Why should we use multifunctional neuroprotective and neurorestorative drugs for Parkinson's disease?
A(2A) receptor antagonists; adenosine; alzheimers-disease; amyloid precursor protein; antagonist; bcl-2 family-members; designed multiple ligands; double-blind; dual mechanism; iron chelation; ladostigil; M30; mao-b; monoamine-oxidase-b; neurodegenerative diseases; Neurosciences & Neurology; nmda receptor; rasagiline; tea polyphenol (-)-epigallocatechin-3-gallate
Parkinson's disease (PD) is a severe neurodegenerative disorder, with no available drugs able to prevent the neuronal cell loss characteristic in brains of patients suffering from PD. Due to the complex cascade of molecular events involved in the etiology of PD, an innovative approach towards neuroprotection or neurorescue may entail the use of multifunctional pharmaceuticals that target an array of pathological pathways, each of which is believed to contribute to events that ultimately lead to neuronal cell death. Here we discuss examples of novel multifunctional ligands that may have potential as neuroprotective and neurorestorative therapeutics in PD. The compounds discussed originate from synthetic chemistry as well as from natural sources where various moieties, identified in research to possess neuroprotective and neurorestorative properties, have been introduced into the structures of several monomodal drugs, some of which are used in the clinic. (C) 2007 Elsevier B.V. All rights reserved.
Youdim M B H; Geldenhuys W J; Van der Schyf C J
Parkinsonism & Related Disorders
2007
2007
Journal Article
<a href="http://doi.org/10.1016/s1353-8020(08)70017-8" target="_blank" rel="noreferrer noopener">10.1016/s1353-8020(08)70017-8</a>
Low-density lipoprotein receptor-related protein mediates in PC12 cell cultures the inhibition of nerve growth factor-promoted neurite outgrowth by pregnancy zone protein and alpha(2)-macroglobulin
phosphorylation; Signal transduction; receptors; Neurosciences & Neurology; binding; gene-expression; Signal transduction; alpha-2-macroglobulin; alpha-macroglobulin; alpha-macroglobulins; amyloid precursor protein; cytosolic adapter; low-density lipoprotein receptor-related protein; lrp; neurological diseases; rat alpha-1-macroglobulin; trk; Trk regulation
Human pregnancy zone protein (PZP) is a major pregnancy-associated plasma protein closely related to human alpha(2)-macroglobulin (alpha(2)M). It has been demonstrated that monoamine-activated forms of human and rat alpha(2)M and rat alpha(2)M can bind to TrkA and, respectively, inhibit and stimulate NGF-promoted neurite outgrowth, Trk phosphorylation, and intracellular signal transduction in PC12 cells. However, the effect of PZP on neurons is unknown, and the molecular mechanism of neuroinhibition by monoamine-activated alpha(2)M is still unclear. In this report, we show that methylamine-activated PZP (MA-PZP), like MA-alpha(2)M, inhibits in a dose-dependent way the NGF-promoted neurite extension and TrkA phosphorylation in PC12 cells. On the other hand, normal PZP (N-PZP) had little or no effect. In addition, the inhibitory effect of activated alpha-macroglobulins (alphaMs) was reversible upon its removal from the cell culture. In addition, PZP, as well as alpha(2)M, is neuroinhibitory without being directly cytotoxic. It is known that the activated alphaMs bind to the multiligand receptor termed low-density lipoprotein receptor-related protein (LRP) and that the receptor-associated protein (RAP) specifically blocks uptake of all known LRP ligands. To investigate the potential role of LRP in neuromodulation by activated PZP/alpha(2)M, the effect of RAP on the neuroinhibitory activities of these alphaMs was also studied. Data presented here show that RAP blocked the neurite- and Trk- inhibitory activities of both MA-PZP and MA-alpha(2)M whereas RAP itself had no neuromodulatory effect. Hence, we conclude that these data suggest that the LRP receptor and its alphaM ligands may play a role in regulating Trk receptors. (C) 2002 Wiley-Liss, Inc.
Chiabrando G A; Sanchez M C; Skornicka E L; Koo P H
Journal of Neuroscience Research
2002
2002-10
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1002/jnr.10369" target="_blank" rel="noreferrer noopener">10.1002/jnr.10369</a>