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Exp Neurobiol 2013; 22(3): 167-172
Published online September 30, 2013
© The Korean Society for Brain and Neural Sciences
Moussa BH Youdim1* and Young J. Oh2
1Abital Pharma Pipeline Ltd, 96 Yuval Alon St., 61500 Tel Aviv, Israel, 2Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul 120-749, Korea
Correspondence to: *To whom correspondence should be addressed.
TEL: 972-4-9090000, FAX: 972-4-9090001
There is an unmet need in progressive neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. The present therapeutics for these diseases at best is symptomatic and is not able to delay disease or possess disease modifying activity. Thus an approach to drug design should be made to slow or halt progressive course of a neurological disorder by interfering with a disease-specific pathogenetic process. This would entail the ability of the drug to protect neurons by blocking the common pathway for neuronal injury and cell death and the ability to promote regeneration of neurons and restoration of neuronal function. We have now developed a number of multi target drugs which possess neuroprotective, and neurorestorative activity as well as being able to active PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α), SIRT1 (NAD-dependent deacetylase protein) and NTF (mitochondrial transcription factor) that are intimately associated with mitochondrial biogenesis.
Keywords: Parkinson's disease, neuroprotective, neurorestorative, multi target drug, iron chelator, mitochondrial biogenesis
There are significant evidence for dysregulation of brain iron metabolism in neurodegenerative disease of Parkinson's disease (PD), Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Iron is thought to participate in oxidative stress initiated by the Fenton reaction  and monoamine oxidase generating hydrogen peroxide. Thus, the concept of iron chelation as a valuable therapeutic approach in neurological disorders led our group to develop multi target, nontoxic, lipophilic, brain permeable compounds with iron chelating-radical scavenging, monoamine oxidase inhibitory activity and anti-apoptotic properties for neurodegenerative diseases, such as PD, AD and ALS . We incorporated the propargylamine moiety of rasagiline into the antioxidant-iron chelator moiety of an 8-hydroxyquinoline derivative of the iron chelating compound, VK28 [2, 3] to develop the multi target chelators M30 and HLA-20. N-propargyl functional group and its drug derivatives were shown in animal and cellular models of various neurodegenerative disorders with different insults that a series of propargyl derivatives exert significant neuroprotective and neurorescue activities [4-8]. The neuroprotection was ascribed mainly to a direct stabilization of the mitochondrial membrane potential and induction of anti-apoptotic pro-survival genes . The novel multifunctional iron chelator, M30 was found to confer potential neuroprotective effects in preclinical neurodegenerative models with distinct etiologies, exerting selective iron chelation potency (compared with zinc and copper), radical scavenging, and inhibition of iron-induced membrane lipid peroxidation [2, 9]. M30 was shown to possess a significant neuroprotective, as well as neurorescue activities against the Parkinsonism-inducing neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice [10, 11]. In addition, both M30 and VK28 were found to significantly improve behavioral performances and attenuate dopaminergic neuronal loss, proteasomal inhibition, iron accumulation, and microglial activation in the substantia nigra of mice injured with the proteasome inhibitor, lactacystin . Furthermore, M30 treatment provided clear benefits in G93A-SOD-1 ALS mice, significantly increasing their survival and delaying the onset of neurological dysfunction .
Neuroprotection by iron chelating agents has been widely attributed to their ability to prevent the iron from redox cycling and thereby, inhibit hydroxyl formation by the Fenton or Haber-Weiss reaction . More recently, an additional level of neuroprotection by iron chelators has been postulated to involve inhibition of the activity of iron-dependent HIF-prolylhydroxylase (PHD) enzymes, resulting in the stabilization/activation of HIF-1 and the consequent activation of a broad set of HIF-1-target genes that may contribute to cell survival, iron regulation, and energy metabolism in the nervous system [18-22]. Indeed, it was demonstrated that desferoxamine (DFO) can activate HIF-1 and prevent neuronal death in both
Our previous studies have shown the novel multifunctional brain permeable iron, chelator M30 [5-(N-methyl-N-propargyaminomethyl)-8-hydroxyquinoline] and its piprezino derivative, HLA-20 possess neuroprotective, neurorescue and neurorestorative activities
Recently we have found 10 gene sets with previously unknown associations with the substantia nigra pars compacta of PD . These gene sets pinpoint defects in mitochondrial electron transport, glucose utilization, and glucose sensing and reveal that they occur early in disease pathogenesis. Genes controlling cellular bioenergetics that are expressed in response to peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) are under expressed in patients with PD. Activation of PGC-1α results in increased expression of nuclear-encoded subunits of the mitochondrial respiratory chain and blocks the dopaminergic neuron loss induced by mutant α-synuclein or the pesticide rotenone in cellular disease models. Our systems biology analysis of PD has identified PGC-1α as a potential therapeutic target for early intervention since a defect in mitochondrial complex I has been shown in PD. Indeed we have recently shown that M30 and HLA-20, which possess neurodifferentiating, neurorescue and neurorestorative properties
The neuroprotective-neurorestorative mechanisms activated following M30 administration, are not completely understood. We have provided further insight into the various endogenous molecular mechanisms and prosurvival signaling pathways, activated in the brain following M30 systemic administration that might mediate neuroprotection. These include functional activation of HIF-1 signaling; regulation of a wide range of HIF-1-related protective genes, induction of mRNA expression levels of neurotrophic growth factors and antioxidant enzymes and upregulation of pro-survival signaling cascades. We have shown that the novel multifunctional compounds are strong chelators for iron and copper with higher selectivity for iron, and chelate iron (III) in a 3:1 M ratio, respectively [2, 27]. The fact that the new chelators have binding capability both for iron and copper, but with higher selectivity for iron may be important factors for the antioxidative-type drugs, since it is the excessive iron stores and iron-mediated generation of free radicals in the brain that are thought to be associated with neurodegenerative diseases [1, 2]. Therefore, the novel chelators with these properties would be expected to chelate iron instead of copper and hence would have potential use as drug candidates in neurodegenerative diseases. The current results demonstrate that M30 treatment produced a significant up-regulation of HIF-1 protein expression in the brain (e.g., cortex, striatum, and hippocampus and spinal cord). In addition, real time RT-PCR revealed that M30 differentially induced the transcription of a broad range of downstream HIF-1-related protective genes within the brain, such as those involved in erythropoiesis (EPO), angiogenesis (VEGF), glycolysis (Glut-1), and oxidative stress (HO-1), indicating a biological HIF-1 activation in the brain in response to M30 administration