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.