Aluminium (Al) is neurotoxic primarily because of its interference with biological enzymes in key mechanisms of metabolic pathways. Mitochondria being a major site of reactive oxygen species (ROS) production, it seems that the oxidative damage to mitochondrial proteins may underlie the pathogenesis of Al induced neurodegeneration. The present study investigates the effectiveness of the anti-oxidant property of lazaroids (U-74500A), a known lipid peroxidation inhibitor as neuroprotective agent against Al induced neurotoxicity. Al chloride was administered orally at a dose level of 100 mg/kg body wt/day in water and U-74500A was administered at a dose of 0.25 mg/kg body wt i.p. in citrate buffer for a period of 8 weeks on alternate days. Following Al exposure there was a significant increase in lipid peroxidation (LPO), ROS levels and reduction in the activity of mitochondrial complexes in all the three regions of rat brain, i.e., cerebral cortex, mid brain, and cerebellum. This decrease in the activities of electron transport complexes in turn affected the ATP synthesis and ATP levels adversely in the mitochondria. These alterations were also depicted in the histology which shows signs of hypoxia, paucity of neurons in cortical region and loosening of fibers in the white matter. U-74500A co-administration was able to restore alterations in the LPO, ROS levels as well as all the three mitochondrial complexes and caspase expression. Therefore, it is suggested that 21-aminosteroids (lazaroids), by attenuating LPO and mitochondrial dysfunction, holds a promise as an agent that can potentially reduce Al-induced adverse effects in brain.

01 Oct 2006·Neuroscience LettersQ4 · MEDICINE

In vitro efficacy of three lazaroids in a model of acute chemical neuronal hypoxia

Q4 · MEDICINE

Article

Author: J.R. Vignes ; J. Hugon

Free radicals are highly reactive chemicals containing an unpaired electron and are normally produced by the cellular metabolism. But the excessive production of free radicals by oxidative stress is engaged in a large variety of diseases. The goal of this work was to determine the neuroprotective effect of free radical scavengers in an acute in vitro model of neuronal hypoxia. Primary cultures of cortical neurons of rats were exposed to 0.5 mM sodium cyanide for 6 h. Neuron death was evaluated with a lactate dehydrogenase assay. This mortality was up to 66.5% in cultures exposed to 0.5 mM sodium cyanide compared to non-exposed control cultures. Three lazaroids (U-74500A, U-74389G, U-83836E), were added to cultures, at different concentrations (10(-7)-10(-5) M), simultaneously with cyanide, during 6h. These agents caused a reduction in neuronal death, compared to exposed cultures. Efficacy varied with lazaroid compounds and U-74500A decreased neuronal death to 37-23.5%, U-74389G to 37-32%, and U-83836E to 42-33%. These results suggest a partial neuroprotective effect of free radical scavengers since lipid peroxidation is a key cellular event in neuronal injury, and its inhibition with lazaroids could help to reduce brain ischaemic lesions.

01 Oct 2004·Journal of Neural TransmissionQ4 · MEDICINE

Novel bifunctional drugs targeting monoamine oxidase inhibition and iron chelation as an approach to neuroprotection in Parkinson?s disease and other neurodegenerative diseases

Q4 · MEDICINE

Article

Author: M. Fridkin ; H. Zheng ; M. B. H. Youdim

Iron has been shown to accumulates at site where neurons degenerate in neurodegenerative diseases of Parkinson's disease, Alzheimer's disease, Huntington disease, amyotrophic lateral sclerosis and Friedreich ataxia. Iron is thought to participate or initiate oxidative stress via generation of reactive oxygen species (ROS), such as hydroxyl radical. Iron chelators are neuroprotective and prevent 6-hydroxydoapmine and MPTP dopaminergic neurotoxicity in rats and mice. However, their action on monoamine oxidase (MAO) A and B have not been determined previously since MAO-B inhibitors have been shown to be neuroprotective in cellular and animal models of Parkinson's disease. The chelators 8-hydroxyquinoline, O-phenanthroline, 2,2'-dipyridyl, U74500A and U74600F showed a preference for inhibition of rat brain mitochondrial MAO-A over MAO-B. Their IC(50) ranged from 10(-3) M to 10(-6) M, with 21-amino steroids (U74500A and U74006F) showing a greater selectivity and potency for MAO-A. Desferrioxamine (desferal), a prototype potent iron chelator, exhibited relatively poor MAO inhibitory. The inhibitions of MAO-A and B by 21-amino steroids (Lazaroids) were time dependent and irreversible. Those initiated by 8-hydroxyquinoline, 2,2'-dipyridyl and O-phenanthroline were fully reversible by enzyme dilution experiments. Both Fe(2+) and Fe(3+) reverse the MAO-A and B inhibition induced by the latter chelators, but not those initiated by 21-amino steroids. The data infer that either the inhibition of MAO by 21-amino steroids is either the resultant of their conversion to an irreversible covalently bound ligand or that the iron chelation moiety and MAO inhibitory activity in these compounds are not mutually shared. The results suggest that bifunctional brain penetrable drugs with iron chelating property and MAO inhibitory activity in could be the most feasible approach for neuroprotection in neurodegenerative diseases. Such drug would prevent participation of elevated iron in oxidative stress and formation of reactive hydroxyl radical, via its interaction with H(2)O2 (Fenton chemistry), generated as a consequence MAO and other oxidative enzyme reactions to generative cytotoxic reactive hydroxyl radical. We have now developed several of these compounds with neuroprotective, MAO inhibitory and iron chelating properties from our prototype iron chelators, VK-28 possessing propargylamine moiety of our anti-parkinson drug, rasagiline.

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Indication	Highest Phase	Country/Location	Organization	Date
Neurodegenerative Diseases	Discovery	GB	Pharmacia & Upjohn, Inc.	-

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