ALS- Fokus inhibitoriseen signaalisilmukkaan

http://www.ncbi.nlm.nih.gov/pubmed/241574
Excitatorisen liikaglutamaatin jvoi vähentää dietääristä tietä kun vähentää esim  viljoja( gluteenia), jolloin  glutamiinin tuotto  on endogeenisesti  ehkä suotuisimmillaan ja  synapsi vasta-aineet  vähimmillään. siitä ryhmästä.
Entä  inhibitorisen pulen säätö? Se voi olla  myös  pahasti epätasapainossa.Miten?  Voisiko halvauiksessa olla inhibitorisen  summakomponentin osuutta,, siis latenttia kykyä toimintaan jos inhbotorinen looppi komponentti saadaan hallintaan. Parkinsonismissahan se on havaittu apomorfiinikäsittelyssä.
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Neuropharmacology. 2014 Jul;82:101-7. doi: 10.1016/j.neuropharm.2013.10.003. Epub 2013 Oct 21.

Spinal inhibitory circuits and their role in motor neuron degeneration.

Ramírez-Jarquín UN¹, Lazo-Gómez R¹, Tovar-Y-Romo LB¹, Tapia R².

Author information

Abstract

In the spinal cord neuronal activity is controlled by the balance between excitatory and inhibitory neurotransmission, mediated mainly by the neurotransmitters glutamate and GABA/glycine, respectively. Alterations of this equilibrium have been associated with spinal motor neuron hyperexcitability and degeneration, which can be induced by excitotoxicity or by decreasing inhibitory neurotransmission. Here we review the ventral horn neuronal network and the possible involvement of inhibitory circuits in the mechanisms of degeneration of motor neurons characteristic of amyotrophic lateral sclerosis (ALS). Whereas glutamate mediated excitotoxicity seems to be an important factor, recent experimental and histopathological evidence argue in favor of a decreased activity of the inhibitory circuits controlling motor neuron excitability, mainly the recurrent inhibition exerted by Renshaw cells. A decreased Renshaw cell activity may be caused by cell loss or by a reduction of its inhibitory action secondary to a decreased excitation from cholinergic interneurons. Ultimately, inhibitory failure by either mechanism might lead to motor neuron degeneration, and this suggests inhibitory circuits and Renshaw cells as pharmacologic targets for ALS treatment.
Copyright © 2013 Elsevier Ltd. All rights reserved.

KEYWORDS:

Acetylcholine; Amyotrophic lateral sclerosis; GABA; Glycine; Inhibitory circuits; Renshaw cell; Spinal motor neuron degeneration


(Lisäksi:  Glysiinisignalointi voi joutua epätasapainoon senkin takia, että glysiini ja tauriini ovat molemmat suhteessa toisiinsa ja molemmilla on  siganloivaa tehtävää.  Tauriininsyntesi on vaikeampi kuin glysiinin ja siksi glysiiniä voi esiintyä liikaa, mikä pulestaan  vahvistaa sekundäärisesti glysiinivälitteisyyttä neuroneissa.  Inhibitoriset neuronaaliset  takakytkeytymisjärjestelmat ovat hyvin sofistisia- joskus luin niistä alkoholismia käsittelevästä teesistä, mutta nyt en kyllä tähän löydä sitä teesiä mistään. Siinä oli  teudiinimuodoilla ja glysiinillä  merkityksensä.
Sapessa tämä taas näkyy konjugaattienvaliutumistasossa.
 On arveltu että tauriinia pitäisi  ehkä saada ravinnossa. essentiellisti tai tukena jo ihan  sappihappojen ja  mikrofloran  säätelyyn.
Tässä pitäisi  tarkistaa niiden moelmpien osuus välineuroneissa.
 Keveästä dieetistä ei varmaan ole haittaa, ettei ainakaan  toksista materiaalia kerry neuronitason  aineenvaihduntaan.
Eikös  ole myös  mainittu statiineista jotain säätelevää hyötyä neurodegeneraatiossa.  ehkä juuri  gly-tauriini tasapainon luomisessa.
Atorvastatiinia on kovasti jo tutkittu:http://alsn.mda.org/article/als-research-roundup-september-2007
Se asia mikä siinä lienee  edullinen on Na/tauriinii-kuljetuksen geenin  ylössäätäminen, mutta   se vaikuttaa niin moniin geeneihin muutenkin, että summavaikutus on epäilyttävä ALS:n varsinaiseksi täsmäterapiaksi- sitä se ei ole, ehkä toisilla  päinvastoin.
 Tauriinin  ja GABA:n  aineenvaihdunnan edellytykset ovat:   essenttiellien puolelta mm B12-funktio ja rikkiaineenvaihdunnan tasapaino ( K-vit), sulfaattien  normaali aineenvaihdunta.
  Dietäärisesti ajatellen  essentiellien saanti ja  liian tyhjien kalorien ja varsinkin liian proteiinin ja  sokerin välttö olisi eduksi.  Siis dietääriseti pitäisi limboa, ihankuin vain  ajatellen syöttää neuronia ja aivoa, puhdas vesi  tietysti on tärkeää. Olen tosin sitä mieltä, että pitäisi aallo9ttaa proteiinin saanti jos on häikkää metaboliassa. siis esim joka toinen päivä runsaammin ja  välipäivinä  vihannes, hedelmäpitoista.  Ainakin nivelien  aineenvaihdunnalle sopii sellainen.
Tahdonalainen ajatteleminen on tärkeää, koska se pitää yllä sitä  aivojen metabolista pyörää, jossa  glutamiinihappo muuttuu myrkyttömäksi - passiivinen  hoito tietysti pitää hermoratoja  signaalin alaisina.  Kyse voi olla aikatekijästä, että löydetään jokin  täsmäapu. 
ALS on mielestäni  jollain tavalla ehkä etiologialta sokeassa pisteessä koska toksinen fokus on vaikea  kartoittaa kaikilta vaikuttavilta faktoreilta.   Se on niin  vaikeassa  rajapinnassa kuin vain voi olla. Synapsitiedekin on aika  nuorta.

Entä jos astrosytaalisen D-seriinin synteesin inhibitio puuttuu?

Article

• The EMBO Journal (2007) 26, 4149 - 4159
• doi:10.1038/sj.emboj.7601840

Published online: 30 August 2007

• Subject Categories:

  • Differentiation and Death | Neuroscience

D-Serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosis

Jumpei Sasabe^1,2, Tomohiro Chiba^1,2, Marina Yamada^1,2, Koichi Okamoto³, Ikuo Nishimoto^a, Masaaki Matsuoka^1,2 and Sadakazu Aiso^1,2

1. Department of Anatomy, KEIO University School of Medicine, Shinjuku-ku, Tokyo, Japan
2. Department of Cell Biology and Neuroscience, KEIO University School of Medicine, Shinjuku-ku, Tokyo, Japan
3. Department of Neurology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

Correspondence to:

Masaaki Matsuoka, Department of Cell Biology and Neuroscience/Anatomy, KEIO University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Tel.: +81 3 5363 8427; Fax: +81 3 5363 8428; E-mail: sakimatu@sc.itc.keio.ac.jp

^aTo our regret, he passed away on 17 October 2003.

Received 8 March 2007; Accepted 30 July 2007

Abstract

Excitotoxicity has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). More recently, glial involvement has been shown to be essential for ALS-related motoneuronal death. Here, we identified an N-methyl-D-aspartate (NMDA) receptor co-agonist, D-serine (D-Ser), as a glia-derived enhancer of glutamate (Glu) toxicity to ALS motoneurons. Cell death assay indicated that primary spinal cord neurons from ALS mice were more vulnerable to NMDA toxicity than those from control mice, in a D-Ser-dependent manner. Levels of D-Ser and its producing enzyme, serine racemase, in spinal cords of ALS mice were progressively elevated, dominantly in glia, with disease progression. In vitro, expression of serine racemase was induced not only by an extracellular pro-inflammatory factor, but also by transiently expressed G93A-superoxide dismutase1 in microglial cells. Furthermore, increases of D-Ser levels were also observed in spinal cords of both familial and sporadic ALS patients. Collectively, Glu toxicity enhanced by D-Ser overproduced in glia is proposed as a novel mechanism underlying ALS motoneuronal death, and this mechanism may be regarded as a potential therapeutic target for ALS.

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• Keywords:

  • ALS,
  • D-serine,
  • excitotoxicity,
  • glia,
  • NMDA

Introduction

Top of page

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, pathologically characterized by massive selective motoneuronal loss, inclusion bodies in remaining neurons and astrocytes, and gliosis around dying neurons in the ventral horns of spinal cords (Bruijn et al, 2004). Approximately 90% of ALS cases are sporadic, while 10% are inherited. About 20% of inherited cases have mutations in the gene encoding superoxide dismutase 1 (SOD1) (Rosen et al, 1993). Although the discovery of mutations in SOD1 has resulted in a considerable number of studies, the mechanism of selective motoneuronal death is still unclear. Among several proposed hypotheses on the pathogenesis of ALS, excitotoxicity mediated by ionotropic glutamate (Glu) receptors has been regarded as a principal cause of motoneuronal death (Bruijn et al, 2004; Van Damme et al, 2005). This notion was supported by the fact that a three-fold increase in the Glu level was detected in the cerebrospinal fluid of patients with ALS due to loss of Glu uptake by astrocytes (Rothstein et al, 1990, 1995) and that an inhibitor of Glu release, Riluzole, is the sole drug clinically effective against ALS. The former observation was confirmed by a cohort study indicating that the Glu level increased in the cerebrospinal fluid of 40% of sporadic ALS patients (Spreux-Varoquaux et al, 2002). Together with the finding that the loss of Glu transporters was detected in ALS model rats with a SOD1 mutant (Howland et al, 2002), it seems most likely that Glu toxicity has some important roles in the pathogenesis of both inherited and sporadic ALS. However, the detailed mechanisms underlying Glu toxicity on motoneurons still remain elusive.

There are three classes of ionotropic Glu receptors: N-methyl-D-aspartate receptors (NMDARs), -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and kainate receptors (Van Damme et al, 2005). The AMPA receptors have been assumed to play a central role in ALS-relevant Glu toxicity, because a defect in the editing of mRNA encoding GluR2, which resulted in increased Ca²⁺ influx, was found in patients with sporadic ALS (Kawahara et al, 2004). At the same time, the NMDARs have been shown in vitro to be as important as the AMPA receptors for Glu toxicity in neurons (Prehn et al, 1995). A more recent finding shed light on the relevance of the NMDARs in ALS pathogenesis: an NMDAR antagonist, memantine, has been reported to prolong survival in ALS model mice (Wang and Zhang, 2005). Activation of the NMDARs essentially requires the binding of a co-agonist to its glycine site. D-Serine (D-Ser) is a physiologically dominant excitotoxic co-agonist to the glycine site compared with glycine (Shleper et al, 2005; Panatier et al, 2006), and is endogenously converted from L-serine (L-Ser) by serine racemase (SRR). SRR is mainly expressed in glia (Wolosker et al, 1999a) and upregulated by glial activation (Wu and Barger, 2004; Wu et al, 2004). Considering that insults generated from activated glia are assumed to be essential for the induction of motoneuronal death (Pramatarova et al, 2001; Clement et al, 2003; Boillee et al, 2006), we hypothesized that in ALS, the excessive amounts of D-Ser generated from the activated glia may contribute to the development of Glu toxicity. In the present study, we demonstrate evidence supporting this hypothesis.

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