Effects of dietary zinc status on seizure susceptibility and hippocampal zinc content in theEl (epilepsy) mouse

Fukahori, Motofumi; Itoh, Masatoshi

doi:10.1016/0006-8993(90)90806-m

Cited by 88 publications

(42 citation statements)

References 38 publications

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“…Thus Ca2* chelators (e.g. EDTA and citrate) and Zn2+-deficient diets result in either seizures or increased seizure susceptibility [15,17,53,55]. Our studies show that SCAIs decreased both de novo citrate synthesis and secretion of citrate by astrocytes ( fig.…”

Section: Discussionmentioning

confidence: 59%

Effect of Carbonic Anhydrase Inhibition and Acetoacetate on Anaplerotic Pyruvate Carboxylase Activity in Cultured Rat Astrocytes

et al. 1997

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In peripheral tissues, carbonic anhydrase (CA) inhibition secondarily decreases the anaplerotic activity of pyruvate carboxylase activity leading to a decline in citric acid cycle intermediates and glutamate. In view of the important role of pyruvate carboxylase in the brain, we examined the effects of CA inhibition on pyruvate-carboxylase-mediated [¹⁴C]CO₂ fixation in cultured astrocytes from postnatal rat brains. Incubation with H[¹⁴C]O3̄ led to radiolabeling of metabolites found both in the cells and in the medium. These were separated by ion exchange chromatography for identification. Ethoxyzolamide (ETZ), a sulfonamide CA inhibitor (SCAT) with a heterocyclic side group, caused a 43–73% decrease in cell lysate [α-ketoglutarate] and ¹⁴C incorporation into major products of pyruvate carboxylation in the cell lysates and cell medium (i.e., released products). Half-maximal inhibition of [¹⁴C]CO₂ fixation was observed between 1 and 3 x l0^–7M. This is similar to the IC₅₀ value for ETZ inhibition of events in other cells that are thought to be mediated by CA. Inhibition was also observed with trifluor-methanesulfonamide, an aliphatic SCAI, providing further evidence that this effect is mediated by CA. Western blot analysis using isozyme-specific anti-sera indicated that astrocytes contain CA II, a cytosolic isozyme, but CA in, CA IV and CA V could not be detected. This finding is unusual since the effects of SCAIs on pyruvate carboxylation in other tissues have been attributed to inhibition of the intramitochondrial isozyme, CA V. [¹⁴C]CO₂ fixation was also decreased by lowering media [pyruvate] or by addition of 5 mM acetoacetate. It is hypothesized that SCAIs may inhibit pyruvate carboxylation in astrocytes by limiting the supply of bicarbonate to this enzyme while ketone bodies, by inhibiting glucose oxidation, may limit the supply of pyruvate. Interestingly, both SCAIs and ketogenic diets are used to treat adolescent forms of epilepsy. The possibility that these treatments might ultimately work by affecting anaplerotic pyruvate carboxylase activity in the brain is discussed.

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Section: Discussionmentioning

confidence: 59%

Effect of Carbonic Anhydrase Inhibition and Acetoacetate on Anaplerotic Pyruvate Carboxylase Activity in Cultured Rat Astrocytes

et al. 1997

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“…Zinc can be coreleased with neurotransmitters at synapses (Frederickson and Moncrieff, 1994), raising the possibility that zinc could act as a modulator of dendritic sodium currents. It has also been reported that zinc can affect susceptibility to epileptic seizures (Fukahori and Itoh, 1990) and can modulate no- Figure 9. The thresholds for activation of ramp currents and peak transient currents are similar.…”

Section: Divalent Modulation Of Closed-state Inactivation and Ramp Cumentioning

confidence: 99%

Slow Closed-State Inactivation: A Novel Mechanism Underlying Ramp Currents in Cells Expressing the hNE/PN1 Sodium Channel

1998

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To better understand why sensory neurons express voltagegated Na ϩ channel isoforms that are different from those expressed in other types of excitable cells, we compared the properties of the hNE sodium channel [a human homolog of PN1, which is selectively expressed in dorsal root ganglion (DRG) neurons] with that of the skeletal muscle Na ϩ channel (hSkM1) [both expressed in human embryonic kidney (HEK293) cells]. Although the voltage dependence of activation was similar, the inactivation properties were different. The V 1/2 for steady-state inactivation was slightly more negative, and the rate of open-state inactivation was ϳ50% slower for hNE. However, the greatest difference was that closed-state inactivation and recovery from inactivation were up to fivefold slower for hNE than for hSkM1 channels. TTX-sensitive (TTX-S) currents in small DRG neurons also have slow closed-state inactivation, suggesting that hNE/PN1 contributes to this TTX-S current. Slow ramp depolarizations (0.25 mV/msec) elicited TTX-S persistent currents in cells expressing hNE channels, and in DRG neurons, but not in cells expressing hSkM1 channels. We propose that slow closed-state inactivation underlies these ramp currents. This conclusion is supported by data showing that divalent cations such as Cd 2ϩ and Zn 2ϩ (50-200 M) slowed closed-state inactivation and also dramatically increased the ramp currents for DRG TTX-S currents and hNE channels but not for hSkM1 channels. The hNE and DRG TTX-S ramp currents activated near Ϫ65 mV and therefore could play an important role in boosting stimulus depolarizations in sensory neurons. These results suggest that differences in the kinetics of closed-state inactivation may confer distinct integrative properties on different Na ϩ channel isoforms.

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“…Thus, administering zinc to the brain by dietary loading [72,73] or by peripheral administration [8] can inhibit seizures, whereas dietary deficiency [72,73] and congenital deficiency of vesicular zinc [74] are all associated with increased seizure susceptibility. Moreover, administration of chelators in vivo can produce either paroxys mal spiking [75] or a lowered threshold for stimulation-induced seizures [7], The latter result has also been reproduced in hippocam pal slices, in which zinc chelation substantial ly lowered the threshold for stimulation-in duced spiking [9; see also ref.…”

Section: Low Doses O Fz N 2+ Protect Neurons and Inhibit Seizuresmentioning

confidence: 99%

Zinc-Containing Neurons

Frederickson

Moncrieff²

1994

Biological Signals

209

117

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Zinc-containing neurons are cells that sequester zinc in their presynaptic vesicles and release it in a calcium- and impulse-dependent manner. The zinc-containing neurons are a subclass of the glutaminergic neurons: all known zinc-containing pathways are also glutaminergic pathways. With a few exceptions, zinc-containing neurons are located only in the telencephalon. The major glutaminergic systems of the brain stem, thalamus, and cerebellum, for example, all lack vesicular zinc, whereas many cerebrocortical systems are zinc containing. Within the telencephalon, the zinc-containing fiber systems form a vast associational network that reciprocally interconnects isocortical, allocortical and ''limbic'' structures. Because the hippocampal, amygdalar, and perirhinal regions are prominent nodes in this network, it is presumed that vesicular zinc is involved in epileptic phenomena (in pathology) and (in normal function) in the synaptic plasticity of developmental and experiential learning. Zinc ions are potent modulators of amino acid receptors [especially the N-methyl-D-aspartate (NMDA) receptor] and corelease of zinc along with glutamate would provide a mechanism for modulating postsynaptic excitability levels. One useful hypothesis is that synaptically released zinc controls a ''window'' of postsynaptic excitability, having little or no effect at physiological firing rates, but selectively depressing excitability (by NMDA receptor depression) when firing rates reach dangerous, paroxysmal levels.

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Effects of dietary zinc status on seizure susceptibility and hippocampal zinc content in theEl (epilepsy) mouse

Cited by 88 publications

References 38 publications

Effect of Carbonic Anhydrase Inhibition and Acetoacetate on Anaplerotic Pyruvate Carboxylase Activity in Cultured Rat Astrocytes

Effect of Carbonic Anhydrase Inhibition and Acetoacetate on Anaplerotic Pyruvate Carboxylase Activity in Cultured Rat Astrocytes

Slow Closed-State Inactivation: A Novel Mechanism Underlying Ramp Currents in Cells Expressing the hNE/PN1 Sodium Channel

Zinc-Containing Neurons

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