautumahäiriö  aivoautonomian alueella.

J Neurol Sci. 2009 Oct 15;285(1-2):146-8. doi: 10.1016/j.jns.2009.06.026. Epub 2009 Jul 12.

Decreased chloride levels of cerebrospinal fluid in patients with amyotrophic lateral sclerosis.

Watanabe S, Kimura T, Suenaga K, Wada S, Tsuda K, Kasama S, Takaoka T, Kajiyama K, Takeda M, Yoshikawa H.

Source

Department of Internal Medicine, Division of Neurology, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan. watasho@hyo-med.ac.jp

Abstract

Recent studies have suggested that the elevation of intracellular chloride contributes to excitotoxic cell death in motor neuron and can be related to the pathogenesis of amyotrophic lateral sclerosis (ALS). We investigated whether chloride levels in cerebrospinal fluid (CSF) and serum were lower in ALS patients than in control patients with other neurological diseases (OND). We also examined the relationship between chloride levels and clinical ALS phenotypes. We measured chloride levels (CSF and serum) in 27 ALS patients and 33 age- and gender-matched OND controls admitted to our hospital for diagnosis. The CSF chloride levels were lower in ALS patients (117 [range 102-130] mmol/L) than in OND controls (126 [range 114-134] mmol/L) . There was no significant difference in CSF chloride levels among the sub-groups of ALS patients classified according to their age, gender, duration of illness, clinical state and type of onset (P>0.05). CSF chloride levels already significantly decreased in ALS patients at the time of diagnosis. We conclude that the elevation of intracellular chloride would cause the reduction of chloride in CSF and be related to the pathogenesis of ALS.

•  (4) 1969 Aivoselkäydinnesteen kloridipitoisuus on korkeampi kuin muissa kehon nesteissä

 Vanha Harper antaa kloridin distribuutiotiedot tähän tapaan, mitä voi pitää viiteellisenä 1960 luvulta. :
Koko veri 250 mg  100 millissä
Plasma tai seerum  365 mg  100 millissä.
Solut 190  mg  100 millissä
Aivoselkäydinneste 440 mg  100 millissä
Lihaskudos 40  mg 100 millissä
Hermokudos 171  mg 100 millissä.

Kloridin tarvpeen määritelyssä varman tuo likvorin  pitoisuus  on merkitsevä seikka.  Tosin siinä on  indiffusible - momentti,   aivo retentoi kloridia tuohon aivotyynyosaan, likvoriin.
likvori taas vaihtuu aika nopeasti useita  kertoja päivässä. Miten siinä  resoptiovaiheessa koridi toimii? Ei ainakaan pyri  suuremmalti erittymään poispäin.