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

Authors: Bousquet, MélanieGibrat, ClaireOuellet, MélissaRouillard, ClaudeCalon, FrédéricCicchetti, Francesca
Abstract: Cystamine has shown significant neuroprotective properties in preclinical studies of Parkinson’s disease (PD) and Huntington’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), naïve 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.
Document Type: Article de recherche
Issue Date: 20 June 2010
Open Access Date: Restricted access
Document version: VoR
Permalink: http://hdl.handle.net/20.500.11794/16962
This document was published in: Journal of neurochemistry, Vol. 114 (6), 1651–1658 (2010)
http://dx.doi.org/10.1111/j.1471-4159.2010.06874.x
Wiley
Alternative version: 10.1111/j.1471-4159.2010.06874.x
20569301
Collection:Articles publiés dans des revues avec comité de lecture

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