Ionic and acid-base regulation of neurons and glia during seizures

Dm, Woodbury; Fl, Engstrom; Hs, White; Cf, Chen; Jw, Kemp; Sy, Chow

doi:10.1002/ana.410160720

Cited by 47 publications

(28 citation statements)

References 15 publications

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“…This enzyme relies mostly on metabolic substrates that are generated during neuronal activity, and directly regulates the intracellular C1' content in neuroglia through a Na+/K'-dependent adenosine triphosphatase (ATPase) anion exchanger that swaps extracellular C1-for intracellular HCO,- (74).…”

Section: Acetazolamidementioning

confidence: 99%

The Pharmacologic Basis of Antiepileptic Drug Action

1999

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Summary:The development of medications used in the treatment of epilepsy has accelerated over the past decade, and has benefited from a parallel growth in our knowledge of the basic mechanisms underlying neuronal excitability and synchronization. This understanding of the pharmacologic basis of antiepileptic drug (AED) action has, in large part, arisen from recent advances in cellular and molecular biology, coupled with avenues of drug discovery that have departed somewhat from the largely empiric approaches of the past. Physicians now have available to them an ever-growing armentarium of AEDs, neTherapy with antiepileptic drugs (AEDs) remains the mainstay of treatment of patients with epilepsy. Before the Victorian era, therapeutic approaches to epilepsy were largely based on superstition and charlatanism. The first demonstrably effective chemotherapy relied on the use of nonspecific depressants of the central nervous system. Sir Charles Locock introduced bromides in the mid-nineteenth century for the treatment of catamenial epilepsies, and phenobarbital (PB) was adopted in 1912 after the observations of Hauptmann (l), who used that compound to sedate a ward of noisy psychiatric patients and those with epilepsy during the night. Introduction of more specific AEDs for clinical application followed the availability of the first animal-seizure model: the maximal electroshock (MES) model (2). The history of AED design has recently been reviewed in some detail (3).The relation of the human epilepsies to the animal models commonly used for AED development, and to the cellular membrane physiology underlying neuronal excitability, continues to be an imperfect one (Fig. 1) cessitating a firmer appreciation of their mechanisms of action if more rational approaches toward both clinical application and research are to be adopted. An important example in this regard is the concept of rational polypharmacy for patients with epilepsy who are refractory to monotherapy. This review summarizes our current understanding of the molecular targets of clinically significant AEDs, comparing and contrasting their differing mechanisms of action. Key Words: Antiepileptic drug-AED-Anticonvulsant-Mechanism-%-zure-Epilepsy-Ion channel.threshold pentylenetetrazol (PTZ) test in mice (see Table 1) have been carefully standardized (4). The MES model has served to identify AEDs that are functionally similar to phenytoin (PHT), and most of these compounds display in common the ability to inactivate voltage-dependent Na+ channels in a use-dependent fashion. Such compounds suppress sustained repetitive firing in cultured neurons. Activity in this model seems highly predictive of the ability of those AEDs to protect against partial and secondarily generalized tonic-clonic seizures (Fig. 2). Carbamazepine (CBZ), as well as several newer agents such as felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), and topiramate (TPM), fit this model of AED activity. Some of these (i.e., PHT, CBZ, LTG) may also attenuate the release of excitatory neurotransmi...

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Section: Acetazolamidementioning

confidence: 99%

The Pharmacologic Basis of Antiepileptic Drug Action

1999

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“…Central nervous system (CNS) seizures are characterised by repeated synchronised neuronal bursts, a subsequent increase in transmitter release, and changes in volume transmission and in the diffusion parameters of the extracellular space (1)(2)(3)(4). Electric activity and intercellular flow of ions and small molecules are regulated in part by gap junctions (GJs) (5,6).…”

Section: Introductionmentioning

confidence: 99%

Long-lasting dephosphorylation of connexin 43 in acute seizures is regulated by NMDA receptors in the rat cerebral cortex

2008

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Abstract. Gap junctions consisting of connexin 43 subunits provide intercellular communication between astrocytes, contributing to their function of maintaining the central nervous system (CNS) microenvironment. Magnetic resonance imaging (MRI) studies demonstrate prolonged astrocyte swelling related to seizures, while in vitro studies show the disruption of intercellular coupling and the cytotoxic swelling of astrocytes in seizure-equivalent environments. We examined the relation between astrocyte swelling and connexin 43 regulation using an in vivo seizure model. Generalised tonic-clonic convulsions were induced in adult rats using intraperitoneally (i.p.)-administered 4-aminopyridine (4-AP). The expression of connexin 43 mRNA and protein at 1, 3 and 24 h after seizure induction was measured. Astrocytic swelling was assessed at the same time points using transmission electron microscopy. mRNA and protein levels remained unaltered at all time periods. However, a significant (~50%) reduction was found in the amount of phosphorylated (P1, P2) to unphosphorylated (NP) forms of connexin 43 at 3 h. The amount increased thereafter, but was still significantly lower than in the controls at 24 h postseizure. Simultaneously, marked astrocytic swelling was measured in the neocortex. Pre-treatment with N-methyl-Daspartate (NMDA) receptor antagonist dizocilpine maleate (MK-801) resulted in the amelioration of seizure symptoms and the prevention of connexin 43 dephosphorylation, as well as significantly reduced astrocytic swelling. Dephosphorylation of connexin 43 was shown to reduce astrocytic gap junction (GJ) permeability. Our results therefore suggest that, during acute seizures, a prolonged inhibition of intercellular coupling develops in the astrocyte network. This accounts for the longlasting astrocyte swelling observed, and potentially impairs buffering function. The results also imply that this uncoupling is regulated through neuronal and/or glial NMDA-type glutamate receptors.

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“…Woodbury [2] and Woodbury et al [3] have reported that SCAIs lower bicarbonate concentrations in astro cytes and thus, in the presence of SCAIs, pyruvate car boxylase may be substrate-limited. To determine the sensitivity of pyruvate carboxylase to substrate limita tion by low pyruvate, experiments were carried out with varied pyruvate concentrations.…”

Section: Effect Of Pyruvate and Acetoacetatementioning

confidence: 99%

“…We report that SCAIs, presumably by lowering astrocyte bicarbonate concentration [2,3], sec ondarily inhibit pyruvate carboxylase. There are seven mammalian isozymes of CA.…”

Section: Introductionmentioning

confidence: 99%

“…Sulfonamide carbonic anhydrase (CA) inhibitors (SCAIs) are used as an adjuvant treatment for childhood epilepsy, particularly so-called absence seizures [1][2][3][4], Despite the fact that this class of drugs is not new, the link between CA inhibition and antiseizure activity has never been adequately explained. Histochemical and immunocytochemical studies show that CA in brain is expressed primarily in the glia [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

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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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Ionic and acid-base regulation of neurons and glia during seizures

Cited by 47 publications

References 15 publications

The Pharmacologic Basis of Antiepileptic Drug Action

The Pharmacologic Basis of Antiepileptic Drug Action

Long-lasting dephosphorylation of connexin 43 in acute seizures is regulated by NMDA receptors in the rat cerebral cortex

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

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