Abstract
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. Principal Findings: 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 signalregulated kinase 1/2 signaling pathway in these processes.
Highlights
Loss of dopaminergic (DA) neurons within the substantia nigra pars compacta (SNpc) is a consistent feature of Parkinson’s disease (PD)
Cell-based screening led to the discovery of a potent neurotrophic compound possessing expected physicochemical properties for blood brain barrier penetration as a serious candidate for therapeutic use in Parkinson disease
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]
Summary
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
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