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At least 37 records · Page 2Linked to original sources
PubMed2005

Minocycline fails to protect cerebellar granular cell cultures against malonate-induced cell death.

Experimental and clinical studies support the view that the semisynthetic tetracycline minocycline exhibits neuroprotective roles in several models of neurodegenerative diseases, including ischemia, Huntington, Parkinson diseases, and amyotrophic lateral sclerosis. However, recent evidence indicates that minocycline does not always present beneficial actions. For instance, in an in vivo model of Huntington's disease, it fails to afford protection after malonate intrastriatal injection. Moreover, it reverses the neuroprotective effect of creatine in nigrostriatal dopaminergic neurons. This apparent contradiction prompted us to analyze the effect of this antibiotic on malonate-induced cell death. We show that, in rat cerebellar granular cells, the succinate dehydrogenase inhibitor malonate induces cell death in a concentration-dependent manner. By using DFCA, monochlorobimane and 10-N-nonyl-Acridin Orange to measure, respectively, H2O2-derived oxidant species and reduced forms of GSH and cardiolipin, we observed that malonate induced reactive oxygen species (ROS) production to an extent that surpasses the antioxidant defense capacity of the cells, resulting in GSH depletion and cardiolipin oxidation. The pre-treatment for 4 h with minocycline (10-100 microM) did not present cytoprotective actions. Moreover, minocycline failed to block ROS production and to abrogate malonate-induced oxidation of GSH and cardiolipin. Additional experiments revealed that minocycline was also unsuccessful to prevent the mitochondrial swelling induced by malonate. Furthermore, malonate did not induce the expression of the iNOS, caspase-3, -8, and -9 genes which have been shown to be up-regulated in several models where minocycline resulted cytoprotective. In addition, malonate-induced down-regulation of the antiapoptotic gene Bcl-2 was not prevented by minocycline, controversially the mechanism previously proposed to explain minocycline protective action. These results suggest that the minocycline protection observed in several neurodegenerative disease models is selective, since it is absent from cultured cerebellar granular cells challenged with malonate.

Animals↗
PubMed1998

Combined malonic and methylmalonic aciduria with normal malonyl-coenzyme A decarboxylase activity: a case supporting multiple aetiologies.

We identified a patient who excreted large amounts of methylmalonic acid and malonic acid. In contrast to other patients who have been described with combined methylmalonic and malonic aciduria, our patient excreted much larger amounts of methylmalonic acid than malonic acid. Since most previous patients with this biochemical phenotype have been reported to have deficiency of malonyl-CoA decarboxylase, we assayed malonyl-CoA decarboxylase activity in skin fibroblasts derived from our patient and found the enzyme activity to be normal. We examined four isocaloric (2000 kcal/day) dietary regimes administered serially over a period of 12 days with 3 days devoted to each dietary regimen. These diets were high in carbohydrate, fat or protein, or enriched with medium-chain triglycerides. Diet-induced changes in malonic and methylmalonic acid excretion became evident 24-36 h after initiating a new diet. Total excretion of malonic and methylmalonic acid was greater (p < 0.01) during a high-protein diet than during a high-carbohydrate or high-fat diet. A high-carbohydrate, low-protein diet was associated with the lowest levels of malonic and methylmalonic acid excretion. Perturbations in these metabolites were most marked at night. On all dietary regimes, our patient excreted 3-10 times more methylmalonic acid than malonic acid, a reversal of the ratios reported in patients with malonyl-CoA decarboxylase deficiency. Our data support a previous observation that combined malonic and methylmalonic aciduria has aetiologies other than malonyl-CoA decarboxylase deficiency. The malonic acid to methylmalonic acid ratio in response to dietary intervention may be useful in identifying a subgroup of patients with normal enzyme activity.

Amino Acid Metabolism, Inborn Errors↗
PubMed2001

Dopamine mediates striatal malonate toxicity via dopamine transporter-dependent generation of reactive oxygen species and D2 but not D1 receptor activation.

Intrastriatal injection of the reversible succinate dehydrogenase inhibitor malonate results in both chemically induced hypoxia and striatal lesions that are similar to those seen in Huntington's disease and cerebral ischaemia. The mechanisms leading to neuronal death involve secondary excitotoxicity, the release of dopamine from nigrostriatal fibres and the generation of reactive oxygen species (ROS) including nitric oxide (NO) and hydroxyl radicals. Here, we further investigated the contribution and mechanism of dopamine on malonate-induced striatal lesions. Prior lesions of the nigrostriatal pathway with 6-OHDA or the depletion of striatal dopamine stores by pretreatment with reserpine, an inhibitor or the vesicular monoamine transporter type-2 (VMAT2), in combination with alpha-methyl-p-tyrosine resulted in a significant reduction of malonate-induced striatal lesion volumes. This was paralleled by block or reduction of the malonate-induced generation of ROS, as measured by the conversions of salicylate to 2,3-dihydroxybenzoic acid (2,3-DHBA) using microdialysis. Systemic or intrastriatal application of L-DOPA or dopamine, respectively, reconstituted malonate toxicity and the generation of ROS in 6-OHDA-lesioned rats. Block of the dopamine transporter by GBR12909 did not result in a reduction of malonate-induced dopamine release, but significantly reduced the generation of hydroxyl radicals. The D2 receptor agonist lisuride and the mixed D1 and D2 receptor agonist apomorphine, but not the D1 receptor agonist SKF38393, partially restored malonate toxicity in 6-OHDA-lesioned rats without increasing the generation of ROS. In line with these results sulpiride, an inhibitor of D2 receptors, reduced the malonate-induced lesion volume, whereas SCH23390, an inhbitor of D1 receptors, was ineffective. Our data suggest that malonate-induced dopamine toxicity to energetically impaired neurons is mediated by two independent pathways: (i) dopamine transporter uptake-dependent, dopamine receptor-independent generation of ROS, and (ii) excessive stimulation of D2 receptors.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2005

Time course of oxidative stress, lesion and edema after intrastriatal injection of malonate in rat: effect of alpha-phenyl-N-tert-butylnitrone.

The aim of this study was to characterize the model of oxidative stress consisting in the infection of malonate (3 mumol), an inhibitor of mitochondrial complex II, in the rat striatum. The striatal concentrations of both the reduced and oxidized forms of glutathione (the major endogenous antioxidant) were determined at various times after malonate injection (1-4 h) in order to evaluate the evolution of oxidative stress. The progression of lesion size and edema was also determined up to 24 h after malonate administration. Finally, the effect of alpha-phenyl-N-tert-butylnitrone (PBN), an antioxidant nitrone, was studied. The levels of reduced glutathione (GSH) progressively decreased after malonate injection up to 40% of those of sham animals at 4 h. An increase in the concentrations of oxidized glutathione (GSSG) was also observed as early as 1 h after malonate administration which was maintained up to 4 h. The size of the lesion was maximal within 2 h of malonate injection, whereas edema continued to increase between 2 and 24 h. Injection of PBN at 100 mg/kg i.p. 30 min before and 2 h after malonate administration abolished the GSSG increase caused by malonate but did not modify the drop in GSH. This moderate antioxidant effect of PBN was associated with a slight decrease of the lesion area at two levels (10.7 and 10.2 mm anterior to the interaural line), but the lesion volume remained unchanged. By contrast, PBN reduced edema by 30%. Taken together, these results show that malonate induced a severe oxidative stress leading to the rapid development of the lesion. PBN demonstrates anti-edematous properties that are not sufficient to reduce the lesion.

Animals↗
PubMed1993

Selection of malonate-resistant stromal cell-derived osteoprogenitor cells in vitro.

Bone marrow stromal cells give rise to osteoprogenitor cell (OPC) colonies, with characteristic mineralized bone nodules in vitro. During differentiation, OPCs in the culture are surrounded by heterogeneous populations of various cell lineages and by different OPC differentiation stages. In the present study, attempts were made to increase the homogeneity of OPCs in culture. The reliance on energy metabolism restricted to glycolysis, which is specific to the premineralizing skeletal cells, was tested as a selectable marker for cells in this stage. Day 12 alkaline phosphatase (ALP) and day 20-21 calcium precipitates were used as early and late OPC differentiation markers. Malonate, a competitive inhibitor of succinate dehydrogenase, was added to the OPC stimulation medium, to interfere with the Krebs cycle-dependent energy metabolism operating in most of the stromal cells. OPCs that entered the stage of energy metabolism restricted to glycolysis were expected to become malonate resistant. Malonate showed dose and time dependence, 10 mM malonate added on day 3, decreased day 12 ALP activity/well to the lowest level. Variations in time and length of exposure to malonate used during the first 12 days of differentiation showed an inverse correlation between specific ALP activity and cell yield. Malonate-treated variations of specific ALP and of cell yield indices were up to 30- to 40-fold larger than variations within day 21 calcium precipitates. Thus, calcifying cells were almost unchanged relatively to noncalcifying cells. These results indicate that malonate-resistant cells are mostly selected, rather than induced, to differentiate by malonate. The results also show that stromal derived OPCs undergo a similar biochemical stage as in chondrocytes.

Alkaline Phosphatase↗
PubMed1992

Anaerobic malonate decarboxylation by Citrobacter diversus. Growth and metabolic studies, and evidence of ATP formation.

Citrobacter diversus ATCC 27156 was able to grow by decarboxylation of malonate to acetate under strictly anaerobic conditions, in the presence of yeast extract. The growth yield, corrected for growth on yeast extract, was 2.03 g cell dry mass per mol malonate. The addition of malonate to ATP-depleted cell suspensions (less than 0.2 nmol ATP/mg cell protein) resulted in a rapid increase in cellular ATP levels to between 4.5 and 6.0 nmol/mg cell protein. Intact cells decarboxylated malonate at rates of up to 1.5 mumol/min.mg protein. Enzyme assays on malonate-grown cells indicated activation of malonate by an ATP-dependent ligase reaction and by CoA transfer from acetyl-CoA, followed by decarboxylation of malonyl-CoA to acetyl-CoA with subsequent recovery of the invested ATP by substrate level phosphorylation through the activity of acetate kinase. Net ATP synthesis is postulated to be mediated by gradient formation coupled to the decarboxylation of malonyl-CoA. The protonophore CCCP and H(+)-ATPase inhibitor DCCD significantly reduced cellular ATP levels, suggesting a role for proton gradients in the energy metabolism of this strain when growing an malonate. Inhibitors of sodium metabolism or ommission of sodium had no effect on ATP levels or malonate decarboxylation.

Adenosine Triphosphate↗
PubMed2004

Intrastriatal malonate administration induces convulsive behaviour in rats.

Malonic acidaemia is an inborn error of metabolism that accumulates malonate, a competitive succinate dehydrogenase (SDH; EC 1.3.99.1) inhibitor. The present study investigated the behavioural effects of unilateral intrastriatal administration of malonate (0.6, 1.8 or 6 micromol) in adult male Wistar rats (n=10-13). Low doses of malonate (1.8 micromol) decreased exploratory activity and caused ipsiversive rotational behaviour. High doses of malonate (6 micromol) induced contralateral rotational behaviour and convulsive episodes. Malonate competitively inhibited SDH in mitochondrion-enriched fractions from striatum ( Ki=0.034+/-0.008 mmol/L). Interestingly, methylmalonate, which is a weaker SDH inhibitor than malonate (Ki=4.22+/-1.3 mmol/L), induced more convulsions than malonate at equimolar doses and did not cause ipsiversive rotational behaviour. It is suggested that the potency of SDH inhibition in vitro does not correlate positively with the convulsant potential of these inhibitors in vivo.

Acute Disease↗
PubMed1996

Manipulation of membrane potential modulates malonate-induced striatal excitotoxicity in vivo.

Malonate is a reversible inhibitor of succinate dehydrogenase (SDH) that produces neurotoxicity by an N-methyl-D-aspartate (NMDA) receptor-dependent mechanism. We have examined the influence of pharmacological manipulation of membrane potential on striatal malonate toxicity in rats in vivo by analysis of lesion volume. Depolarization caused by coinjection of the Na+,K(+)-ATPase inhibitor ouabain or a high concentration of potassium greatly exacerbated malonate toxicity; this combined toxicity was blocked by the noncompetitive NMDA antagonist MK-801. The toxicity of NMDA was also exacerbated by ouabain. The overt toxicity of a high dose of ouabain (1 nmol) was largely prevented by MK-801. Coinjection of the K+ channel activator minoxidil (4 nmol) to reduce depolarization attenuated the toxicity of 1 mumol of malonate by approximately 60% without affecting malonate-induced ATP depletion. These results indicate that membrane depolarization exacerbates malonate neurotoxicity and that membrane hyperpolarization protects against malonate-induced neuronal damage. We hypothesize that the effects of membrane potential on malonate toxicity are mediated through the NMDA receptor as a result of its combined agonist- and voltage-dependent properties.

Adenosine Triphosphate↗
PubMed2006

Reactive oxygen species and p38 mitogen-activated protein kinase activate Bax to induce mitochondrial cytochrome c release and apoptosis in response to malonate.

Malonate, an inhibitor of mitochondrial complex II, is a widely used toxin to study neurodegeneration in Huntington's disease and ischemic stroke. We have shown previously that malonate increased reactive oxygen species (ROS) production in human SH-SY5Y neuroblastoma cells, leading to oxidative stress, cytochrome c release, and apoptotic cell death. Expression of a green fluorescent protein-Bax fusion protein in SH-SY5Y neuroblastoma cells demonstrated a Bax redistribution from the cytosol to mitochondria after 12 to 24 h of malonate treatment that coincided with mitochondrial potential collapse and chromatin condensation. Inhibition of Bax translocation using furosemide, as well as Bax gene deletion, afforded significant protection against malonate-induced apoptosis. Further experiments revealed that malonate induced a prominent increase in the level of activated p38 mitogen-activated protein (MAP) kinase and that treatment with the p38 MAP kinase inhibitor SKF86002 potently blocked malonate-induced Bax translocation and apoptosis. Treatment with vitamin E diminished ROS production, reduced the activation status of p38 MAP kinase, inhibited Bax translocation, and protected against malonate-induced apoptosis. Our data suggest that malonate-induced ROS production and subsequent p38 MAP kinase activation mediates the activation of the pro-apoptotic Bax protein to induce mitochondrial membrane permeabilization and neuronal apoptosis.

Animals↗
PubMed1998

Identification of an Na+-dependent malonate transporter of Malonomonas rubra and its dependence on two separate genes.

Two membrane proteins encoded by the malonate fermentation gene cluster of Malonomonas rubra, MadL and MadM, have been synthesized in Escherichia coli. MadL and MadM were shown to function together as a malonate transport system, whereas each protein alone was unable to catalyze malonate transport. Malonate transport by MadLM is Na+ dependent, and imposition of a DeltapNa+ markedly enhanced the rate of malonate uptake. The kinetics of malonate uptake into E. coli BL21(DE3) cells synthesizing MadLM at different pH values indicated that Hmalonate- is the transported malonate species. The stimulation of malonate uptake by Na+ ions showed Michaelis-Menten kinetics, and a Km for Na+ of 1.2 mM was determined. These results suggest that MadLM is an electroneutral Na+/Hmalonate- symporter and that it is dependent on two separate genes.

Biological Transport↗
PubMed1995

Relative vulnerability of dopamine and GABA neurons in mesencephalic culture to inhibition of succinate dehydrogenase by malonate and 3-nitropropionic acid and protection by NMDA receptor blockade.

The effects of different severities of metabolic stress on dopamine (DA) and gamma-aminobutyric acid (GABA) cell loss were examined in rat mesencephalic culture. Partial metabolic inhibition was induced in 12-day-old cultures by a 24-hr treatment with various concentrations of 3-nitropropionic acid(3-NPA, 0.1-0.5 mM) or malonate (10-50 mM), irreversible and reversible inhibitors of the Krebs cycle enzyme, succinate dehydrogenase. Cell damage to the DA and GABA populations was assessed after a 48-hr recovery period by simultaneous measurement of high affinity uptake for 3H-DA and 14C-GABA. 3-NPA or malonate caused a dose-dependent loss of DA uptake (EC50 0.21 or 42 mM, respectively). 3-NPA treatment was equally detrimental to the GABA population, whereas malonate exposure did not cause any significant loss of GABA uptake. The presence of the NMDA antagonist, MK-801 (1 microM), during 24 hr of 3-NPA or malonate treatment fully protected against DA and GABA loss with 50 mM malonate or 0.25 mM 3-NPA and partially protected versus 0.5 mM 3-NPA. To determine the degree of metabolic stress imposed by 3-NPA and malonate, 12-day-old cultures were treated with 0.5 mM 3-NPA or 50 mM malonate for 3 hr and the rate of lactate formation was measured. lactate was increased nearly 2-fold at 3 hr of treatment with 3-NPA, but was not significantly elevated above basal with malonate treatment. SDH activity was decreased by 48 or 58% after 3 hr of treatment with 0.25 and 0.5 mM 3-NPA, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2007

Malone antegrade continent enema: an alternative to resection in severe defecation disorders.

PURPOSE: This study was designed to evaluate patient self-reported outcome of the Malone antegrade continent enema at a single institution in patients suffering from severe defecatory disorders. METHODS: A total of 18 patients (15 females; median age, 31 (range, 12-63) years) underwent a Malone antegrade continent enema (August 1999 to September 2004). The Malone antegrade continent enema technique has been previously described; however, in this series emphasis was placed on method appendix tunneling. Patients' charts were reviewed and follow-up telephone interviews were conducted. Indications for Malone antegrade continent enema were chronic constipation (n = 12), intractable fecal incontinence (n = 5), or both (n = 1). The underlying pathology included neurogenic (n = 2), congenital (n = 4), postsurgery-related (n = 4), irritable bowel syndrome (n = 6), and megarectum (n = 2). The appendix (n = 17) or cecum (n = 1) was used as a conduit. RESULTS: The mean follow-up was 18.5 (range, 3-67) months. Fourteen patients (78 percent) still use the Malone antegrade continent enema routinely and report good functional outcome. Three patients (20 percent) required stoma creation as subsequent alternate treatment. A total of 10 patients experienced 12 complications: 3 perioperative (infections) and 9 postoperative Malone antegrade continent enema use/nonuse complications (4 stomal orifice strictures, 2 fecal impactions, 2 appendiceal perforations, and 1 irrigation catheter knot). No patient experienced leakage from the appendiceal stoma. During the follow-up interval, one patient underwent proctectomy for megarectum. No failures occurred in patients with congenital or neurogenic disorders. CONCLUSIONS: Malone antegrade continent enema is a reasonable option for the treatment of select patients with severe defecation disorders. Good functional patient self-reported outcome was achieved by 78 percent of patients. The social inconvenience of stoma leakage is avoided with appropriate surgical technique. Malone antegrade continent enema is one option that provides a less invasive surgical alternative than colectomy or ileostomy for severe defecation disorders.

Adolescent↗
PubMed1984

Evaluation of diethyl malonate as a simulant for 1,2,2-trimethylpropyl methylphosphonofluoridate (soman) in shower decontamination of the skin.

A shower decontamination bench model has been used to assess quantitatively the importance of several variables (water pressure and temperature, surfactant concentration in the decontamination fluid, nozzle type, and shower time) on decontamination of nontoxic chemical warfare-agent simulants diethyl malonate and thickened diethyl malonate from pig skin in vitro. Diethyl malonate was validated as a simulant for 1,2,2-trimethylpropyl methylphosphonofluoridate (soman) by comparison of the skin penetration and decontamination of radiolabeled diethyl malonate to the radiolabeled phosphonofluoridate in shower decontamination trials of pig skin in vitro. Percutaneous penetration of diethyl malonate was significantly greater than that of the phosphonofluoridate during the 15-min period after application. However, both were less than 0.1% of the applied dose. Showering or thickener had no significant effect on the percutaneous penetration of diethyl malonate or the phosphonofluoridate. Most of the phosphonofluoridate removed by showering or scrubbing the skin was inactivated. The quantity of intact 1,2,2-trimethylpropyl methylphosphonofluoridate that penetrated through the skin was below the detection limit of the enzymatic analysis. There was no statistically significant difference between the phosphonofluoridate and diethyl malonate in efficacy of shower decontamination. The presence of thickener did not have a significant effect on decontamination efficacy.

Animals↗
PubMed1994

A plasmid responsible for malonate assimilation in Pseudomonas fluorescens.

A novel, broad-host-range 60-kb R-plasmid, which encodes for malonate assimilation, was isolated from Pseudomonas fluorescens and was designated pPSF1. Pseudomonas, which can utilize malonate as a sole carbon source, was unable to grow on malonate medium upon curing with mitomycin C, indicating loss of plasmid pPSF1. Furthermore, Escherichia coli transformed with pPSF1 was able to grow on malonate medium as a sole carbon source. Malonate decarboxylase, a key enzyme in malonate assimilation, was detected in transformed E. coli grown on malonate. pPSF1 also encodes resistance to several antibiotics such as ampicillin, kanamycin, and streptomycin and is transmissible between E. coli and Pseudomonas by conjugation.

Ampicillin Resistance↗
PubMed1981

Effect of substrates on the malonate inhibitory pattern and brefeldin A formation in Curvularia lunata.

The extracellular level of brefeldin A fluctuates with the length of malonate inhibition. Following treatment with malonate, mycelial multiplication as opposed to brefeldin A formation, was preferentially increased in the maleate, fumarate, succinate, citrate, methyl palmitate and glucose replacement cultures. Competitive maleate--malonate, fumarate--malonate, succinate--malonate and citrate--malonate-inhibited replacement cultures gave significantly higher mycelial and brefeldin A yields than the sole malonate-inhibited replacement cultures.

Anti-Bacterial Agents↗
PubMed1996

Damage to dopaminergic nerve terminals in mice by combined treatment of intrastriatal malonate with systemic methamphetamine or MPTP.

The mechanisms involved in methamphetamine (METH)-induced damage to nigrostriatal dopaminergic neurons in experimental animals are unknown. We have examined the possibility that perturbations in energy metabolism contribute to METH-induced toxicity by investigating the effects of systemic METH treatment in mice which received a unilateral intrastriatal infusion of malonate, a metabolic inhibitor which decreases ATP levels. Malonate (1-4 mumol) produced a dose-dependent decrease in striatal dopamine (DA). The combined treatment of intrastriatal malonate with systemic METH resulted in greater damage to dopaminergic neurons than by METH or malonate treatment alone. In parallel studies, MPTP was administered to mice which received intrastriatal infusions of saline or malonate. Similar to results obtained with METH, decreases in striatal DA content and tyrosine hydroxylase (TH) activity were greatest in MPTP-treated mice infused with malonate. The present results lend credence to the hypothesis that METH-induced increases in energy utilization create a state of metabolic stress for DA neurons which may ultimately contribute to the neurodegenerative effects of METH. Moreover, the finding that combined malonate and MPTP treatment produced greater damage than either substance alone is consistent with the hypothesis that perturbations in energy metabolism contribute to the neuronal death produced by MPP+.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2006

Contribution to the chemistry of the Belousov-Zhabotinsky reaction. Products of the Ferriin-Bromomalonic acid and the Ferriin-Malonic acid reactions.

In the present mechanistic schemes of the ferroin-catalyzed oscillatory Belousov-Zhabotinsky (BZ) reaction the oxidation of the organic substrates (bromomalonic or malonic acid) by ferriin (the oxidized form of the catalyst) plays an important role. As the organic products of these reactions were not yet identified experimentally, they were studied here by an HPLC technique. It was found that the main organic oxidation product of bromomalonic acid is bromo-ethene-tricarboxylic acid (BrEETRA), the same compound that is formed when bromomalonic acid is oxidized by Ce4+ (another catalyst of the BZ reaction). Formation of BrEETRA is explained here by a new mechanism that is more realistic than the one suggested earlier. To find any oxidation product of malonic acid in the ferriin-malonic acid reaction was not successful, however. Neither ethane-tetracarboxylic acid (ETA) nor malonyl malonate (MAMA), the usual products of the Ce4+- malonic acid reaction, nor any other organic acid, not even CO2, was found as a product of the reaction. We propose that malonic acid is not oxidized in the ferriin-malonic acid reaction, and it plays only the role of a complex forming catalyst in a process where Fe3+ oxidizes mostly its phenantroline ligand.

Cerium↗
PubMed1995

Inhibition of nitric oxide synthase activity attenuates striatal malonate lesions in rats.

Mitochondrial inhibitors such as malonate are potent neurotoxins in vivo. Intrastriatal injections of malonate result in neuronal damage reminiscent of "excitotoxic" lesions produced by compounds that activate NMDA receptors. Although the mechanism of cell death produced by malonate is uncertain, overactivation of NMDA receptors may be involved; pretreatment of animals with NMDA antagonists provides neuroprotection against malonate lesions. NMDA receptor activation stimulates the enzyme nitric oxide (NO) synthase (NOS). Elevated tissue levels of NO may generate highly reactive intermediates that impair mitochondrial function. We hypothesized that NO may be a mediator of malonate toxicity. We investigated whether in vivo inhibition of NO production by the NOS inhibitor N omega-nitro-L-arginine (NLA) would attenuate lesions produced by intrastriatal injections of malonate. We found that systemic injections of 3 mg/kg of NLA significantly reduced the extent of histologic damage elicited by intrastriatal injections of 1.5 mumol of malonate in adult rats.

Amino Acid Oxidoreductases↗