Chemicals possessing a neurotrophin-like activity on dopaminergic neurons in primary culture.
BACKGROUND
Neurotrophic factors have been shown to possess strong neuroprotective and neurorestaurative properties in Parkinson's disease patients. However the issues to control their delivery into the interest areas of the brain and their surgical administration linked to their unability to cross the blood brain barrier are many drawbacks responsible of undesirable side effects limiting their clinical use. A strategy implying the use of neurotrophic small molecules could provide an interesting alternative avoiding neurotrophin administration and side effects. In an attempt to develop drugs mimicking neurotrophic factors, we have designed and synthesized low molecular weight molecules that exhibit neuroprotective and neuritogenic potential for dopaminergic neurons.


RESULTS
A cell-based screening of an in-house quinoline-derived compound collection led to the characterization of compounds exhibiting both activities in the nanomolar range on mesencephalic dopaminergic neurons in spontaneous or 1-methyl-4-phenylpyridinium (MPP(+))-induced neurodegeneration. This study provides evidence that rescued neurons possess a functional dopamine transporter and underlines the involvement of the extracellular signal-regulated kinase 1/2 signaling pathway in these processes.


CONCLUSIONS
Cell-based screening led to the discovery of a potent neurotrophic compound possessing expected physico-chemical properties for blood brain barrier penetration as a serious candidate for therapeutic use in Parkinson disease.
Schmidt
Fanny
F
Centre National de la Recherche Scientifique, Laboratoire de Pharmacognosie, Université Paris-Sud 11, Faculté de Pharmacie, Châtenay-Malabry, France. fanny.schmidt@gmail.com
Champy
Pierre
P
Séon-Méniel
Blandine
B
Franck
Xavier
X
Raisman-Vozari
Rita
R
Figadère
Bruno
B
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011247:Pregnancy; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D009414:Nerve Growth Factors; D011804:Quinolines; D048049:Extracellular Signal-Regulated MAP Kinases; D004298:Dopamine