Lana Kupershmidt

Neuroprotective and neuritogenic activities of novel multimodal iron-chelating drugs in motor-neuron-like NSC-34 cells and transgenic mouse model of amyotrophic lateral sclerosis

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 A‐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)‐la and HIF‐target genes (enolasel and vascular endothe‐lial 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.— Kupershmidt, L., Weinreb, O., Amit, T., Mandel, S., Carri, M. T., Youdim, M. B. H. Neuroprotective and neuritogenic activities of novel multimodal iron‐chelating drugs in motor‐neuron‐like NSC‐34 cells and transgenic mouse model of amyotrophic lateral sclerosis. FASEBJ. 23, 3766‐3779 (2009). www.fasebj.org

Neuroprotective Multifunctional Iron Chelators: From Redox-Sensitive Process to Novel Therapeutic Opportunities

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 patients 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.

Metallocorroles as cytoprotective agents against oxidative and nitrative stress in cellular models of neurodegeneration

J. Neurochem. (2010) 113, 363–373.

The novel multi-target iron chelating-radical scavenging compound M30 possesses beneficial effects on major hallmarks of Alzheimer's disease.

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) Alzheimers 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.

Manganese corroles prevent intracellular nitration and subsequent death of insulin-producing cells.

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.

Neuroprotective and neurorestorative activities of a novel iron chelator-brain selective monoamine oxidase-A/monoamine oxidase-B inhibitor in animal models of Parkinson's disease and aging

Recently, we have designed and synthesized a novel multipotent, brain-permeable iron-chelating drug, VAR10303 (VAR), possessing both propargyl and monoamine oxidase (MAO) inhibitory moieties. The present study was undertaken to determine the multiple pharmacological activities of VAR in neurodegenerative preclinical models. We demonstrate that VAR affords iron chelating/iron-induced lipid-peroxidation inhibitory potency and brain selective MAO-A and MAO-B inhibitory effects, with only limited tyramine-cardiovascular potentiation of blood pressure. The results show that in 6-hydroxydopamine rat (neuroprotection) and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse (neurorescue) Parkinsons disease models, VAR significantly attenuated the loss of striatal dopamine levels, markedly reduced dopamine turnover, and increased tyrosine-hydroxylase levels. Furthermore, chronic systemic treatment of aged rats with VAR improved cognitive behavior deficits and enhanced the expression levels of neurotrophic factors (e.g., brain-derived neurotrophic factor, glial cell-derived neurotrophic factor, and nerve growth factor), Bcl-2 family members and synaptic plasticity in the hippocampus. Our study indicates that the multitarget compound VAR exerted neuroprotective and neurorestorative effects in animal models of Parkinsons disease and aging, further suggesting that a drug that can regulate multiple brain targets could be an ideal treatment-strategy for age-associated neurodegenerative disorders.

Multi-target, Neuroprotective and Neurorestorative M30 Improves Cognitive Impairment and Reduces Alzheimer's-Like Neuropathology and Age-Related Alterations in Mice

Based on a multimodal drug design strategy for age-related neurodegenerative diseases, we have synthesized a multifunctional nontoxic, brain-permeable iron-chelating compound, M30, possessing the neuroprotective N-propargyl moiety of the anti-Parkinsonian drug, monoamine oxidase-B inhibitor, rasagiline and the antioxidant–iron chelator moiety of the 8-hydroxyquinoline derivative of the iron chelator, VK28. In the present short overview, we describe the neuroprotective and the neurorestorative activity of M30, acting against multiple brain targets, including regulation on amyloid β, neurogenesis, and activation of hypoxia inducible factor signaling pathways. The diverse pharmacological properties and several pathological targets of M30 make this drug potential valuable for therapeutic strategy of Alzheimers-like neuropathology and aging.

The novel multitarget iron chelating and propargylamine drug M30 affects APP regulation and processing activities in Alzheimer's disease models

&NA; In many of the neurodegenerative diseases, such as Alzheimers disease (AD) and AD‐related disorders, as well as in the regular ageing process, excessive generation of oxidative stress (OS) and accumulation of iron levels and deposition have been observed in specific affected‐brain regions and thus, regarded as contributing factors to the pathogenesis of the diseases. In AD, iron promotes amyloid &bgr; (A&bgr;) neurotoxicity by producing free radical damage and OS in brain areas affected by neurodegeneration, presumably by facilitating the aggregation of A&bgr;. In addition, it was shown that iron modulates intracellular levels of the holo amyloid precursor protein (APP) by iron‐responsive elements (IRE) RNA stem loops in the 5′ untranslated region (5′UTR) of the APP transcript. As a consequence of these observations, iron chelation is one of the major new therapeutic strategies for the treatment of AD. This review describes the benefits and importance of the multimodal brain permeable chimeric iron‐chelating/propargylamine drug M30, concerning its neuroprotective/neurorestorative inter‐related activities relevant of the pathological features ascribed to AD, with a special focus on the effect of the drug on APP regulation and processing. HighlightsM30; a multimodal brain permeable chimeric iron‐chelating/propargylamine drug.M30 exerts neuroprotective/neurorestorative in Alzheimers disease models.M30 possesses effects on APP regulation and processing.

Additive Neuroprotective Effects of the Multifunctional Iron Chelator M30 with Enriched Diet in a Mouse Model of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is the most common degenerative disease of the motoneuron system, involving various abnormalities, such as mitochondrial dysfunction, oxidative stress, transitional metal accumulation, neuroinflammation, glutamate excitotoxicity, apoptosis, decreased supply of trophic factors, cytoskeletal abnormalities, and extracellular superoxide dismutase (SOD)-1 toxicity. These multiple disease etiologies implicated in ALS gave rise to the perception that future therapeutic approaches for the disease should be aimed at targeting multiple pathological pathways. In line with this view, we have evaluated in the current study the therapeutic effects of low doses of the novel multifunctional monoamine oxidase (MAO) inhibitor/iron-chelating compound, M30 in combination with high Calorie Energy supplemented Diet (CED) in the SOD1-G93A transgenic mouse model of ALS. Our results demonstrated that the combined administration of M30 with CED produced additive neuroprotective effects on motor performance and increased survival of SOD1-G93A mice. We also found that both M30 and M30/CED regimens caused a significant inhibition of MAO-A and -B activities and decreased the turnover of dopamine in the brain of SOD1-G93A mice. In addition, M30/CED combined treatment resulted in a significant increase in mRNA expression levels of various mitochondrial biogenesis and metabolism regulators, such as peroxisome proliferator-activated receptor-γ (PPARγ)-co activator 1 alpha (PGC-1α), PPARγ, uncoupling protein 1, and insulin receptor in the gastrocnemius muscle of SOD1-G93A mice. These results suggest that a combination of drug/agents with different, but complementary mechanisms may be beneficial in the treatment of ALS.