Multifunctional drugs with different CNS targets for neuropsychiatric disorders

Abstract

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.

Brain Iron Toxicity: Differential Responses of Astrocytes, Neurons, and Endothelial Cells

“…But, there still remains much work to be done to identify effective treatment strategies for patients subject to cerebral hemorrhage due to hemorrhagic stroke or traumatic brain injury, and those with other ironassociated neurodegenerative diseases. In view of these facts, an even better understanding of the interrelationship of responses of individual brain cell types towards iron toxicity, will yield extremely useful information that may direct drug discovery efforts aimed at the development of neuroprotective or neurorescuing agents (152)(153)(154). It is therefore of significant importance that research efforts should be focused at further elucidating these initial discoveries that suggest clear differential responses of brain cells under conditions of iron insult.…”

Rasagiline Promotes Regeneration of Substantia Nigra Dopaminergic Neurons in Post-MPTP-induced Parkinsonism via Activation of Tyrosine Kinase Receptor Signaling Pathway

“…The activation of proÀsurvival PKC isoforms associated with BclÀ2 family members, the MAPK pathway and induction of neuroptrophic factors by rasagiline and its propargyl moiety [18,44,45] are novel mechanisms of action, which are currently considered in developing new neuroprotective drugs that address multiple central nervous system etiological targets associated with neuropsychiatric disorders [46]. The recent studies demonstrating a neuronal restoration of synaptic transmission in brains of PD animal model, suggest a possible diseaseÀmodifying activity of rasagiline [5].…”

Multi-target iron-chelators improve memory loss in a rat model of sporadic Alzheimer's disease

“…Novel anti-AD therapeutic strategies focus on drugs which target multiple pathology aspects of the disease (Van der Schyf et al 2006;Youdim and Buccafusco 2005). M30 ([5-(N-methyl-N-propargyaminomethyl)-8-hydroxyquinoline]) and HLA20 (5-{4-propargylpiperazin-1-ylmethyl}-8-hydroxyquinoline) are multi-target compounds with iron chelating potency, radical scavenging activity and features of inhibition of iron-induced lipid peroxidation (Zheng et al 2005).…”

“…Considering the diverse etiological nature of AD forms, novel therapeutic strategies should be focused on the implementation of drugs directed to various neuronal targets to address the multiple pathology aspects of the disease (Van der Schyf et al 2006;Youdim and Buccafusco 2005). The homeostasis of brain iron is thought to be necessary for normal brain function, especially in learning and memory (Youdim et al 1989).…”