Cystamine prevents MPTP-induced toxicity in young adult mice via the up-regulation of the brain-derived neurotrophic factor.
Preclinical data suggest that cystamine stands as a promising neuroprotective agent against Huntington's and Parkinson's diseases. To decipher the mechanisms of action of cystamine, we investigated the effects of various doses of cystamine (10, 50, and 200mg/kg) on the regulation of the brain-derived neurotrophic factor (BDNF), its receptor tropomyosin-receptor-kinase B (TrkB) and on the heat shock protein 70 (Hsp70) brain mRNA expression in relation to the time after administration. We have determined that the lower cystamine dose is the most efficient to promote putative neuroprotective effects. Indeed, an acute administration of 10mg/kg of cystamine increased the expression of BDNF mRNA in the substantia nigra compacta (SNc), although it did not significantly influence TrkB or Hsp70 mRNA. Higher cystamine doses resulted in the absence of activation of any of these markers or led to non-specific effects. We have also substantiated the neuroprotective effect of a 21-day treatment of 10mg/kg/day of cystamine in young adult mice against MPTP-induced loss of tyrosine hydroxylase-striatal fiber density, nigral dopamine cells and nigral Nurr1 mRNA expression. The neuroprotective action of cystamine in the same animals was associated with an up-regulation of BDNF in the SNc. Taken together, these results strengthen the neuroprotective potential of cystamine in the treatment of Parkinson's disease and point towards the up-regulation of BDNF as an important mechanism of action.
Gibrat
C
C
Centre de Recherche du CHUL (CHUQ), Axe neurosciences, 2705 Boulevard Laurier, Québec, QC, Canada G1V 4G2.
Bousquet
M
M
Saint-Pierre
M
M
Lévesque
D
D
Calon
F
F
Rouillard
C
C
Cicchetti
F
F
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002452:Cell Count; D003538:Cystamine / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D020267:MPTP Poisoning / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
D019208:Brain-Derived Neurotrophic Factor; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; C532621:NuiP protein, mouse; D012333:RNA, Messenger; D014446:Tyrosine 3-Monooxygenase; D020813:Receptor, trkB; D003538:Cystamine