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

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 lM) was 0.15 ± 0.02 lL/g/s and was increased up to 0.34 ± 0.07 lL/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.

Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study

“…Cysteamine, a lysosomotropic drug, has been used for the treatment of cystinosis for more than 25 years 17 and it also crosses the blood-brain barrier 38, 39 . While both cysteamine bitartrate and N-acetylcysteine manifest nucleophilic properties, the efficiency of cleavage of the thioester linkage by cysteamine bitartrate may not be as efficient 40 as previously reported 14 .…”

Investigation of vitamin B6 inadequacy, induced by exposure to the anti-B6 factor 1-amino d-proline, on plasma lipophilic metabolites of rats: a metabolomics approach

“…Cystamine degrades to cysteamine, and they exist in redox equilibrium in cells, which is subsequently converted to hypotaurine and taurine. Cystamine/cysteamine is considered to be a potential treatment of neurodegenerative diseases, including Parkinson's and Huntington's diseases, due to its protective role against the neuron degradation process [33]. Given the crucial role that vitamin B 6 plays in neurotransmitter synthesis [34], plus the fact that 1ADP exposure leads to the development of seizure in rats [18], in vivo cystamine/ cysteamine might have been extensively utilized to protect against neuronal degradation in low pyridoxine status.…”

Antinociceptive effect of intrathecal administration of hypotaurine in rat models of inflammatory and neuropathic pain

“…Several studies have shown that hypotaurine is a strong antioxidant (Aruoma et al 1998;Mehta and Dawson 2001;Bousquet et al 2010). It may be important as an organic osmolyte for proper CNS function, like taurine (Zwingmann and Leibfritz 2005).…”

“…Unlike taurine, the role of hypotaurine in the CNS remains to be fully determined. A large body of evidence indicates that hypotaurine acts as a strong antioxidant (Aruoma et al 1998;Mehta and Dawson 2001;Bousquet et al 2010). A previous report showed that hypotaurine suppressed the spike discharges of Purkinje cells in the guinea pig cerebellum (Okamoto and Sakai 1981).…”