Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.3.5.1 (succinate dehydrogenase)
8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intrastriatal injection of malonate, a reversible inhibitor of succinate dehydrogenase (SDH), produced age-dependent striatal lesions, which were significantly greater in 4- and 12-month-old animals than in 1-month-old animals. Both histologic and neurochemical studies showed that the lesions were significantly attenuated by administration of the noncompetitive NMDA receptor antagonist MK-801. Water-suppressed chemical shift magnetic resonance imaging showed that malonate produces increased striatal lactate concentrations and striatal lesions on T2-weighted scans that were attenuated by MK-801. Neurochemical characterization of the lesions showed significant decreases in markers of medium-sized spiny neurons (GABA and substance P), whereas a marker of medium-sized aspiny neurons (somatostatin) was not different from control values, consistent with an NMDA receptor-mediated mechanism. The effects of intrastriatal injections of malonate on ATP concentrations were compared with those of the irreversible SDH inhibitor 3-nitropropionic acid (3-NP). The ATP depletions following an equimolar injection of malonate were less marked and more transient than those of 3-NP. These results show that the competitive SDH inhibitor malonate produces more transient and milder bioenergetic defects than 3-NP, which are associated with selective activation of NMDA receptors. The results strengthen the possibility that a subtle impairment of energy metabolism may play a role in the pathogenesis of Huntington's disease.
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PMID:Age-dependent striatal excitotoxic lesions produced by the endogenous mitochondrial inhibitor malonate. 768 41

1. Endosulfan insecticide is a polychlorinated compound used for controlling a variety of insects; it is practically water-insoluble, but readily adheres to clay particles and persists in soil and water for several years. Its mode of action involves repetitive nerve-discharges positively correlated to increase in temperature. This compound is extremely toxic to most fish and can cause massive mortalities. In fish, it causes marked changes in Na and K concentrations, decrease in blood Ca(2+) and Mg levels and inhibits Na, K and Mg-dependent ATPase (in brain). 2. Bioaccumulation of endosulfan is reported for marine animals; however, freshwater animals (e.g., crayfish) accumulate it to some extent, but they lose the compound rapidly during depuration. Endosulfan is generally less toxic to aquatic invertebrates than fish. However, it causes decreases in adenylate energy charge, oxygen consumption, hemolymph amino acids, succinate dehydrogenase, heart-beat (mussel) and altered osmoregulation. 3. Generally, mammals are less susceptible to endosulfan's toxicity than aquatic animals. The majority of studies conducted on laboratory mammals can be summarized. (a) Neurotoxicity: male rats are more sensitive than females to endosulfan, which decreases brain and plasma acetylcholinesterase activity. Endosulfan I (a metabolite) causes a significant change in norepinephrine, 5-HT and GABA. (b) Renal toxicity: inhibition of MFOs activity was noticed in rats; other effects included changes in proximal convoluted tubules and necrosis of the tubular epithelium. (c) Hepatotoxicity: chemically-induced aminopyrine N-demethylase and aniline hydrolase were found in rat liver, and reduction in the glycogen level occurred. (d) Hematologic toxicity: endosulfan exposure resulted in a significant decrease in the level occurred. (d) Hematologic toxicity: endosulfan exposure resulted in a significant decrease in the erythrocyte glutathione reductase, hemoglobin amount, RBC number and mean corpuscular volume. 4. Respiratory toxicity: involved dyspnea, acute emphysema, cyanosis and hemorrhages in teh interalveolar portions of rat's lungs. 5. Biochemical: in rats, endosulfan caused increased glucose-6-phosphate dehydrogenase activity, blood glucose level, phospholipid contents of the microsomal and surfactant system, and profoundly induced the activity of alcohol dehydrogenase and cytosolic glutathione S-transferases. It also decreased significantly Na+, K+ and Mg(2+) ATPases, plasma calcium level and alkaline phosphatase in the intestinal epithelium. 6. Immunologic toxicity: rat serum antibody titer to tetanus toxin, IgG, IgM and gammaglobulins were significantly reduced. 7. Reproductive toxicity: degenerative changes in the seminiferous epithelium, induction of the rate-limiting enzyme in testosterone production (3beta-hydroxysteroid transferase and 17 beta-hydroxysteroid transferase), histological changes in reproductive organs, testicular atrophy and the occurrence of ovarian cysts were noticed in rat. Reduction in the weight of secondary sex organ was also observed.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Bioaccumulative potential and toxicity of endosulfan insecticide to non-target animals. 790 Sep 59

Alterations in the glutathione system and impairment in energy metabolism have both been implicated in the loss of dopamine neurons in Parkinson's disease. This study examined the importance of cellular glutathione and the involvement of oxidative stress in the loss of mesencephalic dopamine and GABA neurons due to inhibition of energy metabolism with malonate, the reversible, competitive inhibitor of succinate dehydrogenase. Consistent with previous findings, exposure to malonate for 24 h followed by 48 h of recovery caused a dose-dependent loss of the dopamine population with little effect on the GABA population. Toxicity was assessed by simultaneous measurement of the high-affinity uptake of [3H]dopamine and [14C]GABA. Total glutathione content in rat mesencephalic cultures was decreased by 65% with a 24-h pretreatment with 10 microM buthionine sulfoxamine. This reduction in glutathione level greatly potentiated damage to both the dopamine and GABA populations and removed the differential susceptibility between the two populations in response to malonate. These findings point to a role for oxidative stress occurring during energy impairment by malonate. Consistent with this, several spin-trapping agents, alpha-phenyl-tert-butyl nitrone and two cyclic nitrones, MDL 101,002 and MDL 102,832, completely prevented malonate-induced damage to the dopamine neurons in the absence of buthionine sulfoxamine. The spin-trapping agents also completely prevented toxicity to both the dopamine and GABA populations when cultures were exposed to malonate after pretreatment with buthionine sulfoxamine to reduce glutathione levels. Counts of tyrosine hydroxylase-positive neurons verified enhancement of cell loss by buthionine sulfoxamine plus malonate and protection against cell loss by the spin-trapping agents. NMDA receptors have also been shown to play a role in malonate-induced dopamine cell loss and are associated with the generation of free radicals. Consistent with this, toxicity to the dopamine neurons due to a 1-h exposure to 50 microM glutamate was attenuated by the nitrone spin traps. These findings provide evidence for an oxidative challenge occurring during inhibition of energy metabolism by malonate and show that glutathione is an important neuroprotectant for midbrain neurons during situations when energy metabolism is impaired.
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PMID:Role of oxidative stress and the glutathione system in loss of dopamine neurons due to impairment of energy metabolism. 952 58

Several inhibitors of mitochondrial complex II cause neuronal death in vivo and in vitro. The goal of the present work was to characterize in vitro the effects of malonate (a competitive blocker of the complex) which induces neuronal death in a pattern similar to that seen in striatum in Huntington's disease. Exposure of striatal and cortical cultures from embryonic rat brain for 24 h to methylmalonate, a compound which produces malonate intracellularly, led to a dose-dependent cell death. Methylmalonate (10 mM) caused >90% mortality of neurons although cortical cells were unexpectedly more vulnerable. Cell death was attenuated in a medium containing antioxidants. Further characterization revealed that DNA laddering could be detected after 3 h of treatment. Morphological observations (videomicroscopy and Hoechst staining) showed that both necrotic and apoptotic cell death occurred in parallel; apoptosis was more prevalent. A decrease in the ATP/ADP ratio was observed after 3 h of treatment with 10 mM methylmalonate. In striatal cultures it occurred concomitantly with a decline in GABA and a rise in aspartate content and the aspartate/glutamate ratio. Changes in ion concentrations were measured in similar cortical cultures from mouse brain. Neuronal [Na+]i increased while [K+]i and membrane potential decreased after 20 min of continuous incubation in 10 mM methylmalonate. These changes progressed with time, and a rise in [Ca2+]i was also observed after 1 h. The results demonstrate that malonate collapses cellular ion gradients, restoration of which imposes an additional load on the already compromised ATP-generation machinery. An early elevation in [Ca2+]i may trigger an increase in activity of proteases, lipases and endonucleases and production of free radicals and DNA damage which, ultimately, leads to cells death. The data also suggest that maturational and/or extrinsic factors are likely to be critical for the increased vulnerability of striatal neurons to mitochondrial inhibition in vivo.
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PMID:Methylmalonate toxicity in primary neuronal cultures. 969 61

Defects in mitochondrial energy metabolism have been implicated in the pathology of several neurodegenerative disorders. In addition, the reactive metabolites generated from the metabolism and oxidation of the neurotransmitter dopamine (DA) are thought to contribute to the damage to neurons of the basal ganglia. We have previously demonstrated that infusions of the metabolic inhibitor malonate into the striata of mice or rats produce degeneration of DA nerve terminals. In the present studies, we demonstrate that an intrastriatal infusion of malonate induces a substantial increase in DA efflux in awake, behaving mice as measured by in vivo microdialysis. Furthermore, pretreatment of mice with tetrabenazine (TBZ) or the TBZ analogue Ro 4-1284 (Ro-4), compounds that reversibly inhibit the vesicular storage of DA, attenuates the malonate-induced DA efflux as well as the damage to DA nerve terminals. Consistent with these findings, the damage to both DA and GABA neurons in mesencephalic cultures by malonate exposure was attenuated by pretreatment with TBZ or Ro-4. Treatment with these compounds did not affect the formation of free radicals or the inhibition of oxidative phosphorylation resulting from malonate exposure alone. Our data suggest that DA plays an important role in the neurotoxicity produced by malonate. These findings provide direct evidence that inhibition of succinate dehydrogenase causes an increase in extracellular DA levels and indicate that bioenergetic defects may contribute to the pathogenesis of chronic neurodegenerative diseases through a mechanism involving DA.
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PMID:Role for dopamine in malonate-induced damage in vivo in striatum and in vitro in mesencephalic cultures. 1073 24

Previous work has shown that overstimulation of GABA(A) receptors can potentiate neuronal cell damage during excitotoxic or metabolic stress in vitro and that GABA(A) antagonists or GABA transport blockers are neuroprotective under these situations. Malonate, a reversible succinate dehydrogenase/mitochondrial complex II inhibitor, is frequently used in animals to model cell loss in neurodegenerative diseases such as Parkinson's and Huntington's diseases. To determine if GABA transporter blockade during mitochondrial impairment can protect neurons in vivo as compared with in vitro studies, rats received a stereotaxic infusion of malonate (2 micromol) into the left striatum to induce a metabolic stress. The nonsubstrate GABA transport blocker, NO711 (20 nmol) was infused in some rats 30 min before and 3 h following malonate infusion. After 1 week, dopamine and GABA levels in the striata were measured. Malonate caused a significant loss of striatal dopamine and GABA. Blockade of the GABA transporter significantly attenuated GABA, but not dopamine loss. In contrast with several in vitro reports, GABA(A) receptors were not a downstream mediator of protection by NO711. Intrastriatal infusion of malonate (2 micromol) plus or minus the GABA(A) receptor agonist muscimol (1 micromol), the GABA(A) Cl- binding site antagonist picrotoxin (50 nmol) or the GABA(B) receptor antagonist saclofen (33 nmol) did not modify loss of striatal dopamine or GABA when examined 1 week following infusion. These data show that GABA transporter blockade during mitochondrial impairment in the striatum provides protection to GABAergic neurons. GABA transporter blockade, which is currently a pharmacological strategy for the treatment of epilepsy, may thus also be beneficial in the treatment of acute and chronic conditions involving energy inhibition such as stroke/ischemia or Huntington's disease. These findings also point to fundamental differences between immature and adult neurons in the downstream involvement of GABA receptors during metabolic insult.
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PMID:Protection of malonate-induced GABA but not dopamine loss by GABA transporter blockade in rat striatum. 1209 96

Recent studies have implicated chronic elevated exposures to environmental agents, such as metals (e.g. manganese, Mn) and pesticides, as contributors to neurological disease. Eighteen-month-old rats received intraperitoneal injections of manganese chloride (6 mg Mn/kg/day) or equal volume of saline for 30 days in order to study the effect of manganese on the dopamine- and GABA-neurons. The structures studied were substantia nigra, striatum, ventral tegmental area, nucleus accumbens and globus pallidus. First, we studied the enzymatic activity of mitochondrial complex II succinate dehydrogenase (SDH). We found an overall decrease of SDH in the different brain areas analyzed. We then studied the mRNA levels for tyrosine hydroxylase (TH) and the dopamine transporter (DAT) by in situ hybridization. TH mRNA but not DAT mRNA was significantly induced in substantia nigra and ventral tegmental area following Mn treatment. Correspondingly, TH immunoreactivity was increased in substantia nigra and ventral tegmental area. Manganese treatment significantly decreased GAD mRNA levels in individual GABAergic neurons in globus pallidus but not in striatum. We also quantified the density of glial fibrillary acidic protein (GFAP)-labeled astrocytes and OX-42 positive cells. Reactive gliosis in response to Mn treatment occurred only in striatum and substantia nigra and the morphology of the astrocytes was different than in control animals. These results suggest that the nigrostriatal system could be specifically damaged by manganese toxicity. Thus, changes produced by manganese treatment on 18-month-old rats could play a role in the etiology of Parkinson's disease.
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PMID:Differential regulation of glutamic acid decarboxylase mRNA and tyrosine hydroxylase mRNA expression in the aged manganese-treated rats. 1210 97

Mitochondrial dysfunction may contribute to dopaminergic (DAergic) cell death in Parkinson's disease and GABAergic cell death in Huntington's disease. In the present work, we tested whether blocking A1 receptors could enhance the damage to DAergic and GABAergic neurons caused by mitochondrial inhibition, and whether blocking A2a receptors could protect against damage in this model. Animals received an intraperitoneal injection of 8-cyclopentyl-1,3-dipropylxanthine (CPX) (A1 antagonist) or 3,7-dimethyl-1-propargylxanthine (DMPX) (A2a antagonist) 30 min before intrastriatal infusion of malonate (mitochondrial complex II inhibitor). Damage was assessed 1 week later by measuring striatal dopamine, tyrosine hydroxylase (TH), and GABA content. In mice and rats, malonate-induced depletion of striatal dopamine, TH, or GABA was potentiated by pretreatment with 1 mg/kg CPX and attenuated by pretreatment with 5 mg/kg DMPX. To determine the location of the A1 and A2a receptors mediating these effects, CPX or DMPX was infused directly into the striatum or substantia nigra of rats 30 min before intrastriatal infusion of malonate. When infused into the striatum, CPX (20 ng) potentiated, whereas DMPX (50 ng) prevented malonate-induced GABA loss, but up to 100 ng of CPX or 500 ng of DMPX did not alter malonate-induced striatal dopamine loss. Intranigral infusion of CPX (100 ng) or DMPX (500 ng), however, did exacerbate and protect, respectively, against malonate-induced striatal dopamine loss. Thus, A1 receptor blockade enhances and A2a receptor blockade protects against damage to DAergic and GABAergic neurons caused by mitochondrial inhibition. Interestingly, these effects are mediated by A1 and A2a receptors located in the substantia nigra for DAergic neurons and in the striatum for GABAergic neurons.
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PMID:Adenosinergic protection of dopaminergic and GABAergic neurons against mitochondrial inhibition through receptors located in the substantia nigra and striatum, respectively. 1464 94

An impaired complex II (succinate dehydrogenase, SD) striatal mitochondrial activity is one of the prominent metabolic alterations in Huntington's disease (HD), and intoxication with 3-nitropropionic acid (3-NP), an inhibitor of mitochondrial complex II, mimics the motor abnormalities and the pathology of HD. We found that striatal spiny neurons responded to this toxin with an irreversible membrane depolarization/inward current, while cholinergic interneurons showed a hyperpolarization/outward current. Both these currents were sensitive to intracellular concentration of ATP. The 3-NP-induced depolarization was associated with an increased release of endogenous GABA, while acetylcholine levels were reduced. Moreover, 3-NP induced a higher depolarization in presymptomatic R6/2 HD transgenic mice compared to wild-type (WT) mice, showing an increased susceptibility to SD inhibition. Conversely, the hyperpolarization did not significantly differ from the one recorded in WT mice. The diverse membrane changes induced by SD inhibition may contribute to the cell-type-specific neuronal death in HD.
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PMID:Neuronal vulnerability following inhibition of mitochondrial complex II: a possible ionic mechanism for Huntington's disease. 1496 36

The activities of GABA-catabolizing enzymes (GABA-transaminase and succinic semialdehyde dehydrogenase), succinate dehydrogenase, alanine and aspartate amino transferases, the contents of GABA, glutamate, glutamine, alanine, aspartate and glycine were studied in rat brain regions after acute morphine administration. Intraperitoneal (i.p.) administration of 10 mg/kg morphine increased the glutamate level and decreased GABA and glycine levels in cortex. This may explain an excitable effect of morphine. When the higher doses of morphine were administered (20 and 40 mg/kg, i.p.), the most pronounced changes in the amino acids tested were observed in brain stem, possibly because of higher density of opiate receptors there. Decrease in glutamate level in the brain stem was accompanied by accumulation of its metabolic precursors glutamine and aspartate and decrease of inhibitory amino acids (GABA, glycine) leves, when the dose of 40 mg/kg was used. The data obtained indicate a dose-dependent relationship between the parameters studied and behavioral action of morphine.
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PMID:[GABA metabolism and contents of neuroactive amino acids in rat brain after acute morphine administration]. 1585 Feb 24


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