5-((4-prop-2-ynylpiperazin-1-yl)methyl)quinolin-8-ol and Neurodegenerative-Diseases

Dysregulation of brain iron homeostasis is central to early neuropathological events in Alzheimer's disease (AD), including oxidative stress, inflammatory processes, amyloid deposition, tau phosphorylation, and neuronal cell cycle regulatory failure, leading to apoptosis. Also, there is a direct link between iron metabolism and AD pathogenesis, demonstrated by the presence of an iron-responsive element in the 5' UTR of the amyloid precursor protein transcript. As a consequence of these findings, a new paradigm is emerging that includes the development of iron-chelating neuroprotective-neurorescue drugs with multimodal functions, acting at various pathological brain targets. This concept is challenging the widely held assumption that "silver bullet" agents are superior to "dirty drugs" in drug therapy for neurodegenerative diseases. At best, the so-called magic bullets exhibit moderate symptomatic activity without modifying the course of disease progression. The present review elaborates on conventional and novel therapeutic targets of various multifunctional iron-chelating drugs (e.g., chemically designed compounds; natural polyphenols) that address multiple central nervous system etiologies in AD, aimed at preventing or slowing disease evolution. A similar approach in drug design is being investigated for treatment of cancer, AIDS, cardiovascular diseases, and depression.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain; Catechin; Cell Cycle; Humans; Hydroxyquinolines; Iron; Iron Chelating Agents; Neurodegenerative Diseases; Neuroprotective Agents; PC12 Cells; Piperazines; Rats

A new paradigm is emerging in the targeting of multiple disease aetiologies that collectively lead to neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, post-stroke neurodegeneration and others. This paradigm challenges the widely held assumption that 'silver bullet' agents are superior to 'dirty drugs' when it comes to drug therapy. Accumulating evidence in the literature suggests that many neurodegenerative diseases have multiple mechanisms in their aetiologies, thus suggesting that a drug with at least two mechanisms of action targeted at multiple aetiologies of the same disease may offer more therapeutic benefit in certain disorders compared with a drug that only targets one disease aetiology. This review offers a synopsis of therapeutic strategies and novel investigative drugs developed in the authors' own and other laboratories that modulate multiple disease targets associated with neurodegenerative diseases.

Topics: Acetylcholine; Adenosine A2 Receptor Antagonists; Animals; Apoptosis; Calcium; Calcium Channel Blockers; Carbamates; Cholinesterase Inhibitors; Drug Design; Excitatory Amino Acid Antagonists; Free Radical Scavengers; Humans; Hydroxyquinolines; Iron Chelating Agents; Monoamine Oxidase Inhibitors; Neurodegenerative Diseases; Neuroprotective Agents; Piperazines; Purines; Receptor, Adenosine A2A; Receptors, N-Methyl-D-Aspartate; Selective Serotonin Reuptake Inhibitors; Serotonin Plasma Membrane Transport Proteins

Iron-dependent oxidative stress, elevated levels of iron and of monoamine oxidase (MAO)-B activity, and depletion of antioxidants in the brain may be major pathogenic factors in Parkinson's disease, Alzheimer's disease and related neurodegenerative diseases. Accordingly, iron chelators, antioxidants and MAO-B inhibitors have shown efficacy in a variety of cellular and animal models of CNS injury. In searching for novel antioxidant iron chelators with potential MAO-B inhibitory activity, a series of new iron chelators has been designed, synthesized and investigated. In this study, the novel chelators were further examined for their activity as antioxidants, MAO-B inhibitors and neuroprotective agents in vitro. Three of the selected chelators (M30, HLA20 and M32) were the most effective in inhibiting iron-dependent lipid peroxidation in rat brain homogenates with IC50 values (12-16 microM), which is comparable with that of desferal, a prototype iron chelator that is not has orally active. Their antioxidant activities were further confirmed using electron paramagnetic resonance spectroscopy. In PC12 cell culture, the three novel chelators at 0.1 microM were able to attenuate cell death induced by serum deprivation and by 6-hydroxydopamine. M30 possessing propargyl, the MAO inhibitory moiety of the anti-Parkinson drug rasagiline, displayed greater neuroprotective potency than that of rasagiline. In addition, in vitro, M30 was a highly potent non-selective MAO-A and MAO-B inhibitor (IC50 < 0.1 microM). However, HLA20 was more selective for MAO-B but had poor MAO inhibition, with an IC50 value of 64.2 microM. The data suggest that M30 and HLA20 might serve as leads in developing drugs with multifunctional activities for the treatment of various neurodegenerative disorders.

Topics: Animals; Antioxidants; Cell Survival; Culture Media, Serum-Free; Cysteine; Designer Drugs; Hydroxyl Radical; Hydroxyquinolines; Iron Chelating Agents; Lipid Peroxidation; Monoamine Oxidase Inhibitors; Neurodegenerative Diseases; Neuroprotective Agents; Oxidopamine; PC12 Cells; Piperazines; Rats