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ALS szakirodalmi összefoglalása

135 éve nem tudjuk az ALS kialakulásának mechanizmusát, de kutatjuk.

Az amiotrófiás laterális szklerózis (ALS)-ről a tudományos szakirodalom fényében, különös tekintettel az apiterápia lehetőségeire.

Több, mint 135 éve ismeretlen a ALS kialakulásának mechanizmusa. Az egyes tüntek, mint az oxidációs károk, az intracelluláris anyagok felszaporodása, a mitochondriumok téves működése, az axoni jelátvitel hibái, növekedési faktotok defficitje, RNA mechanizmus sérülése ... a betegség sebességére ill. a lefolyás súlyosságára hatnak. [Rothstein 2009]

Pasinelli és társai összefoglalója szerint [Pasinelli et. al. 2006] több, mint 50 gén mutációja okoz különféle motoneuron betegséget. Ezenfelül 5 Mendelian gén is motoneuron betegséget okoz, amelyek közül kettő az ALS fenotipust prudukálja.

Az ALS megbetegedések 2 %-át a SOD1 gén mutációja okozza. [Boillée 2006]

Az ALS degradáció egyik oka az oxidáció lehet, azonban a klasszikus antioxidánsokra nem reagál a beteg. További vizsgálat tárgyát képezi azon feltételezés igazolása, miszerint a melatonin adagolása segíthet. Toxicitás szempontjából 300 mg/nap adagolást is tolerált a beteg (2 évig is) [Weishaupt et al. 2006].

Egyes feltételezések szerint [Klinghardt] Mycoplasma pneumoniae baktériumnak is szoros kapcsolata lehet a Szklerózis multiplex, az ALS, Chronic Fatigue and Fibromyalgia betegségekkel.

Az ALS-es betegek agytörzsében és gerincvelőjében neurodegeneratív elváltizások ismerhetőek fel, mint pl. az aktivált mikroglia és asztrociták nagyszámú felhalmozódása és a T sejtek alacsony száma is leginkább a  postcapillary Venuleshez tapadóan.  A biokémiai változások közé tartozik a számos molekulához kapcsolódó szabad-gyök támadás és olyan proteinek jelenléte, amelyek a komplement-kaszkád aktiválásával hozhatóak kapcsolatba továbbá megjelenik a ciklooxigenáz enzim 2 (COX-2) jelentős felülszabályozása is. A gyulladáscsökkentő szereknek fontos szerepe lehet az ALS kezelésében. Ugyanakkor a COX-2 enzim szabályozása is fontos kutatási terület lehet az ALS-es betegek gerincvelőben tapasztalható megnövekedett COX-2 szintje miatt. [McGeer et.al. 2002]

A méhméreg fő komponense a melittin, amely egy 26 aminosavból álló protein és a tradicionális kínai orvoslásban rákos sejtek poliferizácója ellen használják. Közismert a gyulladáscsökkentő és anti-arthritikus tulajdonsága is.
Melittin kezelés elégséges volt, hogy a motoros aktivitást növelje, ..., a peptid gátolta a kiterjedt idegigyulladást, amely az idegsejtek elhalásáért felelős. Továbbá azt találták, hogy a α-synuclein-t szabályozta a melittinkezelés. ... Ezen felfedezések az sejtetik, hogy potencionális funkcionális kapcsolat létezik a melittin és az ideggyulladás gátlása között az ALS állati modelljeiben, amley fontos implikációja a Parkinson és az ALS betegek kezelésének.
A 0,1 ug/g fiziológiás sóoldatban higítva bőr alá beadva képezte melittin az injekció alapját. A kezeléseknél Zusanli (ST36) akupunktúrális pontot használták, amely ismert gyulladáscsökkentő pont.
A szerzők ebben a tanulmányban még nem találtak szignifikáns különbséget a melittinnel akupunktúrális pontokon kezelt és a csak akupunktúrás pontokon kezelt állatok között (11-11 állat). Későbbi cikkükben már 18 %-os élethosszabbodásról számoltak be. (Akupunktúra kontroll akupunktúra+méhméreg. Érdekes lett volna a akupunktúra és nem akupunktúra közötti összehasonlítás is.) [Yang et al. 2011]

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Kiválasztott kivonatok


Don W. Cleveland & Jeffrey D. Rothstein(2001): From charcot to lou gehrig: deciphering selective motor neuron death in als. Nature Reviews Neuroscience 2, 806-819 (November 2001) | doi:10.1038/35097565

[http://www.nature.com/nrn/journal/v2/n11/full/nrn1101-806a.html]

Since its description by Charcot more than 130 years ago, the mechanism underlying the characteristic selective degeneration and death of motor neurons in amyotrophic lateral sclerosis has remained a mystery. Modern genetics has now identified mutations in two genes — SOD1 and ALS2 — as primary causes of the disease, and has implicated others as potential contributors. Insights into these abnormalities, together with errors in the handling of synaptic glutamate and the potential excitotoxic response that this alteration provokes, have provided leads for the development of new strategies to identify an as yet elusive remedy for this progressive, fatal disorder.
***
McGeer PL, McGeer EG.(2002): Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve. 2002 Oct;26(4):459-70.
Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, 2255 Westbrook Mall,

Vancouver, British Columbia V6T 1Z3, Canada.

Neuroinflammation is a characteristic of pathologically affected tissue in several neurodegenerative disorders. These changes can be observed in the brainstem and spinal cord of amyotrophic lateral sclerosis (ALS) cases and in mouse models of the disease. They include an accumulation of large numbers of activated microglia and astrocytes, as well as small numbers of T cells, mostly adhering to postcapillary venules. Accompanying biochemical alterations include the appearance of numerous molecules characteristic of free-radical attack, the occurrence of proteins associated with activation of the complement cascade, and a sharp upregulation of the enzyme cyclooxygenase 2 (COX-2). Anti-inflammatory agents may have a role to play in treating ALS. COX-2 is a particularly attractive target because of its marked increase in ALS spinal cord.
***
Pasinelli, Piera & Robert H. Brown(2006): Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nature Reviews Neuroscience 7, 710-723 (September 2006) | doi:10.1038/nrn1971

Amyotrophic lateral sclerosis (ALS) is a paralytic disorder caused by motor neuron degeneration. Mutations in more than 50 human genes cause diverse types of motor neuron pathology. Moreover, defects in five Mendelian genes lead to motor neuron  disease, with two mutations reproducing the ALS phenotype. Analyses of these genetic effects have generated new insights into the diverse molecular pathways involved in ALS pathogenesis. Here, we present an overview of the mechanisms for motor neuron death and of the role of non-neuronal cells in ALS.

***

YANG, Eun Jin Yang,1 Seon Hwy Kim,1 Sun Choel Yang,2 Sang Min Lee,1 and Sun-Mi Choi1 (2011): Melittin restores proteasome function in an animal model of ALS. J Neuroinflammation. 2011; 8: 69. Published online 2011 June 20. doi:  10.1186/1742-2094-8-69

PMCID: PMC3142224

1Department of Standard Research, Korea Institute of Oriental Medicine, 483 Expo-ro, Yuseong-gu, Daejeon, 305-811, Korea
2Department of Instrument Development, Korea Basic Science Institute, 113, Gwahag-ro, Yuseong-gu, Daejeon, 305-333, Korea

Amyotrophic lateral sclerosis (ALS) is a paralyzing disorder characterized by the progressive degeneration and death of motor neurons and occurs both as a sporadic and familial disease. Mutant SOD1 (mtSOD1) in motor neurons induces vulnerability to the disease through protein misfolding, mitochondrial dysfunction, oxidative damage, cytoskeletal abnormalities, defective axonal transport- and growth factor signaling, excitotoxicity, and neuro-inflammation.
Melittin is a 26 amino acid protein and is one of the components of bee venom which is used in traditional Chinese medicine to inhibit of cancer cell proliferation and is known to have anti-inflammatory and anti-arthritic effects.
The purpose of the present study was to determine if melittin could suppress motor neuron loss and protein misfolding in the hSOD1G93A mouse, which is commonly used as a model for inherited ALS. Meltittin was injected at the 'ZuSanLi' (ST36) acupuncture point in the hSOD1G93A animal model. Melittin-treated animals showed a decrease in the number of microglia and in the expression level of phospho-p38 in the spinal cord and brainstem. Interestingly, melittin treatment in symptomatic ALS animals improved motor function and reduced the level of neuron death in the spinal cord when compared to the control group.
Furthermore, we found increased of α-synuclein modifications, such as phosphorylation or nitration, in both the brainstem and spinal cord in hSOD1G93A mice. However, melittin treatment reduced α-synuclein misfolding and restored the proteasomal activity in the brainstem and spinal cord of symptomatic hSOD1G93A transgenic mice.
Our research suggests a potential functional link between melittin and the inhibition of neuroinflammation in an ALS animal model.
Melittin treatment was sufficient to improve motor activity compared to age-matched hSOD1G93A mice, and the peptide inhibited the increased neuroinflammation that is responsible for neuronal death. Furthermore, we found that the post-translational modification of α-synuclein is regulated by melittin treatment and that it is mediated by an increase in Heat Shock Protein70 (HSP70) expression and increased proteasome activity. These findings suggest a potential functional link between melittin and the inhibition of neuroinflammation in an animal model of ALS and could have important implications for the treatment of Parkinson's disease (PD) and ALS.
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Weishaupt JH, Bartels C, Pölking E, Dietrich J, Rohde G, Poeggeler B, Mertens N, Sperling S, Bohn M, Hüther G, Schneider A, Bach A, Sirén AL, Hardeland R, Bähr M, Nave KA, Ehrenreich H. (2006): Reduced oxidative damage in ALS by high-dose enteral melatonin treatment. J Pineal Res. 2006 Nov;41(4):313-23. [PubMed]

Department of Neurology, Georg August University, Göttingen, Germany.

Amyotrophic lateral sclerosis (ALS) is the collective term for a fatal motoneuron disease of different etiologies, with oxidative stress as a common molecular denominator of disease progression. Melatonin is an amphiphilic molecule with a unique spectrum of antioxidative effects not conveyed by classical antioxidants. In preparation of a possible future clinical trial, we explored the potential of melatonin as neuroprotective compound and antioxidant in: (1) cultured motoneuronal cells (NSC-34), (2) a genetic mouse model of ALS (SOD1(G93A)-transgenic mice), and (3) a group of 31 patients with sporadic ALS. We found that melatonin attenuates glutamate-induced cell death of cultured motoneurons. In SOD1(G93A)-transgenic mice, high-dose oral melatonin delayed disease progression and extended survival. In a clinical safety study, chronic high-dose (300 mg/day) rectal melatonin was well tolerated during an observation period of up to 2 yr. Importantly, circulating serum protein carbonyls, which provide a surrogate marker for oxidative stress, were elevated in ALS patients, but were normalized to control values by melatonin treatment. This combination of preclinical effectiveness and proven safety in humans suggests that high-dose melatonin is suitable for clinical trials aimed at neuroprotection through antioxidation in ALS.

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Rothstein JD.(2009): Current hypotheses for the underlying biology of amyotrophic lateral sclerosis.Ann Neurol. 2009 Jan;65 Suppl 1:S3-9.[Pubmed]

Department of Neurology and Neuroscience, Brain Science Institute, Johns Hopkins University, Baltimore, MD 21287, USA.

jrothstein@jhmi.edu

The mechanisms involved in selective motor neuron degeneration in amyotrophic lateral sclerosis remain unknown more than 135 years after the disease was first described. Although most cases have no known cause, mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) have been implicated in a fraction of familial cases of the disease. Transgenic mouse models with mutations in the SOD1 gene and other ALS genes develop pathology reminiscent of the disorder, including progressive death of motor neurons, and have provided insight into the pathogenesis of the disease but have consistently failed to predict therapeutic efficacy in humans. However, emerging research has demonstrated that mutations and pathology associated with the TDP-43 gene and protein may be more common than SOD1 mutations in familial and sporadic ALS. Putative mechanisms of toxicity targeting motor neurons include oxidative damage, accumulation of intracellular aggregates, mitochondrial dysfunction, defects in axonal transport, growth factor deficiency, aberrant RNA metabolism, glial cell pathology, and  glutamate excitotoxicity. Convergence of these pathways is likely to mediate disease onset and progression.

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Boillée S, Vande Velde C, Cleveland DW. (2006) ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron. 2006 Oct 5;52(1):39-59.

Ludwig Institute for Cancer Research and Departments of Medicine and Neuroscience, University of California, San Diego, La

Jolla, California 92093, USA. [http://www.ncbi.nlm.nih.gov/pubmed/17015226]


Amyotrophic lateral sclerosis is a late-onset progressive neurodegenerative disease affecting motor neurons. The etiology of most ALS cases remains unknown, but 2% of instances are due to mutations in Cu/Zn superoxide dismutase (SOD1). Since sporadic and familial ALS affects the same neurons with similar pathology, it is hoped that therapies effective in mutant SOD1 models will translate to sporadic ALS. Mutant SOD1 induces non-cell-autonomous motor neuron killing by an unknown gain of toxicity.
Selective vulnerability of motor neurons likely arises from a combination of several mechanisms, including protein misfolding, mitochondrial dysfunction, oxidative damage, defective axonal transport, excitotoxicity, insufficient growth factor signaling, and inflammation. Damage within motor neurons is enhanced by damage incurred by nonneuronal neighboring cells, via an inflammatory response that accelerates disease progression. These findings validate therapeutic approaches aimed at nonneuronal cells.

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Due to the small size and the lack of a cell wall, this microorganism is capable of infecting a great number of cells in any part of the body and live as a parasite on the surface of the cells. Mycoplasmas can become a parasite in plants, insects, animals, and humans, and can trigger different diseases. Once the Mycoplasma becomes a parasite in the cell, morphologic and physiologic changes are developed and it takes on the appearance of various diseases such as pneumonia, urethritis, pyelonephritis, as well as arthritis, lupus and other immune diseases. In cancer, the tumor cells infected by Mycoplasma are more susceptible to spreading which contributes to metastases in different parts of the body. This is also true with Chronic Fatigue Syndrome (especially when the symptoms are severe), Multiple Sclerosis, and ALS (Amyotrophic Lateral Sclerosis). [forrás]

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