A non-peptidyl neurotrophic small molecule for midbrain dopaminergic neurons.
Abstract A small organic molecule (CUR-162590) that selectively enhances survival of midbrain dopaminergic neurons was identified by screening small molecule compound libraries. In embryonic midbrain cultures, CUR-162590 increased dopamine uptake and the number of dopaminergic neurons without altering the number of total neurons or astroglia or the uptake of GABA or serotonin. CUR-162590 reduced apoptosis of cultured dopaminergic neurons and protected against death induced by toxins such as MPP(+). Several synthetic analogs of CUR-162590 also had similar bioactivities. CUR-162590 thus represents a new class of neurotrophic small molecules that may have utility in the treatment of Parkinson's disease, which is marked by degeneration of midbrain dopaminergic neurons.
Lin
Leu-Fen H
LF
Curis Inc., 61 Moulton Street, Cambridge, MA 02138, USA. Leu-Fen.Lin@regeneron.com
Rubin
Lee L
LL
Xu
Mei
M
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D051100:Glial Cell Line-Derived Neurotrophic Factor; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects* / Q000196:embryology; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity; D051381:Rats; D012680:Sensitivity and Specificity; D012701:Serotonin / Q000378:metabolism / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C487903:CUR 162590; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D009498:Neurotoxins; D013449:Sulfonamides; D013844:Thiazoles; D005576:Colforsin; D012701:Serotonin; D014446:Tyrosine 3-Monooxygenase; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine