Borrell-Pagès M et al. (2006) Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase. J Clin Invest 116: 1410–1424

Tremblay M-È et al. (2006) Neuroprotective effects of cystamine in aged parkinsonian mice. Neurobiol Aging 27: 862–870

Cystamine, a transglutaminase inhibitor, has been demonstrated in two separate studies to have neuroprotective effects in Huntington's disease (HD) and Parkinson's disease. In the first study cysteamine, a reduced form of cystamine, increased levels of the neuronal survival factor brain-derived neurotrophic factor (BDNF) in the brains of HD mice to produce a neuroprotective effect, and also increased serum levels of BDNF in mouse and primate models of HD. In the second study, pretreatment with low doses of cystamine increased levels of four dopaminergic-related markers in aged mice administered the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which causes parkinsonian symptoms.

Borrell-Pagès et al. showed that cystamine and cysteamine promoted secretion of BDNF, the transport of which is weakened in HD but which is crucial for survival of the striatal neurons targeted by this disorder. Cystamine produced this effect by increasing heat-shock DnaJ-containing protein 1b (HSJ1b) transcripts (which stimulate BDNF secretion) and also by inhibiting transglutaminase (which negatively affects BDNF sorting). HSJ1b inhibited polyQ-huntingtin-induced neuronal death in vitro and, in a nematode model of HD, rescued neuronal dysfunction. In addition, cysteamine increased BDNF levels in the brains of HD mice. Data indicated that BDNF levels in blood, which are low in mouse and primate models of HD but were increased by cysteamine injection, could be a useful biomarker of disease progression, and might also be used to test the effects of neuroprotective agents that alter BDNF levels. The effect of cysteamine on BDNF release was transient, but repeat treatments showed continued efficacy, suggesting that cysteamine could be effectively administered repeatedly at short intervals to treat patients with HD.

Building on their previous research into the effects of cystamine in R6/2 transgenic Huntington mice, Cicchetti's group tested different regimens of cystamine in 16-month-old mice with MPTP-induced parkinsonism. A low (10 mg/kg) dose of cystamine beginning 2 days before and continuing during MPTP lesioning reversed the effects of MPTP; there were major differences in cystamine-treated mice compared with MPTP-treated mice, the former having significantly increased tyrosine hydroxylase-positive striatal fiber levels (P <0.01), tyrosine hydroxylase-immunoreactive cell density (P <0.01), substantia nigra Nurr1 messenger RNA levels (P <0.001) and density of substantia nigra cells expressing the dopamine transporter (P <0.001). Cystamine was not as effective at a higher 50 mg/kg dose. The authors acknowledge that more-specific data on the mechanisms of cystamine neuroprotection in MPTP-treated mice are needed, but the results show promise for low-dose cystamine pretreatment in aged parkinsonian mice, and therefore potential in the treatment of Parkinson's disease.