Quinolinic acid neurotoxicity: In vivo increased copper and manganese content in rat corpus striatum after quinolinate intrastriatal injection (original) (raw)
Related papers
Manganese neurotoxicity and glutamate-GABA interaction
Neurochemistry International, 2003
Brain extracellular concentrations of amino acids (e.g. aspartate, glutamate, taurine) and divalent metals (e.g. zinc, copper, manganese) are primarily regulated by astrocytes. Adequate glutamate homeostasis is essential for the normal functioning of the central nervous system (CNS). Glutamate is of central importance for nitrogen metabolism and, along with aspartate, is the primary mediator of the excitatory pathways in the brain. Similarly, the maintenance of proper manganese levels is important for normal brain functioning. Several in vivo and in vitro studies have linked increased manganese concentrations with alterations in the content and metabolism of neurotransmitters, namely dopamine, ␥-aminobutyric acid, and glutamate. It has been reported by our laboratory and others, that cultured rat primary astrocytes exposed to manganese displayed decreased glutamate uptake, thereby increasing the excitotoxic potential of glutamate. Furthermore, decreased uptake of glutamate has been associated with decreased gene expression of glutamate:aspartate transporter (GLAST) in manganese-exposed astroctyes. Additional studies have suggested that attenuation of astrocytic glutamate uptake by manganese may be a consequence of reactive oxygen species (ROS) generation. Collectively, these data suggest that excitotoxicity may occur due to manganese-induced altered glutamate metabolism, representing a proximate mechanism for manganese-induced neurotoxicity.
Manganese neurotoxicity and GABA/glutamate interactions
2003
Brain extracellular concentrations of amino acids (e.g. aspartate, glutamate, taurine) and divalent metals (e.g. zinc, copper, manganese) are primarily regulated by astrocytes. Adequate glutamate homeostasis is essential for the normal functioning of the central nervous system (CNS). Glutamate is of central importance for nitrogen metabolism and, along with aspartate, is the primary mediator of the excitatory pathways in the brain. Similarly, the maintenance of proper manganese levels is important for normal brain functioning. Several in vivo and in vitro studies have linked increased manganese concentrations with alterations in the content and metabolism of neurotransmitters, namely dopamine, γ-aminobutyric acid, and glutamate. It has been reported by our laboratory and others, that cultured rat primary astrocytes exposed to manganese displayed decreased glutamate uptake, thereby increasing the excitotoxic potential of glutamate. Furthermore, decreased uptake of glutamate has been associated with decreased gene expression of glutamate: aspartate transporter (GLAST) in manganese-exposed astroctyes. Additional studies have suggested that attenuation of astrocytic glutamate uptake by manganese may be a consequence of reactive oxygen species (ROS) generation. Collectively, these data suggest that excitotoxicity may occur due to manganese-induced altered glutamate metabolism, representing a proximate mechanism for manganese-induced neurotoxicity.
Brain Research, 1996
Adult rats received chronic intrastriatal dialytic exposure to quinolinic acid (QUIN), malonate, or a combination of QUIN and malonate. The combination of subthreshold concentrations of QUIN (4 mM) and malonate (400 mM) produced lesions larger than did either QUIN or malonate alone. The neurotoxic effect of QUIN combined with malonate was subsequently blocked by co-administration of the NMDA receptor antagonist MK-801 (1 mM). These findings indicate that malonate synergistically enhances NMDA receptor mediated excitotoxicity.
Copper blocks quinolinic acid neurotoxicity in rats: contribution of antioxidant systems
Free Radical Biology and Medicine, 2003
Reactive oxygen species and oxidative stress are involved in quinolinic acid (QUIN)-induced neurotoxicity. QUIN, a N-methyl-D-aspartate receptor (NMDAr) agonist and prooxidant molecule, produces NMDAr overactivation, excitotoxic events, and direct reactive oxygen species formation. Copper is an essential metal exhibiting both modulatory effects on neuronal excitatory activity and antioxidant properties. To investigate whether this metal is able to counteract the neurotoxic and oxidative actions of QUIN, we administered copper (as CuSO 4 ) intraperitoneally to rats (2.5, 5.0, 7.5, and 10.0 mg/kg) 30 min before the striatal infusion of 1 l of QUIN (240 nmol). A 5.0 mg/kg CuSO 4 dose significantly increased the copper content in the striatum, reduced the neurotoxicity measured both as circling behavior and striatal ␥-aminobutyric acid (GABA) depletion, and blocked the oxidative injury evaluated as striatal lipid peroxidation (LP). In addition, copper reduced the QUIN-induced decreased striatal activity of Cu,Zn-dependent superoxide dismutase, and increased the ferroxidase activity of ceruloplasmin in cerebrospinal fluid from QUIN-treated rats. However, copper also produced significant increases of plasma lactate dehydrogenase activity and mortality at the highest doses employed (7.5 and 10.0 mg/kg). These results show that at low doses, copper exerts a protective effect on in vivo QUIN neurotoxicity.
Neurotoxicology, 2010
Manganese (Mn) accumulation in the brain has been shown to alter the neurochemistry of the basal ganglia. Mn-induced alterations in dopamine biology are fairly well understood, but recently more evidence has emerged characterizing the role of γ-aminobutyric acid (GABA) in this dysfunction. The purpose of this study was to determine if the previously observed Mn-induced increase in extracellular GABA (GABA EC ) was due to altered GABA transporter (GAT) function, and whether Mn perturbs other amino acid neurotransmitters, namely taurine and glycine (known modulators of GABA). Extracellular GABA, taurine, and glycine concentrations were collected from the striatum of control (CN) or Mn-exposed Sprague-Dawley rats using in vivo microdialysis, and the GAT inhibitor nipecotic acid (NA) was used to probe GAT function. Tissue and extracellular Mn levels were significantly increased, and the Fe:Mn ratio was decreased 36-fold in the extracellular space due to Mn exposure. NA led to a 2-fold increase in GABA EC of CNs, a response that was attenuated by Mn. Taurine responded inversely to GABA, and a novel 10-fold increase in taurine was observed after the removal of NA in CNs. Mn blunted this response and nearly abolished extracellular taurine throughout collection. Striatal taurine transporter (Slc6a6) mRNA levels were significantly increased with Mn exposure, and Mn significantly increased 3 H-Taurine uptake after 3-minute exposure in primary rat astrocytes. These data suggest that Mn increases GABA EC by inhibiting the function of GAT, and that perturbed taurine homeostasis potentially impacts neural function by jeopardizing the osmoregulatory and neuromodulatory functions of taurine in the brain.
The effects of manganese on glutamate, dopamine and γ-aminobutyric acid regulation
Neurochemistry International, 2006
Exposure to high levels of manganese (Mn) results in a neurological disorder, termed manganism, which shares a similar phenotype to Parkinson's disease due to the involvement of the basal ganglia circuitry in both. The initial symptoms of manganism are likely due to the involvement of the globus pallidus, a region rich in γaminobutyric acid (GABA) projections, while those of Parkinson's disease are related to the degeneration of the substantia nigra, a dopaminergic nucleus. Additionally, it is known that glutamate regulation is affected by increases in brain Mn levels. As Mn predominantly accumulates in the basal ganglia, it potentially could affect the regulation and interactions of all three neurotransmitters. This review will focus on the circuitry of these neurotransmitters within the basal ganglia and address potential sites for, as well as the temporal relationship, between Mn exposure and changes in the levels of these neurotransmitters. While most research has focused on perturbations in the dopaminergic system, there is evidence to support that early consequences of manganism also include disturbances in GABA regulation as well as glutamatergic-related excitotoxicity. Finally, we suggest that current research focus on the interdependence of these basal ganglial neurochemicals, with a greater emphasis on the GABAergic and glutamatergic systems.
Manganese inhibits NMDA receptor channel function: Implications to psychiatric and cognitive effects
NeuroToxicology, 2007
Humans exposed to excess levels of manganese (Mn 2+) express psychiatric problems and deficits in attention and learning and memory. However, there is a paucity of knowledge on molecular mechanisms by which Mn 2+ produces such effects. We now report that Mn 2+ is a potent inhibitor of [ 3 H]-MK-801 binding to the NMDA receptor channel in rat neuronal membrane preparations. The inhibition of [ 3 H]-MK-801 to the NMDA receptor channel by Mn 2+ was activity-dependent since Mn 2+ was a more potent inhibitor in the presence of the NMDA receptor co-agonists glutamate and glycine (K i = 35.9 ± 3.1 μM) than in their absence (K i = 157.1 ± 6.5 μM). We also show that Mn 2+ is a NMDA receptor channel blocker since its inhibition of [ 3 H]-MK-801 binding to the NMDA receptor channel is competitive in nature. That is, Mn 2+ significantly increased the affinity constant (K d) with no significant effect on the maximal number of [ 3 H]-MK-801 binding sites (B max). Under stimulating conditions, Mn 2+ was equipotent in inhibiting [ 3 H]-MK-801 binding to NMDA receptors expressed in neuronal membrane preparations from different brain regions. However, under basal, non-stimulated conditions, Mn 2+ was more potent in inhibiting NMDA receptors in the cerebellum than other brain regions. We have previously shown that chronic Mn 2+ exposure in non-human primates increases Cu 2+ , but not zinc or iron concentrations in the basal ganglia (Guilarte et al., Experimental Neurology 202: 381-390, 2006). Therefore, we also tested the inhibitory effects of Cu 2+ on [ 3 H]-MK-801 binding to the NMDA receptor channel. The data shows that Cu 2+ in the presence of glutamate and glycine is a more potent inhibitor of the NMDA receptor than Mn 2+. Our findings suggest that the inhibitory effect of Mn 2+ and/or Cu 2+ on the NMDA receptor may produce a deficit in glutamatergic transmission in the brain of individuals exposed to excess levels of Mn 2+ and produce neurological dysfunction.
Neuroscience Letters, 1990
Quinolinate (QUIN), an agonist of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor, was used to model glutamate-induced primary or secondary brain damage. Rats intracerebroventriculady injected with QUIN (1/lmol in 2 gl) showed convulsive reactions and heavy neurodegeneration in the hippocampal formation. MgSO4 (1 M solution injected subcutaneously; 0.6 or 0.3 g/kg) was found to protect completely against QUIN neurotoxicity if administered simultaneously or 1 h after exposure to QUIN. Preliminarily, LDs0 for MgSO4 was estimated approximately at 1.2 g/kg. The application of magnesium is discussed to be a potentially powerful therapeutic principle in case of brain injury and convulsive disorders.