Non-synaptic release of [3H]noradrenaline in response to oxidative stress combined with mitochondrial dysfunction in rat hippocampal slices

Milusheva, E.; Sperlágh, Beáta; Shikova, L.; Baranyi, Mária; Tretter, László; Ádám-Vizi, Vera; Vizi, E.S.

doi:10.1016/s0306-4522(03)00340-3

Cited by 28 publications

(15 citation statements)

References 42 publications

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“…Exactly how AMPK integrates with signaling pathways activated by low glucose is unknown. Potential mechanisms in hypothalamic neurons include 1) a direct action on the ATPsensitive potassium channel via phosphorylation sites, in both the inward rectifying Kir6.2 and the sulfonylurea receptor subunit (31), or 2) through activation of nitric oxide synthase (16,34), which could potentially alter ␥-aminobutyric acid (35) or norepinephrine release within the VMH (36).…”

Section: Resultsmentioning

confidence: 99%

Activation of AMP-Activated Protein Kinase Within the Ventromedial Hypothalamus Amplifies Counterregulatory Hormone Responses in Rats With Defective Counterregulation

et al. 2006

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Defective counterregulatory responses (CRRs) to hypoglycemia are associated with a marked increase in the risk of severe hypoglycemia. The mechanisms leading to the development of defective CRRs remain largely unknown, although they are associated with antecedent hypoglycemia. Activation of AMP-activated protein kinase (AMPK) in the ventromedial hypothalamus (VMH) amplifies the counterregulatory increase in glucose production during acute hypoglycemia. To examine whether activation of AMPK in the VMH restores defective CRR, controlled hypoglycemia (ϳ2.8 mmol/l) was induced in a group of 24 Sprague-Dawley rats, all of which had undergone a 3-day model of recurrent hypoglycemia before the clamp study. Before the acute study, rats were microinjected to the VMH with either 5-aminoimidazole-4-carboxamide (AICAR; n ‫؍‬ 12), to activate AMPK, or saline (n ‫؍‬ 12). In a subset of rats, an infusion of H 3 -glucose was additionally started to calculate glucose turnover. Stimulation of AMPK within the VMH was found to amplify hormonal CRR and increase endogenous glucose production. In addition, analysis of tissue from both whole hypothalamus and VMH showed that recurrent hypoglycemia induces an increase in the gene expression of AMPK ␣ 1 and ␣ 2 . These findings suggest that the development of novel drugs designed to selectively activate AMPK in the VMH offer a future therapeutic potential for individuals with type 1 diabetes who have defective CRRs to hypoglycemia. Diabetes 55:1755-1760, 2006 S ingle or recurrent episodes of acute hypoglycemia in nondiabetic or type 1 diabetic (1-3) individuals are known to impair hormonal counterregulatory responses (CRRs) to a subsequent episode of hypoglycemia. Defective hormonal counterregulation to hypoglycemia is closely associated with both altered glucose thresholds for activation of the CRR and reduced symptomatic awareness of hypoglycemia, a combination of clinical syndromes that collectively have been termed hypoglycemia-associated autonomic failure (4). Defective hormonal CRR is in itself associated with a markedly increased risk of severe hypoglycemia (5).The mechanism through which recurrent hypoglycemia per se induces defective hormonal CRR remains largely unknown. Potential candidate mechanisms include alterations in key steps in the glucose-sensing pathway in the brain (6,7), increased glucose and/or alternate fuel uptake by the brain (8 -11), increases in the brain glycogen pool (12), and an effect of hypothalamopituitary axis activation (13,14). In addition, we have recently demonstrated that pharmacological activation of the serine/threonine kinase AMP-activated protein kinase (AMPK) in the ventromedial hypothalamus (VMH), a key central glucose-sensing region (15), amplifies the glucose CRR to acute hypoglycemia. In that study AMPK activation in the VMH during acute hypoglycemia resulted in a marked increase in endogenous glucose production (R a ), with a corresponding reduction in the requirement for exogenous glucose, in the absence of a change in the hormonal CRR (1...

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Section: Resultsmentioning

confidence: 99%

Activation of AMP-Activated Protein Kinase Within the Ventromedial Hypothalamus Amplifies Counterregulatory Hormone Responses in Rats With Defective Counterregulation

et al. 2006

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“…There are two types of neurotransmitter release, synaptic and nonsynaptic (nonexocytotic) (Vizi, 2000). During ischemia the model of nonsynaptic release of neurotransmitter is increased (Milusheva et al, 2003). Previously we have shown that the Phoneutria toxin Tx3-4 decrease Ca 21 -independent release of glutamate (Reis et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Phoneutria spider toxins block ischemia‐induced glutamate release, neuronal death, and loss of neurotransmission in hippocampus

et al. 2009

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The aim of this study was to investigate the effect of spider toxins on brain injury induced by oxygen deprivation and low glucose (ODLG) insult on slices of rat hippocampus. After ODLG insult cell viabilility in hippocampal slices was assessed by confocal microscopy and epifluorescence using the live/dead kit containing calcein-AM and ethidium homodimer and CA1 population spike amplitude recording during stimulation of Schaffer collateral fibers. Spider toxins Tx3-3 or Tx3-4 and conus toxins, omega-conotoxin GVIA or omega-conotoxin MVIIC are calcium channel blockers and protected against neuronal damage in slices subjected to ODLG insult. Confocal imaging of CA1 region of rat hippocampal slices subject to ischemic insult treated with Tx3-3, Tx3-4, omega-conotoxin GVIA or omega-conotoxin MVIIC showed a decrease in cell death that amounted to 68 +/- 4.2%, 77 +/- 3.8%, 32 +/- 2.3%, and 46 +/- 2.9%, respectively. This neuroprotective effect of Tx3-4 was corroborated by eletrophysiological recordings of population spikes amplitudes in CA1. The neuroprotection promoted on hippocampal slices by Tx3-3 or Tx3-4 was also observed when the toxins were applied 10, 20, 30, 60, 90, or 120 min after induction of the ODLG injury. During the ischemic insult, glutamate release from slices was increased by 71% (from 7.0 +/- 0.3 nM/mg of protein control slices not subjected to ischemia to 12 +/- 0.4 nM/mg of protein in slices exposed to ischemia). Tx3-3, Tx3-4, omega-conotoxin GVIA or omega-conotoxin MVIIC inhibited the ischemia-induced increase on glutamate release by 54, 72, 60, and 70%, respectively. Thus Tx3-3 and Tx3-4 provided robust ischemic neuroprotection showing potential as a novel class of agent that exerts neuroprotection in an in vitro model of brain ischemia.

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“…Rotenone was shown to decrease ATP content in hippocampal slices and increases intracellular sodium levels in cerebrocortical synaptosomes [60]. This cellular metabolic insult may be potentiated by the glycolytic inhibitor 2-DG [32,61].…”

Section: Alteration Of Intracellular Sodium Levels: Effects On [ 3 H]mentioning

confidence: 99%

Some Operational Characteristics of Glycine Release in Rat Retina: The Role of Reverse Mode Operation of Glycine Transporter Type-1 (GlyT-1) in Ischemic Conditions

et al. 2015

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Rat posterior eyecups containing the retina were prepared, loaded with [(3)H]glycine and superfused in order to determine its release originated from glycinergic amacrine cells and/or glial cells. Deprivation of oxygen and glucose from the Krebs-bicarbonate buffer used for superfusion evoked a marked increase of [(3)H]glycine release, an effect that was found to be external Ca(2+)-independent. Whereas oxygen and glucose deprivation increased [(3)H]glycine release, its uptake was reduced suggesting that energy deficiency shifts glycine transporter type-1 operation from normal to reverse mode. The increased release of [(3)H]glycine evoked by oxygen and glucose deprivation was suspended by addition of the non-competitive glycine transporter type-1 inhibitor NFPS and the competitive inhibitor ACPPB further suggesting the involvement of this transporter in the mediation of [(3)H]glycine release. Oxygen and glucose deprivation also evoked [(3)H]glutamate release from rat retina and the concomitantly occurring release of the NMDA receptor agonist glutamate and the coagonist glycine makes NMDA receptor pathological overstimulation possible in hypoxic conditions. [(3)H]Glutamate release was suspended by addition of the excitatory amino acid transporter inhibitor TBOA. Sarcosine, a substrate inhibitor of glycine transporter type-1, also increased [(3)H]glycine release probably by heteroexchange shifting transporter operation into reverse mode. This effect of sarcosine was also external Ca(2+)-independent and could be suspended by NFPS. Energy deficiency in retina induced by ouabain, an inhibitor of the Na(+)-K(+)-dependent ATPase, and by rotenone, a mitochondrial complex I inhibitor added with the glycolytic inhibitor 2-deoxy-D-glucose, led to increase of retinal [(3)H]glycine efflux. These effects of ouabain and rotenone/2-deoxy-D-glucose could also be blocked by NFPS pointed to the preferential reverse mode operation of glycine transporter type-1 as a consequence of impaired cellular energy homeostasis. Immunohistochemical studies revealed that glycine transporter type-1, of which reverse mode operation assures [(3)H]glycine release, is expressed in amacrine cells in the inner nuclear and plexiform layers of the retina and also in Müller macroglia cells. We conclude that disruption of the balanced normal/reverse mode operation of glycine transporter type-1 is likely a significant factor contributing to neurotoxic processes of the retina. The possibility to inhibit glycine transporter type-1 mediated glycine efflux by drugs more potently than glycine uptake might offer some therapeutic potential for the treatment of various neurodegenerative disorders of the retina.

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Non-synaptic release of [3H]noradrenaline in response to oxidative stress combined with mitochondrial dysfunction in rat hippocampal slices

Cited by 28 publications

References 42 publications

Activation of AMP-Activated Protein Kinase Within the Ventromedial Hypothalamus Amplifies Counterregulatory Hormone Responses in Rats With Defective Counterregulation

Activation of AMP-Activated Protein Kinase Within the Ventromedial Hypothalamus Amplifies Counterregulatory Hormone Responses in Rats With Defective Counterregulation

Phoneutria spider toxins block ischemia‐induced glutamate release, neuronal death, and loss of neurotransmission in hippocampus

Some Operational Characteristics of Glycine Release in Rat Retina: The Role of Reverse Mode Operation of Glycine Transporter Type-1 (GlyT-1) in Ischemic Conditions

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