ParkinsonCanadaV1, Main, Exploration, bibRecord, 001D31

Cystamine metabolism and brain transport properties: clinical implications for neurodegenerative diseases

Identifieur interne : 001D31 ( Main/Exploration ); précédent : 001D30; suivant : 001D32

Cystamine metabolism and brain transport properties: clinical implications for neurodegenerative diseases

Auteurs : Mélanie Bousquet [Canada] ; Claire Gibrat [Canada] ; Mélissa Ouellet [Canada] ; Claude Rouillard [Canada] ; Frédéric Calon [Canada] ; Francesca Cicchetti [Canada]

Source :

Journal of neurochemistry [ 0022-3042 ] ; 2010.

RBID : Pascal:10-0434654

Descripteurs français

Pascal (Inist)
- Métabolisme, Encéphale, Transport biologique, Test clinique, Métabolite, Taurine, Cystéine, Phosphate, Maladie de Parkinson, Seuil détection, Détection seuil, Barrière hématoencéphalique, Perfusion, Souris.
Wicri :
- topic : Phosphate.

English descriptors

KwdEn :
- Biological transport, Blood brain barrier, Clinical test, Cysteine, Detection threshold, Encephalon, Metabolism, Metabolite, Mouse, Parkinson disease, Perfusion, Phosphates, Taurine, Threshold detection.

Abstract

Cystamine has shown significant neuroprotective properties in preclinical studies of Parkinson's disease (PD) and Hunting-ton's disease (HD). Cysteamine, its FDA-approved reduced form, is scheduled to be tested for clinical efficacy in HD patients. Here, we studied the key cystamine metabolites, namely cysteamine, hypotaurine and taurine, as well as cysteine, in order to identify which one is more distinctively responsible for the neuroprotective action of cystamine. After a single administration of cystamine (10, 50 or 200 mg/kg), naive mice were perfused with phosphate-buffered saline (PBS) at 1, 3, 12, 24 or 48 h post-injection and brain and plasma samples were analyzed by two distinct HPLC methods. Although plasma levels remained under the detection threshold, significant increases in cysteamine brain levels were detected with the 50 and 200 mg/kg doses in mice perfused 1 and 3 h following cystamine injection. To further assess cysteamine as the candidate molecule for pre-clinical and clinical trials in PD, we evaluated its capacity to cross the blood brain barrier. Using an in situ cerebral perfusion technique, we determined that the brain transport coefficient (Clup) of cysteamine (259 μM) was 0.15 ± 0.02 μL/g/s and was increased up to 0.34 ± 0.07 μL/g/s when co-perfused in the presence of cysteine. Taken together, these results strongly suggest that cysteamine is the neuroactive metabolite of cystamine and may further support its therapeutic use in neurodegenerative diseases, particularly in HD and PD.

Affiliations:

Canada

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Le document en format XML

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<front><div type="abstract" xml:lang="en">Cystamine has shown significant neuroprotective properties in preclinical studies of Parkinson's disease (PD) and Hunting-ton's disease (HD). Cysteamine, its FDA-approved reduced form, is scheduled to be tested for clinical efficacy in HD patients. Here, we studied the key cystamine metabolites, namely cysteamine, hypotaurine and taurine, as well as cysteine, in order to identify which one is more distinctively responsible for the neuroprotective action of cystamine. After a single administration of cystamine (10, 50 or 200 mg/kg), naive mice were perfused with phosphate-buffered saline (PBS) at 1, 3, 12, 24 or 48 h post-injection and brain and plasma samples were analyzed by two distinct HPLC methods. Although plasma levels remained under the detection threshold, significant increases in cysteamine brain levels were detected with the 50 and 200 mg/kg doses in mice perfused 1 and 3 h following cystamine injection. To further assess cysteamine as the candidate molecule for pre-clinical and clinical trials in PD, we evaluated its capacity to cross the blood brain barrier. Using an in situ cerebral perfusion technique, we determined that the brain transport coefficient (Clup) of cysteamine (259 μM) was 0.15 ± 0.02 μL/g/s and was increased up to 0.34 ± 0.07 μL/g/s when co-perfused in the presence of cysteine. Taken together, these results strongly suggest that cysteamine is the neuroactive metabolite of cystamine and may further support its therapeutic use in neurodegenerative diseases, particularly in HD and PD.</div>
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	La maladie de Parkinson au Canada (serveur d'exploration)
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Cystamine metabolism and brain transport properties: clinical implications for neurodegenerative diseases

Cystamine metabolism and brain transport properties: clinical implications for neurodegenerative diseases

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