https://www.ncbi.nlm.nih.gov/pubmed/30856117
J Huntingtons Dis. 2019;8(2):129-143. doi: 10.3233/JHD-180312.
J Huntingtons Dis. 2019;8(2):129-143. doi: 10.3233/JHD-180312.
Cysteamine Protects Neurons from Mutant Huntingtin Toxicity.
The
potential benefit of cysteamine for Huntington's disease has been
demonstrated in HD animal models. Cysteamine and its derivate cystamine
were shown to reduce neuropathology and prolong lifespan. Human studies
have demonstrated safety, and suggestive results regarding efficacy.
Despite all the studies available in vivo, there are only few in vitro
studies, and the mechanism of action of cysteamine remains unclear. OBJECTIVE:
The objective of this study is to assess the capacity of cysteamine for neuroprotection against mutant Huntingtin in vitro using cellular models of HD, and to provide initial data regarding mechanism of action. METHODS:
We tested the neuroprotective properties of cysteamine in vitro in our primary neuron and iPSC models of HD. RESULTS:
Cysteamine showed a strong neuroprotective effect (EC50 = 7.1 nM) against mutant Htt-(aa-1-586 82Q) toxicity, in a nuclear condensation cell toxicity assay. Cysteamine also rescued mitochondrial changes induced by mutant Htt. Modulation of the levels of cysteine or glutathione failed to protect neurons, suggesting that cysteamine neuroprotection is not mediated through cysteine metabolism.
Taurine and Hypotaurine, which are metabolites of cysteamine can protect neurons against Htt toxicity, but the inhibition of the enzyme converting cysteamine to hypotaurine does not block either protective activity, suggesting independent protective pathways.
Cysteamine has been suggested to activate BDNF secretion;
however, cysteamine protection was not blocked by BDNF pathway antagonists. CONCLUSIONS:
Cysteamine was strongly neuroprotective with relatively high potency. We demonstrated that the main neuroprotective pathways that have been proposed to be the mechanism of protection by cysteamine can all be blocked and still not prevent the neuroprotective effect. The results suggest the involvement of other yet-to-be-determined neuroprotective pathways. KEYWORDS:
The objective of this study is to assess the capacity of cysteamine for neuroprotection against mutant Huntingtin in vitro using cellular models of HD, and to provide initial data regarding mechanism of action. METHODS:
We tested the neuroprotective properties of cysteamine in vitro in our primary neuron and iPSC models of HD. RESULTS:
Cysteamine showed a strong neuroprotective effect (EC50 = 7.1 nM) against mutant Htt-(aa-1-586 82Q) toxicity, in a nuclear condensation cell toxicity assay. Cysteamine also rescued mitochondrial changes induced by mutant Htt. Modulation of the levels of cysteine or glutathione failed to protect neurons, suggesting that cysteamine neuroprotection is not mediated through cysteine metabolism.
Taurine and Hypotaurine, which are metabolites of cysteamine can protect neurons against Htt toxicity, but the inhibition of the enzyme converting cysteamine to hypotaurine does not block either protective activity, suggesting independent protective pathways.
Cysteamine has been suggested to activate BDNF secretion;
however, cysteamine protection was not blocked by BDNF pathway antagonists. CONCLUSIONS:
Cysteamine was strongly neuroprotective with relatively high potency. We demonstrated that the main neuroprotective pathways that have been proposed to be the mechanism of protection by cysteamine can all be blocked and still not prevent the neuroprotective effect. The results suggest the involvement of other yet-to-be-determined neuroprotective pathways. KEYWORDS:
Huntington’s
disease; cysteamine; huntingtin toxicity; neurodegeneration;
neuroprotection; patient-derived induced pluripotent stem cells; primary
neurons
KYSTEAMINI (merkaptoetyyliamini) on lääkemolekyyli, johdettu koentsyymi A:n degradaatiotiestä. Se menee kehossa lysosomiin, jossa tekee yhdisteen kystiinin kanssa (Cystat) ja tuottaa cysteiini(Cys)-cysteamini-disulfidin ja cysteiiniä (Cys). Täten se saa cystiinipitoisuuden alenemaan ja sitä käytetään kystiinipitoisuuksien alentajana kystinoosissa.
Ett
strålskyddsmedel som oxiderar i luft och bildar cystamin. Det ges
intravenöst eller oralt mot strålsjuka. Bitartratet har använts för oral
behandling av nefropatisk cystinos.
KYSTEAMINI (merkaptoetyyliamini) on lääkemolekyyli, johdettu koentsyymi A:n degradaatiotiestä. Se menee kehossa lysosomiin, jossa tekee yhdisteen kystiinin kanssa (Cystat) ja tuottaa cysteiini(Cys)-cysteamini-disulfidin ja cysteiiniä (Cys). Täten se saa cystiinipitoisuuden alenemaan ja sitä käytetään kystiinipitoisuuksien alentajana kystinoosissa.
Cysteamin Svensk definition
Engelsk definition
A mercaptoethylamine compound that is endogenously derived from the COENZYME A degradative pathway. The fact that cysteamine is readily transported into LYSOSOMES where it reacts with CYSTINE to form cysteine-cysteamine disulfide and CYSTEINE has led to its use in CYSTINE DEPLETING AGENTS for the treatment of CYSTINOSIS.
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