Chemicals Possessing a Neurotrophin-Like Activity on Dopaminergic Neurons in Primary Culture

Fanny Schmidt,Rita Raisman-Vozari,Xavier Franck,Pierre Champy,Bruno Figadère,Blandine Séon-Méniel,Howard E Gendelman

doi:10.1371/journal.pone.0006215

Abstract

BackgroundNeurotrophic 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.Principal FindingsA 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.ConclusionCell-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.

Highlights

Loss of dopaminergic (DA) neurons within the substantia nigra pars compacta (SNpc) is a consistent feature of Parkinson’s disease (PD)
The symptoms of PD can be improved by drugs that replace neurotransmitters, but these treatments are unable to slow down the disease progression and often induce undesirable side effects [5]
Several neurotrophins implicated in the development and maintenance of different neuronal populations have been shown to provide protection against cell death in in vitro and in vivo models of PD through diverse signaling pathways including activation of phosphatidylinositol–3-kinase (PI3-kinase)/Akt, ras-dependent mitogen-activated protein kinase (MAPK), and phospholipase C (PLC) [7]

Summary

Introduction

Loss of dopaminergic (DA) neurons within the substantia nigra pars compacta (SNpc) is a consistent feature of Parkinson’s disease (PD). Despite the therapeutic potential of GDNF, clinical trials have been disappointing [9], probably due to inherent drawbacks associated with the use of polypeptides applied as drugs [10], including pleiotropic effects, short half-life and inability to cross the bloodbrain barrier (BBB), imposing repeated transcranial injections, with dramatic side effects. To obviate these issues, substantial efforts have been made to design non-peptidic small molecules with neurotrophin-like activities. 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

Methods

Results

Conclusion