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

被引:39
|
作者
Bousquet, Melanie [1 ,3 ]
Gibrat, Claire [1 ]
Ouellet, Melissa [1 ,3 ]
Rouillard, Claude [1 ,2 ]
Calon, Frederic [1 ,3 ]
Cicchetti, Francesca [1 ,2 ]
机构
[1] CHUL CHUQ, Ctr Rech, Quebec City, PQ G1V 4G2, Canada
[2] Univ Laval, Dept Psychiat & Neurosci, Quebec City, PQ, Canada
[3] Univ Laval, Fac Pharm, Quebec City, PQ, Canada
基金
加拿大自然科学与工程研究理事会; 加拿大健康研究院;
关键词
cysteamine; cysteine; HPLC; hypotaurine; in situ cerebral perfusion; taurine; TRANSGLUTAMINASE INHIBITOR CYSTAMINE; PERFORMANCE LIQUID-CHROMATOGRAPHY; HUNTINGTONS-DISEASE; CYSTEAMINE DIOXYGENASE; AMINO-ACIDS; MOUSE-BRAIN; L-CYSTEINE; TAURINE; BARRIER; MODEL;
D O I
10.1111/j.1471-4159.2010.06874.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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), 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 mu M) was 0.15 +/- 0.02 mu L/g/s and was increased up to 0.34 +/- 0.07 mu L/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.
引用
收藏
页码:1651 / 1658
页数:8
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