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>
MULTIMODAL DRUGS AND THEIR FUTURE FOR ALZHEIMER'S AND PARKINSON'S DISEASE
designed multiple ligands; gamma agonist; inflammatory response; ischemia-reperfusion injury; mitochondrial-membrane protein; monoamine-oxidase-b; multifunctional drugs; neurodegenerative disorders; pioglitazone; ppar-gamma; receptor antagonist
This chapter discusses the rationale for developing multimodal or multifunctional drugs (also called designed multiple ligands or DMLs) aimed at disease-modifying treatment strategies for the most common neurodegenerative diseases Alzheimer's and Parkinson's disease (AD and PD). Both the prevalence and incidence of AD and PD have seen consistent and dramatic increases, a disconcerting phenomenon which, ironically, has been attributed to extended life expectancy brought about by better health care globally. In spite of these statistics, the development and introduction to the clinic of new therapies proven to prevent or delay the onset of AD and PD have been disappointing. Evidence has accumulated to suggest that the etiopathology of these diseases is extremely complex, with an array of potential drug targets located within a number of deleterious biochemical pathways. Therefore, in these diseases, it is unlikely that the complex pathoetiological cascade leading to disease initiation or progression will be mitigated by any one drug acting on a single pathway or target. The pursuit of novel DMLs may offer far better outcomes. Although certainly not the only, and perhaps not even the best, approach but farthest along the drug development pipeline in the DML paradigm are drugs that combine inhibition of monoamine oxidase with associated etiological targets unique to either AD or PD. These compounds will constitute the major focus of this chapter, which will also explore radically new paradigms that seek to combine cognitive enhancers with proneurogenesis compounds.
Van der Schyf C J; Geldenhuys W J
Monoamine Oxidases and Their Inhibitors
2011
2011
Book Section
<a href="http://doi.org/10.1016/b978-0-12-386467-3.00006-6" target="_blank" rel="noreferrer noopener">10.1016/b978-0-12-386467-3.00006-6</a>
Multifunctional drugs with different CNS targets for neuropsychiatric disorders
alzheimers-disease; alzheimers-disease; amyotrophic lateral sclerosis; Biochemistry & Molecular Biology; depressive illness; designed multiple ligands; hetero-cage compounds; iron chelator; Lewy body disease; monoamine oxidase inhibitor; mptp-induced neurotoxicity; neurodegenerative diseases; Neurosciences & Neurology; nicotinic acetylcholine-receptors; nonsteroidal antiinflammatory drugs; parkinsons-disease; parkinsons-disease; schizophrenia
The multiple disease etiologies that lead to neuropsychiatric disorders, such as Parkinson's and Alzheimer's disease, amyotrophic lateral sclerosis, Huntington disease, schizophrenia, depressive illness and stroke, offer significant challenges to drug discovery efforts aimed at preventing or even reversing the progression of these disorders. Transcriptomic tools and proteomic profiling have clearly indicated that such diseases are multifactorial in origin. Further, they are thought to be initiated by a cascade of molecular events that involve several neurotransmitter systems. In response to this complexity, a new paradigm has recently emerged that challenges the widely held assumption that 'silver bullet' agents are superior to 'dirty drugs' in therapeutic approaches aimed at the prevention or treatment of neuropsychiatric diseases. A similar pattern of drug development has occurred in strategies for the treatment of cancer, AIDS and cardiovascular diseases. In this review, we offer an overview of therapeutic strategies and novel investigative drugs discovered or developed in our own and other laboratories, that address multiple CNS etiological targets associated with an array of neuropsychiatric disorders.
Van der Schyf C J; Geldenhuys W J; Youdim M B H
Journal of Neurochemistry
2006
2006-11
Journal Article
<a href="http://doi.org/10.1111/j.1471-4159.2006.04141.x" target="_blank" rel="noreferrer noopener">10.1111/j.1471-4159.2006.04141.x</a>