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: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Magnesium is an essential cofactor for many enzymatic reactions, especially those involved in energy metabolism. Deficits of magnesium are prevalent due to inadequate intake or malabsorption and due to the renal loss of magnesium that occurs in certain disease states (alcoholism, diabetes) and with drug therapy (diuretics, aminoglycosides, cisplatin, digoxin, cyclosporin, amphotericin B). Protracted deficits of magnesium in humans and animals result in neurological disturbances, including hyperexcitability, convulsions and various psychiatric symptoms ranging from apathy to psychosis, some of which can be reversed with magnesium supplementation, others requiring correction of the dysregulation mechanism. Although the role of magnesium in neuronal function is not completely understood, a lowering of CSF or brain magnesium can induce epileptiform activity and there is an association between decreased CSF magnesium and the development of seizures. CSF concentrations of magnesium are normally higher than magnesium plasma ultrafiltrate (diffusible) concentrations due to the active transport of magnesium across the blood-brain barrier. Under conditions of magnesium deficiency, CSF concentrations decline, although this decline lags behind and is less pronounced than the changes observed in plasma magnesium concentrations. Decreases in CSF magnesium concentrations correlate with the alterations observed in extracellular brain magnesium concentrations in animals following the dietary deprivation of magnesium. CSF magnesium concentrations can readily be repleted following magnesium supplementation, although high dose magnesium therapy, such as that used in the treatment of convulsions in eclampsia, will only increase CSF magnesium concentrations to a very limited degree (approximately 11-18 per cent) above physiological concentrations. Greater increases in CSF magnesium may occur in neonates since neonatal swine, following treatment with magnesium, have CSF magnesium concentrations that are similar to their plasma concentrations. There has been a recent resurgence of interest in magnesium deficiency and its neurological consequences due to the finding that magnesium, at physiological concentrations, blocks N-methyl-D-aspartate (NMDA) receptors in neurones. NMDA receptors are normally activated by glutamate and/or aspartate which represent the principal neurotransmitters for excitatory synaptic transmission in vertebrate CNS. Magnesium deficiency produces epileptiform activity in the CNS which can be blocked by NMDA receptor antagonists. Other mechanisms, including alterations in Na+/K(+)-ATPase activity, cAMP/cGMP concentrations and calcium currents in pre- and postsynaptic membranes, may also be at least partially responsible for the neuronal effects associated with low brain magnesium. Further studies are necessary to increase our understanding of the neurological implications of magnesium deficit in the central nervous system.
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PMID:Brain and CSF magnesium concentrations during magnesium deficit in animals and humans: neurological symptoms. 129 67

During the last decade, a multitude of experimental arguments have led to the concept that EDRF is nitric oxide (NO), a messenger not only involved in the control of vasomotor tone but also in vascular homeostasis, neuronal and immunological functions. Regardless of its origin, endogenous NO is produced through the conversion of L-arginine to L-citrulline by NO-synthase (NOS) from which several isoforms have recently been isolated, purified and cloned. NOS-type I (isolated from brain) and type III (isolated from endothelial cells) are termed "constitutive-NOS" and produce picomolar levels of NO from which only a small fraction elicits physiological responses. These isoforms are regulated by Ca(2+)-calmodulin with NADPH, FAD/FMN and tetrahydrobiopterin as co-factors and reveal a high degree of homology with the amino-acid sequence of cytochrome P450 reductase within the C-terminal domain. Functionally, neuronal-NOS type I is important in neurotransmission (modulation of NMDA receptor), the central control of vascular homeostasis and possibly learning and memory. In the peripheral nervous system, NOS appears to be linked to nonadrenergic noncholinergic (NANC) neuronal pathways. Endothelial-NOS type III is essential for the control of vascular tone in response to the release of endogenous mediators, although shear stress is the major trigger of endothelial-NOS activity under physiological conditions. NOS-type III also contributes to the prevention of abnormal platelet aggregation. NOS-types II and IV (isolated from macrophages) are Ca(2+)-calmodulin independent and are termed "inducible-NOS" since their activation is only promoted under pathophysiological situations where macrophages exert cytotoxic effects in response to cytokines. In contrast with NOS-types I and III, activation of NOS-type II in these cells induces the formation of nanomolar levels of NO which act as a defense mechanism of the immune system. Dysfunctions of the L-arginine-NO pathway have been characterized in multiple diseases (atherosclerosis, hypertension, diabetes, sepsis, cerebral ischemia, etc) and the design of more selective activators/inhibitors of NOS isoforms is a new challenge for the understanding of their pathophysiology and treatment.
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PMID:Nitric oxide: an ubiquitous messenger. 829 80

The mechanisms by which diabetes impairs cognitive function are not well-established. In the present study, we determined the electrophysiological and biochemical nature of disturbances in the mechanism of long-term potentiation (LTP) in diabetic rats. As previously reported, the administration of streptozotocin (STZ) was found to reduce the magnitude of LTP in the CA1 region of the hippocampus, while the same treatment did not interact with the capacity of the hippocampus to generate long-term depression induced by low-frequency stimulation. In addition, STZ treatment did not modify the component of excitatory postsynaptic potentials mediated by activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, suggesting that NMDA receptor function remained intact in STZ-treated slices. At the biochemical level, the capacity of calcium to increase [3H](RS)-alpha-amino-3-hydroxy-5-methylisoxazole propionic acid (3H-AMPA) binding to glutamate/AMPA receptors in rat brain tissue sections was markedly affected in most regions of the hippocampus of STZ-treated rats. Moreover, changes in 3H-AMPA binding properties elicited by both exogenous phospholipase A2 and melittin, a potent activator of endogenous phospholipases, were also altered in synaptoneurosomes from diabetic rats. Taken together, the present data suggest that the loss of LTP maintenance in STZ-treated rats is more likely the result of disruption of calcium-dependent processes that are suspected to modulate postsynaptic AMPA receptors during synaptic potentiation. Understanding the biochemical factors participating in the impairment of AMPA receptor modulation might provide important clues revealing the very basis of memory deficits in diabetes.
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PMID:Impaired modulation of AMPA receptors by calcium-dependent processes in streptozotocin-induced diabetic rats. 936 22

1. Rats develop tactile allodynia to stimulation of the plantar surface of the hindpaw with von Frey filaments within days of the onset of streptozotocin-induced diabetes. This is prevented by insulin and alleviated by systemic lignocaine, but the aetiology is unknown. 2. Using indwelling lumbar intrathecal catheters to deliver pharmacological agents, we have investigated whether tactile allodynia in streptozotocin-diabetic rats is dependent on mechanisms associated with spinal sensitization, by assessing the efficacy of agents that inhibit specific components of spinal nociceptive processing. 3. Dose-dependent inhibition of tactile allodynia in diabetic rats was noted with the N-type calcium channel antagonist SNX 239, the alpha2-adrenoceptor agonist dexmedetomidine, the mu-opioid receptor agonist morphine, the N-methyl-D-aspartate (NMDA) receptor antagonist AP5 and the non-NMDA receptor antagonist NBQX. 4. No effect on tactile allodynia was noted after intrathecal administration of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), the cyclo-oxygenase inhibitor ketorolac, the L-type calcium channel inhibitor diltiazem or any vehicle. 5. These data suggest that the tactile allodynia of diabetic rats involves spinal glutamatergic pathways but is not associated with spinal release of nitric oxide or prostaglandins.
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PMID:Spinal pharmacology of tactile allodynia in diabetic rats. 942 Dec 98

This study used streptozotocin (STZ; 50 mg/kg i.p.) diabetic rats and monitored weekly thermal and mechanical nociceptive thresholds for 8 weeks diabetes. Rats developed mechanical hyperalgesia as soon as 2 weeks after STZ injection. Thermal nociceptive threshold was not altered up to 8 weeks after STZ injection. Four week-diabetic rat mechanical hyperalgesia showed reduced sensitivity to the antinociceptive effect of morphine (5-20 mg/kg i.p.). Furthermore, a reduced sensitivity to the antinociceptive effect of the GABA(B) agonist, (+/-)baclofen, was observed. A dose as high as 16 mg/kg i.p. of (+/-)baclofen was necessary to reverse 4 week-diabetic rat hyperalgesia, whereas in control rats the highest antinociceptive dose devoid of muscle-relaxant effect was 4 mg/kg i.p. The non-peptide antagonist for the substance P, neurokinin, (NK1) receptor, RP 67580 (3-9 mg/kg i.p.) was not effective in reversing the mechanical hyperalgesia associated with 4 week-diabetes. A six day-treatment with an antagonist for the N-methyl-D-aspartate (NMDA) receptor for glutamate, (+)MK-801 (0.1 mg/kg i.p. twice a day), gradually but completely reversed 4 week-diabetes-induced mechanical hyperalgesia. These data suggest that diabetes-induced hyperalgesia may be the consequence of increased activity of primary afferent fibres leading to an increased excitatory tone within the spinal cord. An increased release of glutamate and activation of the NMDA receptor, would maintain the hyperalgesic state. Reduced activity of both opioidergic and GABA(B)ergic inhibitory systems, might exacerbate the increased excitation thus contributing to the ongoing pain. It is suggested that NMDA receptor antagonists may constitute an alternative therapy for diabetic neuropathic pain.
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PMID:A pharmacologic analysis of mechanical hyperalgesia in streptozotocin/diabetic rats. 969 68

The glutamatergic synapse is the key structure in the development of activity-dependent synaptic plasticity in the central nervous system. The analysis of the complex biochemical mechanisms at the basis of the long-term changes in synaptic efficacy have received a tremendous impulse by the observation that the post-synaptic constituents of the synapse can be separated and purified through a simple procedure involving detergent treatment of synaptosomes and differential centrifugation. In this fraction, called post-synaptic density (PSD), the functional interactions of its constituents are preserved. The various subunits of ionotropic glutamate receptors are held in register with the presynaptic active zone through their interaction with linker proteins. N-methyl-D-aspartate (NMDA) subunits NR2A and NR2B, bind to the PSD protein called PSD-95, which in turn binds neuroligins, providing a handle for interacting with neurexin, located in the plasma membrane at the presynaptic active zone. Additional clustering of NMDA receptors is provided through the binding of NRI subunits to the cytoskeletal protein alpha-actinin-2. AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and kainate receptors are other important constituents of PSDs and bind to different anchoring proteins. Phosphorylation processes have long been known to modulate NMDA receptor functional activity: the finding that several protein kinases, particularly Ca2+/Calmodulin-dependent protein kinase II and protein tyrosine kinases of the src family, are major constituents of PSDs has allowed to demonstrate that these enzymes are localized in a strategic position of the glutamatergic synapse, so that their activation provides a means for NMDA receptor function regulation upon its activation. The relevance of these mechanisms has been demonstrated in experimental models of pathologies involving deficits in synaptic plasticity, such as in streptozotocin-induced diabetes and in an animal model of prenatal induced ablation of hippocampal neurons. Both animal models display disturbances in long-term potentiation and cognitive deficits, thus providing in vivo models to study pathology related changes in both the structure and the function of the excitatory synapse.
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PMID:Pathophysiological implications of the structural organization of the excitatory synapse. 1044 87

Quantitative autoradiography was used to characterise the binding of selective radiolabelled antagonists for the N-methyl-D-aspartate (NMDA) receptor and the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor in the dorsal, intermediate and ventral subregions of the grey matter of the upper thoracic spinal cord in male and female lean and obese-diabetic (ob/ob) mice. The density of binding sites for both receptor subtypes was greater in diabetic mice, in all three subregions of the grey matter, than the corresponding subregions in the lean mice. The affinity of the binding site for the NMDA antagonist was significantly higher in obese mice than lean mice, consistent with the presence of two subpopulations of NMDA receptors with different ligand binding affinities in obese mice. The increase in expression of the glutamate receptor subtypes, and altered ligand affinity for the NMDA receptor subtype in the obese mice may be causally involved in the peripheral neuropathies which can accompany diabetes mellitus.
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PMID:NMDA and AMPA glutamate receptor subtypes in the thoracic spinal cord in lean and obese-diabetic ob/ob mice. 1059 85

The obese gene product leptin is an important signaling protein that regulates food intake and body weight via activation of the hypothalamic leptin receptor (Ob-Rb; Jacob et al., 1997). However, there is growing evidence that Ob-Rb is also expressed in CNS regions, not directly associated with energy homeostasis (Mercer et al., 1996; Hakansson et al., 1998). In the hippocampus, an area of the brain involved in learning and memory, we have found that leptin facilitates the induction of synaptic plasticity. Leptin converts short-term potentiation of synaptic transmission induced by primed burst stimulation of the Schaffer collateral commissural pathway into long-term potentiation. The mechanism underlying this effect involves facilitation of NMDA receptor function because leptin rapidly enhances NMDA-induced increases in intracellular Ca(2+) levels ([Ca(2+)](i)) and facilitates NMDA, but not AMPA, receptor-mediated synaptic transmission. The signaling mechanism underlying these effects involves activation of phosphoinositide 3-kinase, mitogen-activated protein kinase, and Src tyrosine kinases. These data indicate that a novel action of leptin in the CNS is to facilitate hippocampal synaptic plasticity via enhanced NMDA receptor-mediated Ca(2+) influx. Impairment of this process may contribute to the cognitive deficits associated with diabetes mellitus.
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PMID:Leptin enhances NMDA receptor function and modulates hippocampal synaptic plasticity. 1173 1

In animal models of diabetes mellitus, such as the streptozotocin-diabetic rat (STZ-rat), spatial learning impairments develop in parallel with a reduced expression of long-term potentiation (LTP) and enhanced expression of long-term depression (LTD) in the hippocampus. This study examined the time course of the effects of STZ-diabetes and insulin treatment on the hippocampal post-synaptic glutamate N-methyl-D-aspartate (NMDA) receptor complex and other key proteins regulating hippocampal synaptic transmission in the post-synaptic density (PSD) fraction. In addition, the functional properties of the NMDA-receptor complex were examined. One month of STZ-diabetes did not affect the NMDA receptor complex. In contrast, 4 months after induction of diabetes NR2B subunit immunoreactivity, CaMKII and Tyr-dependent phosphorylation of the NR2A/B subunits of the NMDA receptor were reduced and alphaCaMKII autophosphorylation and its association to the NMDA receptor complex were impaired in STZ-rats compared with age-matched controls. Likewise, NMDA currents in hippocampal pyramidal neurones measured by intracellular recording were reduced in STZ-rats. Insulin treatment prevented the reduction in kinase activities, NR2B expression levels, CaMKII-NMDA receptor association and NMDA currents. These findings strengthen the hypothesis that altered post-synaptic glutamatergic transmission is related to deficits in learning and plasticity in this animal model.
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PMID:Effects of streptozotocin-diabetes on the hippocampal NMDA receptor complex in rats. 1190 65

Phenformin is a biguanide compound that can modulate glucose metabolism and promote weight loss and is therefore used to treat patients with type-2 diabetes. While phenformin may indirectly affect neurons by changing peripheral energy metabolism, the possibility that it directly affects neurons has not been examined. We now report that phenformin suppresses responses of hippocampal neurons to glutamate and decreases their vulnerability to excitotoxicity. Pretreatment of embryonic rat hippocampal cell cultures with phenformin protected neurons against glutamate-induced death, which was correlated with reduced calcium responses to glutamate. Immunoblot analyses showed that levels of the N-methyl-d-aspartate (NMDA) subunits NR1 and NR2A were significantly decreased in neurons exposed to phenformin, whereas levels of the AMPA receptor subunit GluR1 were unchanged. Whole-cell patch clamp analyses revealed that NMDA-induced currents were decreased, and AMPA-induced currents were unchanged in neurons pretreated with phenformin. Our data demonstrate that phenformin can protect neurons against excitotoxicity by differentially modulating levels of NMDA receptor subunits in a manner that decreases glutamate-induced calcium influx. These findings show that phenformin can modulate neuronal responses to glutamate, and suggest possible use of phenformin and related compounds in the prevention and/or treatment of neurodegenerative conditions.
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PMID:Phenformin suppresses calcium responses to glutamate and protects hippocampal neurons against excitotoxicity. 1200 68


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