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The concept of chelation therapy as a valuable therapeutic approach in neurological disorders led us to develop multi-target, non-toxic, lipophilic, brain-permeable compounds with iron chelation and anti-apoptotic properties for neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), age-related dementia and amyotrophic lateral sclerosis (ALS). Herein, we reviewed our two most effective such compounds, M30 and HLA20, based on a multimodal drug design paradigm. The compounds have been tested for their mechanisms of action using animal and cellular models such as APP/PS1 AD transgenic (Tg) mice, G93A-SOD1 mutant ALS Tg mice, C57BL/6 mice, Neuroblastoma × Spinal Cord-34 (NSC-34) hybrid cells, a battery of behavior tests, and various immunohistochemical and biochemical techniques. These novel iron chelators exhibit neuroprotective activities by attenuating relevant neurodegenerative pathology, promoting positive behavior changes, and up-regulating neuroprotective signaling pathways. Taken together, these results suggest that our multifunctional iron-chelating compounds can upregulate several neuroprotective-adaptive mechanisms and pro-survival signaling pathways in the brain and might function as ideal drugs for neurodegenerative disorders, such as PD, AD, ALS, and aging-related cognitive decline, in which oxidative stress and iron-mediated toxicity and dysregulation of iron homeostasis have been implicated. [ABSTRACT FROM AUTHOR]

Novel therapeutic approaches for the treatment of neurodegenerative disorders comprise drug candidates designed specifically to act on multiple central nervous system targets. We have recently synthesized multifunctional, nontoxic, brain-permeable iron-chelating drugs, M30 and HLA20, possessing the N-propargylamine neuroprotective moiety of rasagiline (Azilect) and the iron-chelating moiety of VK28. The present study demonstrates that M30 and HLA20 possess a wide range of pharmacological activities in mouse NSC-34 motor neuron cells, including neuroprotective effects against hydrogen peroxide- and 3-morpholinosydnonimine-induced neurotoxicity, induction of differentiation, and up-regulation of hypoxia-inducible factor (HIF)-1α and HIF-target genes (enolasel and vascular endothelial growth factor). Both compounds induced NSC-34 neuritogenesis, accompanied by a marked increase in the expression of brain-derived neurotrophic factor and growth-associated protein-43, which was inhibited by PD98059 and GF109203X, indicating the involvement of mitogen-activated protein kinase and protein kinase C pathways. A major finding was the ability of M30 to significantly extend the survival of G93A-SOD1 amyotrophic lateral sclerosis mice and delay the onset of the disease. These properties of the novel multimodal iron-chelating drugs possessing neuroprotective/ neuritogenic activities may offer future therapeutic possibilities for motor neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Aims: The aim of the present study was to evaluate the therapeutic effect of the novel neuroprotective multi-target nontoxic, lipophilic, brain permeable monoamine oxidase inhibitor and iron chelating-radical scavenging drug, M30, on the neuropathology and deficits of spatial learning and memory in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (Tg) Alzheimer's disease (AD) mice., Results: Here, we report that systemic treatment of APP/PS1 Tg mice with M30 for 9 months, significantly attenuated cognitive impairments in a variety of tasks of spatial learning and memory retention, working memory, learning abilities, anxiety levels, and memory for novel food and nesting behavior. Furthermore, we found that M30 reduced cerebral iron accumulation accompanied by a marked decrease in several AD-like phenotypes, including cerebral APP levels, amyloid β (Aβ) levels and plaques, phospho-APP and phospho-tau. Signaling studies revealed that M30 markedly downregulated the levels of phosphorylated cyclin-dependent kinase 5 and increased protein kinase B and glycogen synthase kinase 3β phosphorylation., Innovation: Accumulation and deposition of brain iron is central to various neuropathological processes in AD, including oxidative stress, amyloid deposition, and tau phosphorylation. Thus, the concept of iron chelation holds considerable promise as a therapeutic strategy for AD pathogenesis. Here, for the first time, we demonstrated that, when systemically administered to APP/PS1 Tg mice, our novel multifunctional iron chelating/radical scavenging compound, M30, effectively reduced Aβ accumulation and tau phosphorylation, and attenuated memory deficits., Conclusions: These findings suggest that M30 is a potential therapeutic agent for the prevention and treatment of AD.

Based on a multimodal drug design paradigm, we have synthesized a multifunctional non-toxic, brain permeable iron chelating compound, M30, possessing the neuroprotective N-propargyl moiety of the anti-Parkinsonian drug, monoamine oxidase (MAO)-B inhibitor, rasagiline and the antioxidant-iron chelator moiety of an 8-hydroxyquinoline derivative of the iron chelator, VK28. Here, we report that a chronic systemic treatment of aged mice with M30 (1 and 5mg/kg; 4 times weekly for 6 months), had a significant positive impact on neuropsychiatry functions and cognitive age-related impairment. M30 significantly reduced cerebral iron accumulation as demonstrated by Perl's staining, accompanied by a marked decrease in cerebral β-amyloid plaques. In addition, our results demonstrate that M30 caused a significant inhibition of both MAO-A and -B activities in the cerebellum of aged mice, compared with vehicle-treated aged control mice. In summary, the present study indicates that the novel MAO inhibitor/iron chelating drug, M30, acting against multiple brain targets could reverse age-associated memory impairment and provide a potential treatment against the progression of neurodegeneration in ageing., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Accumulating evidence suggests that many cytotoxic signals occurring in the neurodegenerative brain can initiate neuronal death processes, including oxidative stress, inflammation, and accumulation of iron at the sites of the neuronal deterioration. Neuroprotection by iron chelators has been widely recognized with respect to their ability to prevent hydroxyl radical formation in the Fenton reaction by sequestering redox-active iron. An additional neuroprotective mechanism of iron chelators is associated with their ability to upregulate or stabilize the transcriptional activator, hypoxia-inducible factor-1alpha (HIF-1alpha). HIF-1alpha stability within the cells is under the control of a class of iron-dependent and oxygen-sensor enzymes, HIF prolyl-4-hydroxylases (PHDs) that target HIF-1alpha for degradation. Thus, an emerging novel target for neuroprotection is associated with the HIF system to promote stabilization of HIF-1alpha and increase transcription of HIF-1-related survival genes, which have been reported to be regulated in patient's brains afflicted with diverse neurodegenerative diseases. In accordance, a new potential therapeutic strategy for neurodegenerative diseases is explored, by which iron chelators would inhibit PHDs, target the HIF-1-signaling pathway and ultimately activate HIF-1-dependent neuroprotective genes. This review discusses two interrelated approaches concerning therapy targets in neurodegeneration, sharing in common the implementation of iron chelation activity: antioxidation and HIF-1-pathway activation.

Reactive oxygen species are heavily involved in the pathogenesis of diabetes mellitus (DM) because the insulin-producing beta cells are particularly vulnerable to free-radical-mediated cytotoxicity. Catalytic anti-oxidants have been successfully applied for attenuation of DM and its consequences, but most recent research revealed that preventing the nitration of vital proteins/enzymes might be an even more powerful strategy. We now report an unprecedented efficiency of manganese(III) corroles regarding the protection of rat pancreatic beta cells against intracellular nitration by peroxynitrite and subsequent cell death. A comparison between analogous corroles and porphyrin metal complexes reveals significant superiority of the former in all examined aspects. This is particularly true for the positively-charged manganese(III) corrole, which decomposes peroxynitrite fast enough and through a unique catalytic mechanism that is devoid of potentially nitrating reaction intermediates.