Intracellular pH modulates spontaneous and epileptiform bioelectric activity of hippocampal CA3-neurones

Bonnet, Udo; Bingmann, D.; Wiemann, Martin

doi:10.1016/s0924-977x(99)00063-2

Cited by 71 publications

(51 citation statements)

References 34 publications

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“…This is also supported by in vitro studies showing NHE1 and NHE2 inhibition with amiloride and HOE 642 to reduce neuronal activity, at least in the hippocampus, where all types of NHE (except NHE3) are present (29).…”

Section: Role Of Nhe3 Versus Other Nhe Subtypes In Central Chemosensimentioning

confidence: 81%

“…In agreement with this assumption, intracellular pH measurements in brainstem slices (15,17) and organotypic cell cultures of medullary neurons (16,18) point to pH i as an adequate stimulus for central respiratory chemosensitivity. The extracellular pH also seems to be involved, although more indirectly, as among numerous effects, including ion channel gating, transmitter release, or metabolic changes (34), pH e modulates the degree of acid extrusion in chemosensitive sites (17) and changes the affinity of receptors for neuronal transmitters (29,30). In principle, all these alterations may also modify or even orchestrate the response of the respiratory network to hypercapnia.…”

Section: Intracellular [H ϩ ] As the Adequate Stimulus To Central Chementioning

confidence: 98%

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A Novel Inhibitor of the Na⁺/ H⁺ Exchanger Type 3 Activates the Central Respiratory CO₂ Response and Lowers the Apneic Threshold

Kiwull-Schöne

Wiemann²,

Frede³

et al. 2001

Am J Respir Crit Care Med

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Cultured CO2-sensitive neurons from the ventrolateral medulla of newborn rats enhanced their bioelectric activity upon intracellular acidification induced by inhibition of the Na+/H+ exchanger type 3 (NHE3). Now we detected NHE3 also in the medulla oblongata of adult rabbits. Therefore, this animal model was employed to determine whether NHE3 inhibition also affects central respiratory chemosensitivity in vivo. Seven anesthetized (pentobarbital), vagotomized, paralyzed rabbits were artificially ventilated with O2-enriched air. From the phrenic nerve compound discharge, integrated burst amplitude (IPNA), respiratory rate (fR), and phrenic minute activity (IPNA. fR) were taken as measures of central respiratory rhythm and drive. Effects of potent NHE3 inhibition with the novel brain permeant substance S8218 were studied by comparing respiratory characteristics before and after up to 9.2 +/- 1.1 mg/kg cumulative drug application, yielding average plasma concentrations of 0.9 +/- 0.2 microg/ml. In response to S8218, the baseline level of IPNA. fR was significantly enhanced by an average of 51.0 +/- 6.4% (n = 27, p < 0.0001). The influence of NHE3 inhibition on the respiratory CO2 response was studied at plasma concentrations of S8218 maintained in the range of 0.3 microg/ml (10(-6) M). Although the metabolic acid-base status thereby remained widely unchanged, the group mean apneic threshold PaCO2 was significantly lowered by 0.45 +/- 0.11 kPa (n = 7, p < 0.01), whereby in four of seven animals even strong hyperventilation failed to suppress phrenic nerve rhythmicity completely. Likewise, S8218 significantly augmented IPNA. fR, in the range of PaCO2 between 1 and 6 kPa above threshold, by an average of 38.0 +/- 8.5% (n = 35, p < 0.0001). These in vivo results are compatible with the effects of NHE3 inhibition on chemosensitive brainstem neurons in vitro. Moreover, rhythmogenesis is supported through NHE3 inhibition by lowering the threshold PCO2 for central apnea.

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Section: Role Of Nhe3 Versus Other Nhe Subtypes In Central Chemosensimentioning

confidence: 81%

Section: Intracellular [H ϩ ] As the Adequate Stimulus To Central Chementioning

confidence: 98%

A Novel Inhibitor of the Na⁺/ H⁺ Exchanger Type 3 Activates the Central Respiratory CO₂ Response and Lowers the Apneic Threshold

Kiwull-Schöne

Wiemann²,

Frede³

et al. 2001

Am J Respir Crit Care Med

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“…The lipid phase solubility enables PPA to cross the lipid bilayer of cells and permits PPA to enter and equilibrate in neuronal and glial cells. Previous studies have shown that cellular concentration of PPA produces a reversible intracellular acidosis and this effect is potentiated by minor reductions in extracellular pH [52,[86][87][88][89] . In addition to passive accumulation in CNS cells, there is also evidence that PPA and other short chain fatty acids are specifically taken up by monocarboxylate receptors in cerebrovascular endothelium, neurons and glia [90][91][92] .…”

Section: Fig 6: Group Means (±Sem) For (A) Glutathione (Gsh) (B) Glmentioning

confidence: 99%

A Novel Rodent Model of Autism: Intraventricular Infusions of Propionic Acid Increase Locomotor Activity and Induce Neuroinflammation and Oxidative Stress in Discrete Regions of Adult Rat Brain

MacFabe¹,

Rodríguez-Capote²,

Hoffman³

et al. 2008

American J. of Biochemistry and Biotechnology

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Innate neuroinflammatory changes, increased oxidative stress and disorders of glutathione metabolism may be involved in the pathophysiology of autism spectrum disorders (ASD). Propionic acid (PPA) is a dietary and gut bacterial short chain fatty acid which can produce brain and behavioral changes reminiscent of ASD following intraventricular infusion in rats. Adult Long-Evans rats were given intraventricular infusions of either PPA (.26M, 4µl animal −1 ) or phosphate buffered saline (PBS)vehicle, twice daily for 7 days. Immediately following the second daily infusion, the locomotor activity of each rat was assessed in an automated open field (Versamax) for 30 min. PPA-treated rats showed significant increases in locomotor activity compared to PBS vehicle controls. Following the last treatment day, specific brain regions were assessed for neuroinflammatory or oxidative stress markers. Immunohistochemical analyses revealed reactive astrogliosis (GFAP), activated microglia (CD68, Iba1) without apoptotic cell loss (Caspase 3' and NeuN) in hippocampus and white matter (external capsule) of PPA treated rats. Biomarkers of protein and lipid peroxidation, total glutathione (GSH) as well as the activity of the antioxidant enzymes superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S-transferase (GST) were examined in brain homogenates. Some brain regions of PPA treated animals (neocortex, hippocampus, thalamus, striatum) showed increased lipid and protein oxidation accompanied by decreased total GSH in neocortex. Catalase activity was decreased in most brain regions of PPA treated animals suggestive of reduced antioxidant enzymatic activity. GPx and GR activity was relatively unaffected by PPA treatment while GST was increased, perhaps indicating involvement of GSH in the removal of PPA or related catabolites. Impairments in GSH and catalase levels may render CNS cells more susceptible to oxidative stress from a variety of toxic insults. Overall, these findings are consistent with those found in ASD patients and further support intraventricular PPA administration as an animal model of ASD.

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“…Changes in intraneuronal pH modulate neuronal activity and intraneuronal acidification reduces seizure-like activity in in-vitro preparations [Bonnet et al 2000]. In hippocampal slices acutely applied LEV for up to 20 min acidified the internal pH of CA3 neurons [Leniger et al 2004].…”

Section: Action Of Lev On Voltage-gated Ion Channels and Regulation Omentioning

confidence: 99%

Review: Is levetiracetam different from other antiepileptic drugs? Levetiracetam and its cellular mechanism of action in epilepsy revisited

Surges¹,

Volynski²,

Walker³

2008

Ther Adv Neurol Disord

114

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Levetiracetam (LEV) is a new antiepileptic drug that is clinically effective in generalized and partial epilepsy syndromes as sole or add-on medication. Nevertheless, its underlying mechanism of action is poorly understood. It has a unique preclinical profile; unlike other antiepileptic drugs (AEDs), it modulates seizure-activity in animal models of chronic epilepsy with no effect in most animal models of acute seizures. Yet it is effective in acute in-vitro 'seizure' models. A possible explanation for these dichotomous findings is that LEV has different mechanisms of actions, whether given acutely or chronically and in 'epileptic' and control tissue. Here we review the general mechanism of action of AEDs, give an updated and critical overview about the experimental findings of LEV's cellular targets (in particular the synaptic vesicular protein SV2A) and ask whether LEV represents a new class of AED.

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Intracellular pH modulates spontaneous and epileptiform bioelectric activity of hippocampal CA3-neurones

Cited by 71 publications

References 34 publications

A Novel Inhibitor of the Na⁺/ H⁺ Exchanger Type 3 Activates the Central Respiratory CO₂ Response and Lowers the Apneic Threshold

A Novel Inhibitor of the Na⁺/ H⁺ Exchanger Type 3 Activates the Central Respiratory CO₂ Response and Lowers the Apneic Threshold

A Novel Rodent Model of Autism: Intraventricular Infusions of Propionic Acid Increase Locomotor Activity and Induce Neuroinflammation and Oxidative Stress in Discrete Regions of Adult Rat Brain

Review: Is levetiracetam different from other antiepileptic drugs? Levetiracetam and its cellular mechanism of action in epilepsy revisited

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Intracellular pH modulates spontaneous and epileptiform bioelectric activity of hippocampal CA3-neurones

Cited by 71 publications

References 34 publications

A Novel Inhibitor of the Na+/ H+ Exchanger Type 3 Activates the Central Respiratory CO2 Response and Lowers the Apneic Threshold

A Novel Inhibitor of the Na+/ H+ Exchanger Type 3 Activates the Central Respiratory CO2 Response and Lowers the Apneic Threshold

A Novel Rodent Model of Autism: Intraventricular Infusions of Propionic Acid Increase Locomotor Activity and Induce Neuroinflammation and Oxidative Stress in Discrete Regions of Adult Rat Brain

Review: Is levetiracetam different from other antiepileptic drugs? Levetiracetam and its cellular mechanism of action in epilepsy revisited

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Product

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A Novel Inhibitor of the Na⁺/ H⁺ Exchanger Type 3 Activates the Central Respiratory CO₂ Response and Lowers the Apneic Threshold

A Novel Inhibitor of the Na⁺/ H⁺ Exchanger Type 3 Activates the Central Respiratory CO₂ Response and Lowers the Apneic Threshold