99 replies to this topic

[nootropi]

The use of antioxidants in Friedreich's ataxia treatment.

Rustin P.

INSERM U393, Tour Lavoisier, Hopital des Enfants-Malades, 149, rue de Sevres, 75743 Paris Cedex 15, France. rustin@necker.fr

Friedreich's ataxia is the most common recessive ataxia associated with life-threatening cardiomyopathy. It results from a loss of function of frataxin that ultimately leads to oxidative insult, particularly to neurons and cardiomyocytes. The disease is progressive, the oxidative insult being presumably subsequent to an abnormal iron/sulfur cluster synthesis that causes mitochondrial respiratory chain disease and impaired signalling of one antioxidant pathway. After a detailed in vitro study, idebenone, a short chain homologue of coenzyme Q(10) with potent antioxidant properties, was given to patients. The antioxidant had a dramatic and rapid effect on the cardiomyopathy in most patients. Although a subset of patients also report various improvements, implying that idebenone could have a broader spectrum of action including some neurological improvements, the antioxidant did not have noticeable effects on the ataxia. Several hypotheses on the mechanisms that could account for the contrasting effects of the antioxidant on clinical symptoms of Friedreich's ataxia are discussed in this review. The considerable difficulties still being encountered in ascertaining the effect of antioxidants on the course of the neurological condition are also considered.

[nootropi]

Neurosci Lett. 2002 Aug 23;329(1):21-4.  Related Articles, Links
   
Ethanol-induced injury in rat primary cortical astrocytes involves oxidative stress: effect of idebenone.

Muscoli C, Fresta M, Cardile V, Palumbo M, Renis M, Puglisi G, Paolino D, Nistico S, Rotiroti D, Mollace V.

Department of Pharmacobiological Sciences, University of Catanzaro Magna Graecia, Complesso Nini Barbieri, I-88021 Roccelletta di Borgia, Catanzaro, Italy.

Ethanol-induced neurological disorders have recently been characterised. Indeed, evidence has been collected indicating that chronic ethanol consumption leads to direct or indirect changes in the viability of central nervous system cells. Here we investigated the role of free radical overproduction in primary cortical rat astroglial cells undergoing chronic treatment with ethanol (100 microM). In particular, exposure of astroglial cell cultures to ethanol for 12 consecutive days produced an increased release of lactic dehydrogenase, a decrease on glutamine synthase activity being both effects accompanied by decrease in astroglial viability as detected by MTT (Thiazolyl Blue) test. These effects were accompanied by an increased formation of malondialdehyde (a marker of lipid peroxidation) and by abnormal formation of heat shock protein, being both effects antagonised by liposomally entrapped idebenone, a non-peptidyl free radical scavenger. Taken together, these results suggest that ethanol-induced injury on astroglial cells are mediated by abnormal formation of free radical species and this may represent a useful approach in the treatment of ethanol-related brain disorders. Copyright 2002 Elsevier Science Ireland Ltd.

[nootropi]

Heart hypertrophy and function are improved by idebenone in Friedreich's ataxia.

Rustin P, Rotig A, Munnich A, Sidi D.

Unite de Recherches sur les Handicaps Genetiques de l'Enfant (INSERM U393), Hopital Necker-Enfants Malades, Paris, France. rustin@necker.fr

Friedreich's ataxia (FRDA) is a neuro-degenerative disease causing limb and gait ataxia and hypertrophic cardiomyopathy. It results from a triplet expansion in the first intron of the frataxin gene encoding a mitochondrial protein of yet unknown function. Cells with low frataxin content display generalized deficiency of mitochondrial iron-sulfur cluster-containing proteins, which presumably denotes overproduction of superoxide radicals in these organelles. Idebenone, a short-chain quinone, may act as a potent free radical scavenger protecting mitochondria against oxidative stress. We therefore carried out an open trial of idebenone (oral supplementation; 5mg/kg/day) in a large series of FRDA patients and followed their left ventricular mass and function. Consistent and definitive worsening being observed in the natural course of the disease and cardiac hypertrophy having no chance of spontaneous reversal and to be subject to a placebo effect, the patient's heart status before and after the treatment was used to unambiguously establish the effect of the drug. After six months, heart ultrasound revealed more than 20% reduction of left ventricular mass in about half of the patients (p < 0.001) and no significant change in the other half. Since any measurable reversion of this pathogenic trait is highly significant, this demonstrates the efficiency of idebenone in controlling heart hypertrophy in FRDA. Owing to the absence of side effects of the drug, idebenone (up to 15mg/kg/day) should be prescribed for FRDA patients continuously as early as possible.

PMID: 12069112 [PubMed - indexed for MEDLINE]

[nootropi]

Friedreich's ataxia: idebenone treatment in early stage patients.

Artuch R, Aracil A, Mas A, Colome C, Rissech M, Monros E, Pineda M.

Biochemistry Department, Hospital Sant Joan de Deu, University of Barcelona, Spain. rartuch@hsjdbcn.org

BACKGROUND: Antioxidant therapy has been applied to Friedreich's ataxia patients. We assessed the effect of idebenone treatment in patients with Friedreich's ataxia. METHODS: Design: open-label trial. Nine Friedreich's ataxia patients (age range 11 - 19 years) were treated with idebenone (5 mg/kg/day). Patients were evaluated before the start of the therapy and throughout one year of treatment by International Cooperative Ataxia Rating Scales (ICARS) scores, neurophysiological investigations and echocardiographic measurements. Serum idebenone concentrations were measured by HPLC with electrochemical detection. The number of GAA repeats at the frataxin gene was analyzed by PCR. RESULTS: Serum idebenone concentrations ranged between 0.04 - 0.37 micro mol/L. Significantly positive correlation was observed between idebenone values and the percentage of difference between the ICARS scores before and 12 months after the start of the therapy (r = 0.883; p = 0.002). Significant reduction was observed comparing the ICARS scores in baseline conditions and after 3 months of treatment (p = 0.017). No differences were observed in echocardiographic measurements after the start of the therapy. CONCLUSIONS: Cerebellar improvement was notable in mild patients after the first 3 months of therapy. Idebenone treatment at early stages of the disease seems to reduce the progression of cerebellar manifestations. Further blind trials with a greater number of patients and higher doses are needed to fully assess the therapeutic potential of idebenone in Friedreich's ataxia.

[nootropi]

A cellular model for Friedreich Ataxia reveals small-molecule glutathione peroxidase mimetics as novel treatment strategy.

Jauslin ML, Wirth T, Meier T, Schoumacher F.

MyoContract Ltd, Hammerstrasse 25, CH-4410 Liestal, Switzerland.

Friedreich Ataxia (FRDA), the most prevalent of the inherited ataxias, is a multi-systemic disease with loss of sensory neurons and life-threatening hypertrophic cardiomyopathy as its most severe manifestations. Reduced levels of the mitochondrial protein frataxin lead to cell-damaging oxidative stress and consequently FRDA is considered as a model for more common neurodegenerative disorders in which reactive radicals and oxidative stress are involved. We have developed a cellular assay system that discriminates between fibroblasts from FRDA patients and unaffected donors on the basis of their sensitivity to pharmacological inhibition of de novo synthesis of glutathione. With this assay we observed that supplementation with selenium effectively improved the viability of FRDA fibroblasts, indicating that basal selenium concentrations are not sufficient to allow an adequate increase in the activity of certain detoxification enzymes (such as GPX). Furthermore, we characterized potential drug candidates and found that idebenone, a mitochondrially localized antioxidant that ameliorates cardiomyopathy in FRDA patients, as well as other lipophilic antioxidants protected FRDA cells from cell death. Our results also demonstrate for the first time that small-molecule GPX mimetics have potential as a novel treatment strategy for Friedreich Ataxia and presumably also for other neurodegenerative diseases with mitochondrial impairment.

[nootropi]

Improved antioxidant effect of idebenone-loaded polyethyl-2-cyanoacrylate nanocapsules tested on human fibroblasts.

Palumbo M, Russo A, Cardile V, Renis M, Paolino D, Puglisi G, Fresta M.

Institute of Biochemistry, University of Catania, Italy.

PURPOSE: The protective antioxidant role of idebenone both as free drug and drug-loaded Tween 80-coated polyethyl-2-cyanoacrylate (PECA) nanocapsules is reported. The relationship between oxidative damage and apoptotic or nonapoptotic cell death is evaluated in vitro. METHODS: Idebenone-loaded nanocapsules were prepared with the interfacial polymerization method in the presence of Tween 80. Human nonimmortalized fibroblasts. under different stress conditions, either 0.5 mM diethylmaleate (DEM) for 60 min or 0.1 mM H2O2 for 30 min, were used as the experimental in vitro model. The production of reactive oxygen species, the cell viability, and the nuclear DNA damage were evaluated. The presence of apoptotic damage was evaluated both by the determination of caspase-3-like protein activity and by Promega's fluorescent apoptotic detection system. RESULTS: DEM and H2O2 affected the cultured cells in different ways. DEM induced a moderate cellular insult, which was efficaciously antagonized by idebenone-loaded PECA nanocapsules. H2O2 elicited severe damage to nuclear DNA, which was reduced by idebenoneloaded PECA nanocapsules. The free drug was less effective than idebenone-loaded nanocapsules. CONCLUSIONS: The findings reported here demonstrate that an improved antioxidant effect was obtained with a low idebenone concentration (0.5 microM) when the drug was entrapped within Tween 80-coated PECA nanocapsules.

[nootropi]

Neurosci Lett. 2001 Jun 29;306(3):169-72.  Related Articles, Links
   
    Idebenone in patients with Friedreich ataxia.

    Schols L, Vorgerd M, Schillings M, Skipka G, Zange J.

    Department of Neurology, St. Josef Hospital, Ruhr-University, Bochum, Germany. ludger.schoels@ruhr-uni-bochum.de

  Friedreich ataxia (FA), the most common form of degenerative ataxia, is thought to be caused by respiratory deficiency due to mitochondrial iron accumulation and oxidative stress. Idebenone, a free-radical scavenger, protects mitochondrial function in in vitro models of FA. In a placebo-controlled crossover trial we studied the effect of idebenone on respiratory function in nine ambulant FA patients. (31)P magnetic resonance spectroscopy demonstrated mitochondrial impairment in vivo in skeletal muscle of all FA patients, but no recovery with idebenone. No effects were seen in clinical scores. Echocardiography did not confirm a preliminary study reporting improvement of FA-associated cardiomyopathy with idebenone.

[nootropi]

1: Int J Mol Med. 2001 Jun;7(6):581-9.  Related Articles, Links

    Friedreich's ataxia and frataxin: molecular genetics, evolution and pathogenesis (Review).

    Palau F.

    Laboratory of Genetics and Molecular Medicine, Instituto de Biomedicina, CSIC, 46010 Valencia, Spain. fpalau@ibv.csic.edu

    Friedreich's ataxia is an autosomal recessive neuro-degenerative disorder involving both central and peripheral nervous system. Patients also show a systemic clinical picture presenting heart disease and diabetes mellitus or glucose intolerance. The disease is caused by mutations in the FRDA gene mapped on chromosome 9q13. The product of the gene is frataxin, an 18 kDa soluble mitochondrial protein with 210 amino acids. Crystal structure suggests a new, not previously reported, protein fold. The most frequent mutation is the expansion of a GAA trinucleotide repeat located within the first intron of the gene, and represents 98% of the mutations. Point mutations are described in compound heterozygous subjects with one expanded allele. A two-step model of GAA normal alleles towards premutation alleles, which might generate further full expanded mutations in the population with Indo-European ancestry, has been postulated. Clinical phenotype is variable and an inverse correlation with the GAA expansion size has been observed. Analysis of the GAA triplet is a strong molecular tool for clinical diagnosis, genetic counselling and prenatal diagnosis. Friedreich's ataxia patho-genesis is not solved yet. Substantial data from organism models, such the S. cerevisae yeast and more recently conditioned knock-outs in mouse, and studies in heart biopsies and fibroblast cultures from patients suggest an important role of mitochondrial iron in the development of the disease. Iron is accumulated in the mitochondrial matrix of both the yeast frataxin deficient mutant and the patient fibroblasts. It has been postulated that iron-induced oxygen radical affects the oxidative phosphorylation in frataxin deficiency states favouring the disease pathology. A second hypothesis postulates a direct role of frataxin in the mitochondrial energy activation and oxidative phosphorylation. Iron chelator drugs and antioxidant drugs have been postulated for Friedreich's treatment. No results from clinical trials are available yet, but idebenone, a short-chain quinone, seems to reduce the size of hypertrophic cardiomyopathy and levels of oxidative stress molecules in patients.

[nootropi]

Comment in:

    * Neurology. 2000 Dec 12;55(11):1600-1.


Oxidative stress in patients with Friedreich ataxia.

Schulz JB, Dehmer T, Schols L, Mende H, Hardt C, Vorgerd M, Burk K, Matson W, Dichgans J, Beal MF, Bogdanov MB.

Department of Neurology, University of Tubingen, Germany. joerg.b.schulz@uni-tuebingen.de

Increased generation of reactive oxygen species may underlie the pathophysiology of Friedreich ataxia (FRDA). The authors measured concentrations of 8-hydroxy-2'-deoxyguanosine (8OH2'dG), a marker of oxidative DNA damage, in urine and of dihydroxybenzoic acid (DHBA), a marker of hydroxyl radical attack, in plasma of 33 patients with FRDA. They found a 2.6-fold increase in normalized urinary 8OH2'dG but no change in plasma DHBA as compared with controls. Oral treatment with 5 mg/kg/day of the antioxidant idebenone for 8 weeks significantly decreased urinary 8OH2'dG concentrations, indicating that 8OH2'dG may be useful in monitoring therapeutic interventions in patients with FRDA.-1721

[nootropi]

1: Am J Med. 2000 Nov;109(7):577-85.  Related Articles, Links
   
    Oxidative injury in diseases of the central nervous system: focus on Alzheimer's disease.

    Pratico D, Delanty N.

    Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Alzheimer's disease is one of the most challenging brain disorders and has profound medical and social consequences. It affects approximately 15 million persons worldwide, and many more family members and care givers are touched by the disease. The initiating molecular event(s) is not known, and its pathophysiology is highly complex. However, free radical injury appears to be a fundamental process contributing to the neuronal death seen in the disorder, and this hypothesis is supported by many (although not all) studies using surrogate markers of oxidative damage. In vitro and animal studies suggest that various compounds with antioxidant ability can attenuate the oxidative stress induced by beta-amyloid. Recently, clinical trials have demonstrated potential benefits from treatment with the antioxidants, vitamin E, selegiline, extract of Gingko biloba, and idebenone. Further studies are warranted to confirm these findings and explore the optimum timing and antioxidant combination of such treatments in this therapeutically frustrating disease.

[nootropi]

1: Neurosci Res. 2000 Jul;37(3):227-36.  Related Articles, Links
   
    Oxidative glutamate toxicity involves mitochondrial dysfunction and perturbation of intracellular Ca2+ homeostasis.

    Pereira CF, Oliveira CR.

    Faculty of Medicine and Center for Neuroscience of Coimbra, University of Coimbra, Portugal. cpereira@cnc.uc.pt

    Glutamate toxicity on PC12 cells is mediated by oxidative stress as a consequence of the inhibition of a cystine uptake system with depletion of GSH. In this study we report that glutamate decreases PC12 cell viability, inhibiting the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). This decrease was prevented by the antioxidants vitamin E, idebenone and L-deprenyl, which were also shown to be effective in reducing the accumulation of reactive oxygen species (ROS) in cells exposed to glutamate, decreasing the fluorescence of 2',7'-dichlorofluorescein (DCF).Incubation of PC12 cells with high glutamate concentrations induced mitochondrial dysfunction, leading to the loss of mitochondrial transmembrane potential, evaluated as a decrease in rhodamine 123 (Rh123) retention by mitochondria, and to the decrease of intracellular ATP levels. The mitochondrial dysfunction, induced by glutamate, can be involved in the observed increase of [Ca2+]i. The elevation of [Ca2+]i occurred after GSH depletion, suggesting that oxidative stress is involved in the disturbances of intracellular calcium homeostasis. In conclusion, our data indicate that glutamate, at concentrations which block cystine uptake in PC12 cells leading to GSH depletion and inducing oxidative stress, increases ROS accumulation and decreases cell survival by a mechanism involving mitochondrial dysfunction and impairment of Ca2+ homeostasis.

[nootropi]

Clin Biochem. 2000 Jun;33(4):285-90.  Related Articles, Links
   
    c-fos and c-jun mRNA expression in a pig liver model of ischemia/reperfusion: effect of extended cold storage and the antioxidant idebenone.

    Wieland E, Oellerich M, Braun F, Schtuz E.

    Abteilung Klinische Chemie, Georg-August-Universitat, Gottingen, Germany. ewieland@med.uni-goettingen.d
    OBJECTIVES: Expression of immediate early genes has been reported during reperfusion after ischemia in rat livers due to oxygen radical formation. This study investigates in perfused pig livers the effect of the antioxidant idebenone and of cold ischemia time on the gene expression of c-fos and c-jun. DESIGN AND METHODS: Livers were perfused for 210 min after 0.5 h or 20 h ischemic storage (4 degrees C). One group of pigs was fed idebenone (280 mg/day/7days) prior to organ harvesting. C-fos and c-jun mRNA were determined by RT-PCR at 3, 30, 60, 120 180, 210 min during reperfusion. RESULTS: Lipid peroxidation increased in liver tissue form 0.54 +/- 0.21 to 1. 09 +/- 0.54 nmol MDA/mg protein during reperfusion after 20 h compared to 0.5 h cold storage. This was antagonized by idebenone (0. 68 +/- 0.20 nmol/MDA/mg protein). C-fos and c-jun were strongly induced in livers stored for 20 h, which was attenuated by idebenone (p < 0.05). CONCLUSIONS: These findings suggest that cold ischemia time and oxygen radicals are critical for immediate early gene expression and that application of an effective antioxidant can attenuate this early stress reaction of the pig liver.

[nootropi]

J Neurosci Methods. 1999 Sep 15;91(1-2):47-54.  Related Articles, Links

    A new Alamar Blue viability assay to rapidly quantify oligodendrocyte death.

    Back SA, Khan R, Gan X, Rosenberg PA, Volpe JJ.

    Department of Neurology, Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.

    We developed a rapid fluorometric viability assay for primary cultures of OL precursors (preOLs) or mature OLs that utilized the oxidation/reduction indicator dye Alamar Blue (AB). PreOLs had a lower rate of AB reduction than did mature OLs (0.02 +/- 0.01 units/min per cell versus 0.07 +/- 0.01). The assay was tested under two conditions toxic to preOLs: oxidative stress induced by glutathione depletion or kainate excitotoxicity. When glutathione was depleted by a 24-h exposure to cystine-depleted medium, the EC50 values for the dependence upon cystine for survival did not differ significantly when determined by AB reduction (2 +/- 2 microM), by the trypan blue exclusion method (3 +/- 3 microM) or by MTT histochemistry (1 +/- 0.4 microM). Quantification of preOL viability with AB was unaffected by the presence of free radical scavengers (alpha-tocopherol or idebenone) or the antioxidant enzymes Cu,Zn-superoxide dismutase and catalase. There was no difference in preOL viability as determined by AB or MTT after a 24-h exposure to kainate at concentrations up to 1 mM. AB offers a rapid objective measure of OL viability in primary culture and is a valid means to quantify OL death.

[nootropi]

Comment in:

    * Lancet. 1999 Oct 9;354(9186):1300-1.


Effect of idebenone on cardiomyopathy in Friedreich's ataxia: a preliminary study.

Rustin P, von Kleist-Retzow JC, Chantrel-Groussard K, Sidi D, Munnich A, Rotig A.

Unite de Recherches sur les Handicaps Genetiques de l'Enfant (INSERM U393), Paris, France.

BACKGROUND: Friedreich's ataxia is caused by a deficiency of frataxin, a protein involved in regulation of mitochondrial iron content. We have reported a combined deficiency of a Krebs-cycle enzyme, aconitase, and three mitochondrial respiratory-chain complexes in endomyocardial biopsy samples from patients with this disorder. All four enzymes share iron-sulphur cluster-containing proteins that are damaged by iron overload through generation of oxygen free radicals. We used an in-vitro system to elucidate the mechanism of iron-induced injury and to test the protective effects of various substances. On the basis of these results, we assessed the effect of idebenone (a free-radical scavenger) in three patients with Friedreich's ataxia. METHODS: Heart homogenates from patients with valvular stenosis were tested for respiratory-chain complex II activity, lipoperoxidation, and aconitase activity by spectrophotometric assays, in the presence of reduced iron (Fe2+), oxidised iron (Fe3+), desferrioxamine, ascorbic acid, and idebenone. The Friedreich's ataxia patients (aged 11 years, 19 years, and 21 years) underwent ultrasonographic heart measurements at baseline and after 4-9 months of idebenone (5 mg/kg daily). FINDINGS: Fe2+ (but not Fe3+) decreased complex II activity and increased lipoperoxidation in heart homogenate. Addition of ascorbate or desferrioxamine increased some of the iron-induced adverse effects. Idebenone protected against these effects. In the three patients, left-ventricular mass index decreased from baseline to 4-9 months of idebenone treatment (patient 1, 145 g to 114 g; patient 2, 215 g to 151 g; patient 3, 408 g to 279 g). INTERPRETATION: Our in-vitro data suggest that both iron chelators and antioxidant drugsthat may reduce iron are potentially harmful in patients with Friedreich's ataxia. Conversely, our preliminary findings in patients suggest that idebenone protects heart muscle from iron-induced injury.

[nootropi]

Eur J Neurosci. 1999 Jan;11(1):83-90.  Related Articles, Links
   
    Protective effects of idebenone and alpha-tocopherol on beta-amyloid-(1-42)-induced learning and memory deficits in rats: implication of oxidative stress in beta-amyloid-induced neurotoxicity in vivo.

    Yamada K, Tanaka T, Han D, Senzaki K, Kameyama T, Nabeshima T.

    Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Japan.

    Amyloid beta-peptide (A beta), the major constituent of the senile plaques in the brains of patients with Alzheimer's disease, is cytotoxic to neurons and has a central role in the pathogenesis of the disease. Previous studies have suggested that oxidative stress is involved in the mechanisms of A beta-induced neurotoxicity in vitro. In the present study, we examined whether oxidative stress contributes to learning and memory deficits caused by continuous intracerebroventricular infusion of A beta-(1-42). In the A beta-(1-42)-infused rats, spontaneous alternation behaviour in a Y-maze and spatial memory in a water maze task were significantly impaired, as compared with A beta-(40-1)-infused control rats. The retention of passive avoidance learning was also significantly impaired by treatment with A beta-(1-42). Potent antioxidants idebenone and alpha-tocopherol prevented the behavioural deficits in Y-maze and water maze, but not passive avoidance, tasks in A beta-(1-42)-infused rats when they were repeatedly administered by mouth once a day from 3 days before the start of A beta infusion to the end of behavioural experiments. Lipid peroxide levels in the hippocampus and cerebral cortex of A beta-(1-42)-infused rats did not differ from those in control animals, and neither idebenone nor alpha-tocopherol affected the lipid peroxide levels. These results suggest that treatment with antioxidants such as idebenone and alpha-tocopherol prevents learning and memory deficits caused by A beta.

[nootropi]

Changes in oxidative stress in the rat brain during post-cardiac arrest reperfusion, and the effect of treatment with the free radical scavenger idebenone.

Grieb P, Ryba MS, Debicki GS, Gordon-Krajcer W, Januszewski S, Chrapusta SJ.

Laboratory of Experimental Pharmacology, Polish Academy of Sciences Medical Research Centre, Warsaw. pgrieb@ibb.waw.pl

The study was designed to determine the effect of idebenone, an electron-trapping agent and free radical scavenger capable of crossing the blood-brain barrier, on cardiac arrest-induced oxidative brain stress. Stress indices used were the brain contents of thiobarbituric acid-reactive material (TBAR), conjugated dienes and protein and non-protein thiols. Twenty-four hours after receiving one oral dose of placebo or 100 mg kg(-1) idebenone, the rats were anaesthetized with diethyl ether and either decapitated immediately, or subjected to 7.5 min cardiac arrest induced by compression of the heart vessel bundle. The next groups of rats were sacrificed at the end of the cardiac arrest session, or resuscitated by external chest compression and artificial ventilation with air and sacrificed 15 min, 60 min, 24 h, and 72 h later while re-anesthetized with diethyl ether. Subsequent placebo or idebenone (100 mg kg(-1)) doses were given to the appropriate surviving rats once daily, beginning 8-10 min after the end of cardiac arrest session. Compared to pre-arrest values, TBAR and conjugated dienes' contents increased, respectively, by 339 and 286%, and protein and non-protein thiol contents decreased, respectively, by 69 and 85% within 60 min after the resuscitation in placebo-treated rats. Normalization of all oxidative stress indices in these rats was slow and incomplete even at 72 h. Idebenone treated rats showed no increase in TBAR contents, and a marked attenuation of changes in the other indices. These results show that oral idebenone greatly reduces oxidative brain stress following transient circulatory arrest in the rat. This effect could not be explained by simple stoichiometric scavenging of free radicals. Possible mechanisms of idebenone action are discussed.

[nootropi]

Idebenone protects hippocampal neurons against amyloid beta-peptide-induced neurotoxicity in rat primary cultures.

Hirai K, Hayako H, Kato K, Miyamoto M.

Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Osaka, Japan.

The application of amyloid beta-peptide (Abeta) 1-40 (10 microM) caused neurodegeneration of hippocampal neuronal cells, as indicated by the release of lactate dehydrogenase (LDH) into the culture medium. Treatment with idebenone (10-1000 nM), a potent antioxidant in mitochondria, protected the hippocampal neurons against the Abeta1-40(10 microM)-induced neurotoxicity. To determine the morphological change in neurons during the Abeta1-40-induced cytotoxicity, the cells were immunostained with anti-MAP2 antibodies. After 4-day exposure to 10 microM Abeta1-40, the number of neurons was reduced, and the surviving neurons had an apparently reduced number of neurites which were shorter than those of control neurons. When idebenone was added to the culture medium with Abeta1-40, the number of surviving neurons was significantly increased, and their neurites were as long as seen in control culture. These results suggest that reactive oxygen species mediate neurotoxicity of Abeta1-40, and idebenone protects neurons against the Abeta1-40-induced neurotoxicity.

[nootropi]

Chem Res Toxicol. 1998 Jan;11(1):54-63.  Related Articles, Links
   
    Antioxidant properties of 2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone (idebenone).

    Mordente A, Martorana GE, Minotti G, Giardina B.

    Institute of Biological Chemistry, Catholic University School of Medicine, Rome, Italy. ibicb@rm.unicatt.it

  Idebenone [2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone] is a synthetic analogue of coenzyme Q that is currently employed in the treatment of vascular and degenerative diseases of the central nervous system. There is some evidence to suggest that idebenone might function as an antioxidant; however, it has not been demonstrated whether this function pertains to the quinone or hydroquinone form of idebenone. Here we demonstrate that idebenone can scavenge a variety of free radical species, including organic radicals such as 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) and diphenylpicrylhydrazyl, peroxyl and tyrosyl radicals, and peroxynitrite. Idebenone can also redox couple with hypervalent species of Mb or Hb, thus preventing lipid peroxidation promoted by these species. Likewise, idebenone inhibits microsomal lipid peroxidation induced by ADP-iron complexes or organic hydroperoxides. In so doing, idebenone prevents the destruction of cytochrome P450, which otherwise would accompany lipid peroxidation. Irrespective of the experimental system under investigation, idebenone functions by virtue of the electron-donating properties of the hydroquinone form. Redox coupling of this hydroquinone with free radicals generates the quinone compound, which per se lacks antioxidant activity. In many experiments, the antioxidant effects of idebenone become appreciable at approximately 2 microM, which is well in the range of plasma levels attainable in patients given oral doses of this drug. Moreover, comparative experiments have shown that the antioxidant efficiency of idebenone varies from no less than 50% to slightly more than 100% of that of vitamin E or Trolox. We would therefore propose that the neuroprotective effects of idebenone can be attributed, at least in part, to its ability to function as an antioxidant, involving redox cycling between hydroquinone and quinone.

[nootropi]

Cognitive enhancement therapy for Alzheimer's disease. The way forward.

Parnetti L, Senin U, Mecocci P.

Perugia University, Italy. parnetti@unipg.it

Although at present there is no definitive treatment or cure for Alzheimer's disease, different pharmacological strategies are being actively investigated. At present, cholinergic therapy and nootropics and some neuronotrophic agents represent the available approaches to symptomatic treatment of Alzheimer's disease. The use of cholinesterase inhibitors (ChEI) constitutes the best cholinergic approach to increase acetylcholine levels. Available data suggest that about 15 to 40% of Alzheimer's disease patients show a varying degree of cognitive improvement while taking these medications; however, haematological complications (neutropenia or agranulocytosis), together with hepatotoxicity, need to be considered carefully. Recent data suggest that long term administration of nootropics may lead to a significant improvement of cognitive functions in Alzheimer's disease patients compared with untreated individuals, having excellent tolerability. Protocols for the intracerebroventricular administration of neuronotrophic substances are also ongoing. The most promising approaches for the future currently undergoing investigation involve attempts to slow the production of beta-amyloid and/or to inhibit beta-amyloid aggregation. Another rational therapeutic approach would be to inhibit the formation of paired helical filaments (PHF) by increasing and/or modulating the activities of protein phosphatases and kinases. Antioxidant therapy should disrupt or prevent the free radical/beta-amyloid recirculating cascade and the progressive neurodegeneration. Idebenone, a synthetic compound acting as an 'electron trapper' and free radical scavenger, has shown some efficacy in degenerative and vascular dementia; at present, other different molecules having antioxidative properties [lazaroids (21-aminosteroids), pyrrolopyrimidines, nitric oxide blockers, selegiline, some vitamins] are under investigation. Lowering absorption or brain tissue concentrations of aluminium also offers possible therapeutic opportunities for slowing the rate of clinical progression of the disease; in this sense, some evidence exists using the aluminium chelating agent deferoxamine (desferrioxamine). Inflammation also may play a significant pathogenetic role in Alzheimer's disease. As shown by several retrospective analyses, there is an inverse association of anti-inflammatory drug use with the frequency of Alzheimer's disease diagnosis. Consequently, clinical trials using both nonsteroidal and steroidal molecules have been proposed. These lines of pharmacological intervention represent an important premise for future therapeutic strategies capable of counteracting the pathogenesis of Alzheimer's disease.

[nootropi]

Free Radic Biol Med. 1997;23(4):637-47.  Related Articles, Links
   
    Glutamate toxicity on a PC12 cell line involves glutathione (GSH) depletion and oxidative stress.

    Pereira CM, Oliveira CR.

    Center for Neurosciences of Coimbra, Department of Zoology, University of Coimbra, Portugal.

    The effect of antioxidants and reducing agents on glutamate-induced cytotoxicity was examined using PC12 cells. The antioxidants vitamin E, idebenone, and selegiline protected cells against the cytotoxicity observed 24 h after exposure to 0.5 or 10 mM glutamate, as determined by lactate dehydrogenase leakage, even when added 3 h after glutamate. The reducing agents, glutathione (GSH) and dithiothreitol (DTT), also provided protection against the cytotoxicity of glutamate. Preincubation of PC12 cells with the antioxidants mentioned above, or the incubation with those antioxidants after exposure to glutamate for 3 h, prevented the reduction of viability caused by glutamate. Cystine uptake was inhibited by exposure of cells to glutamate, as determined by L-[35S]-cystine uptake. Incubation of cells with 0.5 or 10 mM glutamate caused a marked decrease in cellular GSH levels, not prevented by antioxidants. The activity of GSSG reductase was decreased by glutamate and this inhibition was reverted in the presence of the reducing agents GSH and DTT. These results indicate that glutamate toxicity on PC12 cells results from the inhibition of cystine uptake with consequent GSH depletion and oxidative stress, suggesting that antioxidants may reduce the cellular damage in pathologic conditions associated with excessive glutamate release.

[nootropi]

1: MAGMA. 1996 Sep-Dec;4(3-4):247-50.  Related Articles, Links

    An analysis of the intracerebral ability to eliminate a nitroxide radical in the rat after administration of idebenone by an in vivo rapid scan electron spin resonance spectrometer.

    Yokoyama H, Tsuchihashi N, Ogata T, Hiramatsu M, Mori N.

    Institute for Life Support Technology, Yamagata Technopolis Foundation, Japan.

    Electron spin resonance (ESR) measurements after intracerebroventricular injection of a nitroxide radical were carried out in rats (n = 6) that received oral idebenone for 2 weeks and in control rats (n = 5), using an in vivo rapid scan ESR spectrometer. The half-life of nitroxide, which was estimated from the change in the peak height (delta M = +1) of the ESR signals from the head, was used as a marker for the elimination of the nitroxide radical. The half-life in the rats treated with idebenone was significantly shorter than it was in the controls (p < 0.05). This finding indicates that the treatment with idebenone can enhance the intracerebral-eliminating ability of the nitroxide radical.

[nootropi]

Mov Disord. 1996 Sep;11(5):549-54.  Related Articles, Links

    A controlled trial of idebenone in Huntington's disease.

    Ranen NG, Peyser CE, Coyle JT, Bylsma FW, Sherr M, Day L, Folstein MF, Brandt J, Ross CA, Folstein SE.

    Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    One hundred patients with clinically diagnosed Huntington's disease (HD) were randomized to either idebenone, an antioxidant and enhancer of oxidative metabolism, or placebo, in a 1-year, double-blind, parallel-group study aimed at slowing the rate of progression of the disease. Ninety-one patients completed the study. There were no significant differences between groups on the primary outcome measures of the Huntington's Disease Activities of Daily Living Scale (ADL-an index of functional status) and the Quantified Neurologic Examination (QNE). Sample size calculations based on progression of the ADL and QNE in this study group revealed that a larger study group is necessary to detect any differences less than an almost complete halting of the disease. This argues for multicenter efforts for future therapeutic trials in HD.

[nootropi]

1: Neurology. 1996 Aug;47(2):583-5.  Related Articles, Links

    Idebenone improves cerebral mitochondrial oxidative metabolism in a patient with MELAS.

    Ikejiri Y, Mori E, Ishii K, Nishimoto K, Yasuda M, Sasaki M.

    Division of Clinical Neurosciences, Hyogo Institute for Aging Brain and Cognitive Disorders, Himeji, Japan.

    We report a 36-year-old man with MELAS in whom a 5-month course of high-dose oral idebenone, a derivative of coenzyme Q10, increased markedly cerebral metabolic ratio of oxygen and oxygen extraction fraction without increased cerebral blood flow with PET. The results indicate that idebenone improves mitochondrial oxidative metabolism in the brain and suggest a therapeutic potential of idebenone for MELAS.

[nootropi]

Eur Neuropsychopharmacol. 1996 May;6(2):95-102.  Related Articles, Links
   
    Effect of idebenone on in vivo serotonin release and serotonergic receptors in young and aged rats.

    Scavini C, Rozza A, Lanza E, Favalli L, Racagni G, Brunello N.

    Institute of Pharmacology, University of Pavia, Italy.

    The effect of idebenone on the serotonergic system was evaluated in the aging rat by measuring the kinetic constants of 3H-5HT and 3H-ketanserin binding sites in the cerebral cortex of rats at 3, 15 and 24 months of age following acute and subchronic administration of the drug. Idebenone displayed no in vitro affinity toward any population of serotonin receptors and did not modify their kinetic parameters after a single dose of 100 mg/kg, at any age tested. A subchronic treatment with the drug for 21 days at the dose of 30 mg/kg did not induce any relevant change in 3- and 15-month-old rats, whereas it significantly increased the density of both 3H-5HT and 3H-ketanserin binding sites in 24-month-old rats, where a lower number of receptors is detected as a consequence of aging. This effect was rather specific, since under the same experimental conditions no changes were detected in the density of cortical beta-adrenergic receptors in aged animals. In microdialysis studies, acute administration with idebenone did not affect 5HT and 5HIAA release at any age. Conversely, the pattern of serotonin metabolism was significantly modified in aged rats following repeated treatment with idebenone and was partially restored to a value similar to the one observed in young animals. These results suggest that idebenone, a putative neuroprotective agent which has been shown to improve brain metabolism in ischemic conditions, might also attenuate age-associated neuronal damage, acting probably on several neurotransmitter systems which undergo selective modification during aging.

[nootropi]

Transplantation. 1995 Sep 15;60(5):444-51.  Related Articles, Links

    Idebenone protects hepatic microsomes against oxygen radical-mediated damage in organ preservation solutions.

    Wieland E, Schutz E, Armstrong VW, Kuthe F, Heller C, Oellerich M.

    Abteilung Klinische Chemie, Georg-August-Universitat Gottingen, Germany.

    The ability of the benzoquinone coenzyme Q-10 or its derivative QSA-10 (idebenone) to protect against lipid peroxidation and protein damage mediated by the pro-oxidative system NADPH/ADP/Fe3+ was tested in a rat liver microsomal model incubated in University of Wisconsin (UW) or histidine-tryptophan-ketoglutarate (HTK) solutions. Lipid peroxidation, as followed by direct determination of lipid hydroperoxides and by monitoring of malondialdehyde equivalents, was 1.8-fold enhanced in HTK and 3-fold attenuated in UW compared with HEPES buffer. Function and integrity of microsomal enzymes were investigated using glutathione S-transferase and cytochrome P-450 IIIA activity as assessed by lidocaine N-deethylation to monoethylglycinexylidide as well as by Western blot analysis of the cytochrome P-450 IIIA protein. Glutathione S-transferase activity was reduced by about 70% in HEPES compared with 50% in HTK and 36% in UW. Cytochrome P-450 IIIA was inactivated by about 75% in HEPES and HTK, compared with 55% in UW. The enzyme inactivation was paralleled by a loss of immunoreactive cytochrome P-450 IIIA protein. Supplementation of HTK with 0.1 mumol/L QSA-10 offered complete protection against lipid peroxidation, compared with 100 mumol/L with Q-10. QSA-10 (20 mumol/L) prevented protein damage in both preservation solutions, whereas Q-10 (20 mumol/L) offered only partial protection in UW and had no effect in HTK. The use of QSA-10 during liver transplantation may therefore have the potential of increasing the efficacy of organ preservation, maintaining donor organ quality, and preventing reperfusion injury. It is suitable for human use and has energy-conserving properties in addition to its antioxidant nature.

[nootropi]

: Neurosci Lett. 1994 Sep 12;178(2):193-6.  Related Articles, Links

    Protective action of idebenone against excitotoxic degeneration in cultured cortical neurons.

    Bruno V, Battaglia G, Copani A, Sortino MA, Canonico PL, Nicoletti F.

    Institute of Pharmacology, School of Medicine, University of Catania, Italy.

    The novel free radical scavenger and electron-trapping agent, idebenone, protects cultured cortical neurons against necrotic degeneration induced by either a brief exposure to N-methyl-D-aspartate (NMDA) or a prolonged exposure to kainate. As opposed to the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]- cyclohepten-5,10-imine hydrogen maleate (MK801), idebenone rescued cortical neurons even when applied 30 min after the NMDA pulse, suggesting that the drug interferes with the chain of toxic reactions triggered by an excessive stimulation of excitatory amino acid receptors.

[nootropi]

Drugs Aging. 1994 Aug;5(2):133-52.  Related Articles, Links

    Idebenone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in age-related cognitive disorders.

    Gillis JC, Benefield P, McTavish D.

    Adis International Limited, Auckland, New Zealand.

    Idebenone is a benzoquinone compound which has been investigated in elderly patients with dementia. Its precise mechanism(s) of action remains unknown, but in vitro and in vivo studies suggest the drug may diminish nerve cell damage due to ischaemia, correct neurotransmitter defects and/or cerebral metabolism and facilitate memory and learning. In the small number of studies available for evaluation, idebenone was generally superior to placebo and comparable with bifemelane, oxiracetam and nebracetam on the basis of a number of objective and subjective tests and rating scales in patients with mild to moderate cognitive decline. Clinical trial results indicate that patients with mild dementia seem more likely to respond than those with greater functional decline. The degree of benefit conferred by idebenone is often difficult to determine, but in those who respond, improvement is generally mild to moderate. Therapy with idebenone appears well tolerated for up to 2 years, and no changes in vital signs or laboratory values have been seen in clinical trials. In view of the lack of a proven agent to limit or halt the progression of dementia in the elderly, idebenone may warrant consideration in patients with mild cognitive dysfunction on the basis of preliminary evidence of predominantly mild improvement of functional status in some patients and good tolerability. However, further well designed studies, including comparisons with newer and commonly used agents, such as tacrine, are required to better define the role of idebenone in this complex area of treatment.

[nootropi]

Oral administration of idebenone, a stimulator of NGF synthesis, recovers reduced NGF content in aged rat brain.

Nitta A, Hasegawa T, Nabeshima T.

Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Japan.

The relationship between nerve growth factor (NGF) and senile dementia of the Alzheimer type is of interest. We demonstrate here that the oral administration of idebenone, a stimulator of NGF synthesis in vitro, produced recovery of reduced NGF content in aged rat brain. Twenty-one-day successive administration of idebenone produced significant recovery of reduced NGF content in the frontal cortex and parietal cortex of aged rats. These results suggest that NGF content in the brain is low in aged rats and that oral administration of idebenone leads to a recovery of this reduction.

[nootropi]

Artery. 1993;20(6):314-23.  Related Articles, Links

    Protective effects of idebenone on vascular endothelial cells against toxicity induced by oxidatively modified low density lipoprotein.

    Naito M, Hayashi T, Yamada K, Asai K, Yoshimine N, Iguchi A.

    Department of Geriatrics, Nagoya University School of Medicine, Japan.

    We examined the protective effects of idebenone, 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone, on the cytotoxicity of oxidatively-modified low density lipoprotein (oxLDL), using cultured vascular endothelial cells from fetal bovine aorta. When the cells were incubated with idebenone, the toxicity of oxLDL was inhibited dose-dependently (10(-7)-10(-5) M). When cells were preincubated with idebenone, the toxicity of oxLDL was inhibited only at a high concentration (10(-5) M). However, idebenone had no significant effects on copper-induced modification of LDL. The protective effects of idebenone on oxLDL-induced endothelial toxicity may be beneficial for the inhibition of the development of atherosclerosis in the brain and other arterial systems.

[nootropi]

Neuropharmacology. 1989 Jun;28(6):569-73.  Related Articles, Links

    Idebenone and vinpocetine augment long-term potentiation in hippocampal slices in the guinea pig.

    Ishihara K, Katsuki H, Sugimura M, Satoh M.

    Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.

    The effects of idebenone and vinpocetine which reportedly prevent impairment of learning and memory were studied in vitro, on the long-term potentiation of the population spike in the pyramidal layer of CA3 region of slices of hippocampus in the guinea pig. Idebenone (10(-9) M-10(-6) M) or vinpocetine (10(-7) M-10(-6) M) significantly augmented long-term potentiation in the mossy fibre-CA3 pyramidal cell system, without any significant changes in population spikes in the absence of tetanic stimulation. These results suggest that both drugs have direct actions on the hippocampal neurones to augment long-term potentiation at fairly small concentrations. Further, when the two drugs were applied together, the augmenting effects were additive.