Novel Multifunctional Anti-Alzheimer Drugs with Various CNS Neurotransmitter Targets and Neuroprotective Moieties

Schyf, Cornelis J. Van der; Mandel, Silvia; Geldenhuys, Werner J.; Amit, Tamar; Avramovich, Yael; Zheng, Hailin; Fridkin, Mati; Gal, Sang Wan; Weinreb, Orly; Bar, Orit; Sagi, Yotam; Youdim, Moussa B. H.

doi:10.2174/156720507783018226

Cited by 27 publications

(18 citation statements)

References 87 publications

(144 reference statements)

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“…Much research remains to be done to fully characterize the potential targets and therapeutic approaches to optimize mGluRs as a multipotential intervention. Recent reviews extensively outline critical considerations for the development of mutli-target-directed ligands for treatment of neurodegenerative disorders 10, 93…”

Section: Resultsmentioning

confidence: 99%

Metabotropic Glutamate Receptors as Targets for Multipotential Treatment of Neurological Disorders

2009

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Summary:Glutamate is a major excitatory neurotransmitter in the CNS that is involved in numerous cellular functions, including cell death and survival. Metabotropic glutamate receptors (mGluR) are G-protein coupled receptors that have been classified into three groups on the basis of signal transduction pathways and pharmacological profiles. Group I, II, and III mGluRs are found on cell types within and peripheral to the CNS, including neurons, microglia, astrocytes, oligodendrocytes, T-and B-cell lymphocytes, osteoblasts, hepatocytes, and endothelial cells, among others. These receptors have a number of effects on cells that can influence outcome after trauma, including reducing neuronal and oligodendroglial cell death, inflammation, and endothelial permeability. Thus, mGluRs are a promising multipotential therapeutic approach. Because the pathology of CNS trauma and neurodegeneration is multifactorial (including, for example, oxidative stress, mitochondrial breakdown, and inflammation), therapies that serve to modulate multiple pathophysiological pathways may prove more effective than those directed at a single target. This review examines the multipotential therapeutic utility of mGluR modulation in acute and chronic injury and neurodegeneration.

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Section: Resultsmentioning

confidence: 99%

Metabotropic Glutamate Receptors as Targets for Multipotential Treatment of Neurological Disorders

2009

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“…The development of clinically viable drugs that act as disease-modifying agents rather than providing only symptomatic relief is therefore crucial for the treatment of this devastating disorder. PD is a complex disease with multiple pathogenic factors and thus it would be of great value to develop novel therapeutics that can act on various mechanisms associated with the overall disease process (Van der Schyf et al 2007, Youdim 2010, Youdim 2013). In our continued efforts to discover multi-pronged therapeutics targeting multiple complex factors involved in PD neuropathology, we have developed a series of dopamine D2/D3 agonist compounds that possess potential antioxidant, iron-chelator, and neuroprotective properties (Li et al 2010, Gogoi et al 2011, Johnson et al 2012).…”

Section: Introductionmentioning

confidence: 99%

The high‐affinity D2/D3 agonist D512 protects PC12 cells from 6‐OHDA‐induced apoptotic cell death and rescues dopaminergic neurons in the MPTP mouse model of Parkinson's disease

Shah

Rajagopalan

et al. 2014

Journal of Neurochemistry

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In this study, in vitro and in vivo experiments were carried out with the high-affinity multifunctional D2/D3 agonist D-512 in order to explore its potential neuroprotective effects in models of Parkinson’s disease (PD) and the potential mechanism(s) underlying such properties. Pretreatment with D-512 in vitro was found to rescue rat adrenal phaeochromocytoma PC12 cells from toxicity induced by 6-hydroxydopamine (6-OHDA) administration in a dose-dependent manner. Neuroprotection was found to coincide with reductions in intracellular reactive oxygen species, lipid peroxidation, and DNA damage. In vivo, pretreatment with 0.5 mg/kg D-512 was protective against neurodegenerative phenotypes associated with systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), including losses in striatal dopamine (DA), reductions in numbers of DAergic neurons in the substantia nigra (SN), and locomotor dysfunction. These observations strongly suggest that the multifunctional drug D-512 may constitute a novel viable therapy for PD.

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“…16 The concept of synergistic actions of multiple-functions from a singlemolecule drug has been realized in the use of Sutent with inhibition of various kinases for successfully curing several kinds of cancers. 18 Therefore, the new potential approaches pioneered by Youdim 16,19 have been developed expressly to target multiple sites in the brain with single molecular entities for the treatment of memory and cognition impairment; and single drugs developed with a network approach target two or more of the following factors synergistically for cognitive enhancements: AChE, ␤-amyloid (A␤), tau protein, monoamine oxidase, metal ions, reactive oxygen species (ROS), and neuroprotection. Encouragingly, well-controlled trials of memantine/donepezil dual therapy have shown superior efficacy in moderate to severe AD patient subgroups.…”

Section: Introductionmentioning

confidence: 99%

Novel Anti-Alzheimer's Dimer Bis(7)-Cognitin: Cellular and Molecular Mechanisms of Neuroprotection Through Multiple Targets

Mak

Jiang

et al. 2009

Neurotherapeutics

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Summary:Alzheimer's disease (AD) is a progressive and degenerative brain disorder that has emerged as one of the major public health problems in adults. Unfortunately, its molecular pathology and therapeutic strategies remain elusive. Because there are multiple factors closely indicated in the pathogenesis of AD, multiple drug therapy will be required to address the varied pathological aspects of this disease. Existing pharmacological approaches with one-molecule-one-target are limited in their ability to modify the pathology of AD. Novel therapeutics strategies comprise multifunctional compounds specifically designed to target concurrently on different sites at multifactorial etiopathogenesis of AD, thereby providing greater therapeutic efficacy. Over the past decade, our group has developed several series of dimeric acetylcholinesterase (AChE) inhibitors derived from tacrine and huperzine A, a unique anti-Alzheimer's drug originally discovered from a traditional Chinese medicinal plant. Bis(7)-Cognitin, one of our novel dimers, through inhibition of AChE, N-methyl-D-aspartate receptor, nitric oxide synthase, and amyloid precursor protein/␤-amyloid cascade concurrently, possesses remarkable neuroprotective activities. More importantly, the synergism between these targets might serve as one of the most effective therapeutic strategies to arrest/modify pathological process of AD in addition to improving the cognitive functions for AD.

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Novel Multifunctional Anti-Alzheimer Drugs with Various CNS Neurotransmitter Targets and Neuroprotective Moieties

Cited by 27 publications

References 87 publications

Metabotropic Glutamate Receptors as Targets for Multipotential Treatment of Neurological Disorders

Metabotropic Glutamate Receptors as Targets for Multipotential Treatment of Neurological Disorders

The high‐affinity D2/D3 agonist D512 protects PC12 cells from 6‐OHDA‐induced apoptotic cell death and rescues dopaminergic neurons in the MPTP mouse model of Parkinson's disease

Novel Anti-Alzheimer's Dimer Bis(7)-Cognitin: Cellular and Molecular Mechanisms of Neuroprotection Through Multiple Targets

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