InTechOpen uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

Medicine » Mental and Behavioural Disorders and Diseases of the Nervous System » "Clinical and Genetic Aspects of Epilepsy", book edited by Zaid Afawi, ISBN 978-953-307-700-0, Published: September 15, 2011 under CC BY-NC-SA 3.0 license. © The Author(s).

Chapter 9

The Potential Role of ATP-sensitive Potassium Channels in Treating Epileptic Disorders

By Chin-Wei Huang
DOI: 10.5772/20709

Article top

The Potential Role of ATP-sensitive Potassium Channels in Treating Epileptic Disorders

Chin-Wei Huang1

1. Introduction

Despite antiepileptic drug (AED) therapy, epilepsy remains uncontrolled in around one third of patients. The majority of current AEDs fall into two pharmacological classes, those that modulate neuronal voltage-gated sodium and calcium channels and those that modulate neurotransmitters. There is a need for new AEDs with novel mechanisms of action to serve as adjunct therapy for the treatment of intractable epilepsy. Among the diverse molecular targets, to selectively modify the excitability of neurons so that high frequency epileptic firing can be blocked without disturbing normal neuronal activity, potassium is a potential target. Potassium channels play a major role in the control of resting membrane potential, responsiveness to synaptic inputs, spike frequency adaptation and neurotransmitter release. Among them, the important metabolic coupler to electrical activity- ATP-sensitive potassium (KATP) channels provides a distinct link between the metabolic and electrical state of cells. We have demonstrated the role of KATP channels in epileptic seizures in diabetic hyperglycemia, providing the direct evidence that increases in extracellular glucose and intracellular ATP attenuate KATP channels, leading to a more excitable state. We also examined the KATP channel agonist mediating neuroprotection in diabetic individuals with status epilepticus. Here, we report how we investigated the diabetic hyperglycemia-related epileptic disorder from clinical observation to experimental studies, and review this potential novel mechanism underlying attenuating epileptic activities by opening KATP channels, especially related to metabolic syndrome.

2. Epileptic seizures in diabetic hyperglycemia: From clinical observation

More than 200 million persons worldwide will be diagnosed with diabetes (Mandrup-Poulsen, 1998). Epileptic seizures with diabetic hyperglycemia (DH) (Maccario et al., 1965; Venna and Sabin, 1981; Huang et al., 2005) are not uncommon and around one-fourth of DH patients have reported seizures (Venna and Sabin, 1981; Singh and Strobos, 1989). In more than half of these patients, seizures reveal previously undiagnosed diabetes (Venna and Sabin, 1981; Tiamkao et al., 2003; Harden et al., 1991).

Most seizures in DH are partial motor seizures (Singh and Strobos, 1989; Loeb, 1974; Tiamkao et al., 2003), while 15% present as status epilepticus (SE). The level of hyperosmolarity and hyponatremia, accompanied by a wide range of hyperglycemic symptoms, however, are inconsistent (Grant and Warlow, 1985). Previous case reports suggest that DH-related epileptic seizures often develop at higher levels of glucose than non-DH-related seizures (Maccario et al., 1965; Venna and Sabin, 1981; Harden et al., 1991).

We conducted a prospective comparative follow-up study, focusing on newly diagnosed unprovoked seizures in adult patients, with and without DH, from 2000 to 2004 (Huang et al., 2008). We found that seizure clustering in initial presentation and in recurrence in the DH group was significantly higher than that in the non-DH group. Patients with poor glycemic control (HbA1c >9%) had significantly higher risk of seizure recurrence and clustering. Thus, DH might play a role in the severity of newly diagnosed adult epileptic seizures. Severe seizures might beget seizures in these patients. DH should be intensively investigated in adult patients with newly diagnosed seizures and aggressive blood sugar control might benefit seizure treatment in these patients, more than AEDs would.

The pathophysiology of epileptic seizures in DH is probably multi-factorial. Glucose itself could enhance synaptic transmission and propagation, leading to more excitable neurons (Tutka et al., 1998; Gispen and Biessels, 2000) and even epileptic seizures (Schwechter et al., 2003), regardless of the presence of organic lesions. Underlying focal ischemia has also been suggested as having a role in triggering these partial seizures (Singh and Strobos, 1989). Seizure susceptibility even in only moderate degrees of hyperglycemia has been reported in previous studies (Tiamkao et al., 2003; Brick et al., 1989); our study suggests that glucose itself is a pro-convulsant in DH.

In clinical observation, in the DH group, patients with recurrent seizures had more frequent SE at initial seizure presentation than those without, suggesting potential kindling during poorly controlled DH. In poorly controlled diabetes, neither the continued use of AEDs nor the presence of organic structural lesions affects seizure recurrence. Although simple partial seizures are more common in DH-related epileptic seizures, complex partial seizures, as the second most common in this study, and some rarer presentations, such as reflex, parieto-occipital, and sensory seizures (Brick et al., 1989; Huang et al., 2005, 2006, 2010; Lavin, 2005), should be carefully evaluated.

In animal experiments, a higher glucose level have facilitated amygdaloid kindling in rats (Priel et al., 1991) and decreased the time required for 50% of rats to recover sufficiently from a first maximal electroshock seizure (MES) to be able to have another MES (White et al., 1986). This is compatible with seizure clustering in the DH group observed in this study. This further suggests that kindling may continue and seizures may recur if blood glucose remains high.

Failure to identify the possible association between DH and seizures is common in clinical practice, potentially leading to inadequate treatment and seizure recurrences. Early recognition of the link will help early diagnosis and treatment, and prevent unnecessary interventions.

3. Epileptic seizures in experimental animals with diabetic hyperglycemia

As we all know, glucose plays a major role in metabolism and cerebral functions. However, the effects of hyperglycemia on the central nervous system (CNS) and neuronal excitability (Biessel et al., 1994; Stewart et al., 1999; Gispen and Biessel, 2000) are not fully understood. High glucose concentrations have been associated with a lower seizure threshold in an animal model with a single seizure (Schwechter et al., 2003) and neuronal excitability and seizures are related to rapid glucose utilization and glycolysis (Greene et al., 2003). Experimentally, the correlation between extracellular glucose concentration and excitability (seizure) has been established in previous studies (Margineanu et al., 1998; Tutka et al., 1998; Schwechter et al., 2003).

In addition to increasing excitability, higher glycosylated hemoglobin values have been associated with moderate declines in motor speed and psychomotor efficiency (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group et al., 2007). In animal models of diabetes, spatial-learning impairments occur in association with distinct changes in hippocampal synaptic plasticity (Biessels et al., 1998; Kamal et al., 2000). On the other hand, cognitive impairments after SE have been reported in both clinical and experimental studies (Helmstaedter, 2007). Nevertheless, how synaptic plasticity change responds to SE in DH is currently unknown. In addition, it remains to be determined whether DH exaggerates the cognitive and pathological outcome of SE.

We examined whether SE in rats with DH caused acute neuronal damage in the hippocampus, and impaired learning and memory, and synaptic plasticity, to determine the behavioral, pathological, and electrophysiological effects of SE on diabetic animals. Adult male Sprague-Dawley rats (150-200 g) were first divided into groups with and without streptozotocin (STZ)-induced diabetes, and then into treatment groups given a normal saline (NS) (STZ-only and NS-only) or a lithium-pilocarpine injection to induce SE (STZ+SE and NS+SE). Serial Morris water-maze test and hippocampal pathology results were examined before and 24 hours after SE. We found the STZ+SE group had a significantly higher percentage of severe seizures and SE-related death and worse learning and memory performances than the other three groups. The STZ+SE group, followed by the NS+SE group, showed the most severe neuronal loss and mossy fiber sprouting in the hippocampal CA3 area.

Tetanic stimulation-induced long-term potentiation (LTP) in a hippocampal slice from these rats was recorded in a multi-electrode dish system (Huang et al., 2006a). LTP was markedly attenuated in the STZ+SE group, followed by the NS+SE group. We also used a simulation model to evaluate intracellular ATP and neuronal excitability and we found increased intracellular ATP concentration promoted action potential firing.

From our animal study, we found that compared with non-diabetic rats, diabetic rats were more susceptible to seizures, had higher SE-related mortality, performed significantly worse on hippocampus-dependent behavioral tests, lost more hippocampal neurons during the acute stage after SE, and exhibited an impaired LTP after SE. This finding suggests the importance of intensively treating hyperglycemia and seizures in diabetic patients with epilepsy (Huang et al., 2009).

SE-induced damage and network reorganization in lithium-pilocarpine-treated rats occurs as a consequence of neuronal loss and SE-induced sprouting (Lehmann et al., 2001). In addition to SE-related excitotoxicity (Curia et al., 2008), DH plus SE may amplify the adverse effects of hyperglycemia on neurons, both the direct effects and the indirect effects, such as diabetic oxidative stress (Vincent et al., 2007; Zupan et al., 2008), microvascular changes (Mraovitch et al., 2005; Qiu et al., 2008), and altered calcium homeostasis (Raza et al., 2004; Biessels et al., 2005). Because neuronal glucose uptake depends on the extracellular concentration of glucose, cellular damage can ensue after persistent episodes of hyperglycemia (Tomlinson and Gardiner, 2008). Diabetes may induce morphological changes in the presynaptic mossy fiber terminals that form excitatory synaptic contacts with the proximal CA3 apical dendrites (Magariños and McEwen, 2000).

Although impaired, synaptic plasticity is still present in animals with pilocarpine-induced epilepsy (Trudeau et al., 2004). The post-SE water maze analyses showed the STZ+SE group, followed by the NS+SE group, performed significantly worse than the other two groups. These findings again suggest the great negative impact of concomitant DH and SE on cognition, indicating that these two conditions interact in the brain. It has been suggested (Trudeau et al., 2004) that LTP deficits in diabetes might arise from dysfunction of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors in the early stages of the disease. In addition, loss of LTP maintenance in STZ-treated rats has been suggested to be a result of disrupting the calcium-dependent process modulating post-synaptic alpha-amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) receptors (Chabot et al., 1997). The aggravating effect of SE on the glutamatergic system, supported an additional effect of DH on worsening LTP (Pitsch et al., 2007).

One of the empirically based clinical guideline for treating SE is to give glucose immediately (Chen and Wasterlain, 2006). Our study suggests that physicians pay attention to glucose management when encountering concomitant SE and DH. Because seizure clustering and SE in DH are frequently seen in clinical practice, we advocate intensively treating hyperglycemia and seizures in this special population.

4. Epileptic seizures in diabetic hyperglycemia: A mechanistic view

The mechanisms underlying hyperglycemia-increased neuronal excitability remains incompletely understood. As a coupling of metabolism to membrane electrical activity, Adenosine triphosphate (ATP)-sensitive K+ channels (KATP) is an important regulator of neuronal excitability and neuroprotection in metabolic stress, such as DH (Liss and Roeper, 2001; Seino and Miki, 2003). The direct connection between the level of electrical activity and intracellular ATP concentration suggests KATP potential for an antiepileptic role. The physiological regulation of KATP during metabolic inhibition involves protein kinase C-mediated KATP internalization to lessen the action potential duration shortening (Hu et al., 2003). Whether the epileptic circuit in individuals with DH involves KATP functional adaptation need further investigation.

KATP exist in many excitable cells, including cardiac myocytes, pancreatic β cells, muscle cells, and neurons (Liu et al., 1999, Seino, 1999). In pancreatic β cells, these channels are known to couple cellular metabolism to electrical activity by opening and closing as the intracellular ATP/ADP ratio decreases and increases, respectively (Ashcroft and Gribble, 1998). They are octameric complexes composed of four pore-forming units with inward rectifying characteristics (Kir 6.1 or Kir 6.2) and four sulfonylurea (SUR) binding sites (SUR1, SUR2A, or SUR2B) (Shyng and Nichols, 1997), regulated by intracellular ATP as well as pharmacological agents (e.g., diazoxide). These channels are highly responsive to changes in intracellular ATP levels generated during glucose metabolism. Rising levels of intracellular ATP close the KATP leading to depolarization and firing (Rowe et al., 1996; Ashcroft and Gribble, 1998). When the [ATP]/[ADP] ratio decreases, SUR1 and Kir 6.2 interaction reduces the latter’s affinity for ATP, thereby opening the KATP.

In pancreatic β cells, elevation in blood glucose and the closure of KATP trigger events leading to calcium influx, cellular depolarization, and insulin secretion (Miki and Seino, 2005). In the CNS, KATP exist in many tissues, particularly the hippocampus and neocortex (Dunn-Meynell et al., 1998). Except for a similar role in sensing central glucose in hypothalamic glucose-responsive neurons (Miki et al., 2001), they are not involved in specific neuroendocrine functions. Therefore, a more general role for these channels, functionally expressed in neurons, needs be investigated. In the brain, cells containing Kir 6.2 mRNA are widely distributed (Dunn-Meynell et al., 1998). A striking overlap with SUR1 mRNA suggests that the Kir 6.2/SUR1 complex is the best candidate for the brain functional KATP (Zawar et al., 1999; Betourne et al., 2009).

Owing to the abundant expression of KATP in the brain (Hicks et al., 1994; Mourre et al., 1990), the activation of KATP during ATP-depleted conditions has become a subject of studies. Mice lacking Kir6.2 (Kir 6.2 (-/-) mice) are vulnerable to hypoxia, exhibiting a reduced threshold for generalized seizure (Yamada et al., 2001). Transgenic mice, overexpressing the SUR1 gene in the forebrain, show a significant increase in the threshold for kainate-induced seizures (Hernandez-Sanchez et al., 2001). However, with excessive extracellular glucose and ATP in the hippocampal neurons, how KATP react is still marginally understood.

We hypothesized increases in extracellular glucose and intracellular ATP would attenuate KATP, with cells becoming more depolarized, leading to a more excitable state in hippocampal neurons. Thus, we investigated the effects of higher extracellular glucose on hippocampal KATP channel activities and neuronal excitability by using the cell-attached patch clamp configuration on cultured hippocampal cells (H19-7 cells) and the multi-electrode recording system on hippocampal slices. We found that incremental extracellular glucose could attenuate the activities of hippocampal KATP channels. Glucose significantly attenuates KATP channel activity in a concentration-dependent manner, mainly through a decrease in open probabilities. Higher levels of extracellular glucose could enhance neuropropagation which could be attenuated by diazoxide, a KATP channel agonist. Additionally, we found high levels of intracellular ATP, enhanced the firing of action potentials in model neurons. The stochastic increases in intracellular ATP levels also demonstrated an irregular and clustered neuronal firing pattern. Thus, this phenomenon of KATP channel-attenuation could be one of the underlying mechanisms of glucose-related neuronal hyper-excitability and propagation (Huang et al., 2007) (Figure 1).


Figure 1.

The scheme of potential role of KATP underlying epileptic seizures in diabetic hyperglycemia.

From our study, we found glucose could enhance propagation through inhibition of KATP channel activity. The single-channel conductance, open-time, channel-bursting, ATP-sensitivity and voltage-insensitivity observed in these H19-7 cells were nearly identical to those described in native pancreatic β cells (Kir 6.2/SUR1) (Mukai et al., 1998). Despite the heterogeneous expression profiles of KATP channel subunits reported in hippocampal pyramidal neurons (Zawar et al., 1999), our study emphasized the role of β-cell type KATP channel in the hippocampus.

The effect of glucose on propagation has been suggested to be related to post-synaptic NMDA receptor activities (Abulrob et al., 2005). We implies the novel role of KATP channels. The increment in glucose leads to attenuation of KATP channel activities which would enhance field effects of EPSP, potentially caused by electrotonic spread of depolarization. Both pre- and post-synaptic KATP channels were involved in the electrical coupling effects in neurons (Matsumoto et al., 2002). Our study could support the role of post-synaptic KATP channel in neuropropagation, as there were more dominant effects on fEPSP with a relatively limited effect on pre-synaptic fiber volley and paired-pulse facilitation, in the presence of high glucose concentration.

The concentration-dependent attenuation of glucose on KATP-channel activity also aids in understanding the higher seizure susceptibility in higher degrees of hyperglycemia. Moreover, the stochastic simulation in this study suggested that in a state of intracellular ATP fluctuation, the neuronal firing pattern would show irregularity. This could be in parallel with the clinical situation where hyperglycemia-related seizures might develop as a result of paroxysmal action potential development in a steady state of hyperglycemia.

5. The therapeutic point-of-view on epileptic seizures in metabolic syndrome

As we investigated, the important metabolic couplers to electrical activity, KATP are potential mechanistic candidates when we treat these seizures (Figure 1). For clinical application, we started from the current available AEDs and we found there have been a few reports concerning the effects of Pregabalin (PGB), a newer AED, on some modulating effects on voltage-gated potassium channel (Mc Clelland et al., 2004). Gabapentin-lactam, the derivative of gabapentin, has been found to exert an opening effect on KATP on the mitochondria (Pielen et al., 2004), which is a role in neuroprotection, added to the reduction of neuronal excitability. Moreover, it has been demonstrated that gabapentin can inhibit K+-evoked [3H]-noradrenaline release through the activation of KATP in both rat hippocampal and human neocortical cortex (Freiman et al., 2001). However, studies regarding the effects of PGB on KATP are still lacking.

We thus conducted an in vitro cellular study to investigate the effect of PGB on the activity of KATP present in H19-7 neurons. The inside-out configuration of the patch-clamp technique was employed to investigate KATP channel activities. Interestingly, PGB significantly opened these KATP channel activities in a concentration-dependent fashion with an EC50 value of 18 μM. There was a significant increase in the mean open-life time of KATP channels in the presence of PGB.

This study suggests that in differentiated hippocampal neuron-derived H19-7 cells, the opening effect on KATP channels could be one of PGB’s underlying mechanisms in the reduction of neuronal excitability (Huang et al., 2006b). It’s a novel finding regarding the mechanisms of PGB. Of interest, PGB applied to the intracellular surface of the excised patches is able to activate KATP channels in these cells, suggesting that its binding side could be primarily on the intracellular leaflet.

The opening of KATP channels has been noted as neuroprotective, especially the β-cell-type KATP channels comprised of Kir6.2 and SUR1 (Yamada et al., 2001). Therefore, it is conceivable that the activation of KATP channels by PGB is anti-epileptic and potentially neuroprotective. PGB has been shown to rapidly penetrate the blood-brain barrier in pre-clinical animal studies (Ben-Menachem, 2004). In PGB treatment (600mg/d) for epilepsy, the usual therapeutic concentration range is around 2.8-8.2 mg/L (≒15-43 μM) at steady state (Berry et al., 2005). From our study, the EC50 for PGB in opening KATP channel activities is around 18 μM. From this point, it appears that the clinically relevant concentration would be similar to the concentration noted in our study.

Although we have shown (Huang et al., 2007) that, in in vitro hippocampal neurons, KATP agonists lead to membrane hyperpolarization and attenuate action-potential firing when extracellular glucose concentrations are high, there were no in vivo studies on whether KATP agonists protect against seizure severity and consequent SE-induced hippocampal damage in rats with DH. In addition, the functional relationship between Kir 6.2 and SUR1 in DH-related seizures remains unclear. We hypothesized diazoxide is protective in diabetic rats with SE, and, if so, whether the opening of KATP mediates this protection. KATP openers, including diazoxide, protect beta cells (Kir 6.2/SUR1) and preserve human and rat islets in high concentrations of glucose (Björklund et al., 2004; Maedler et al., 2004). Molecular and electrophysiological studies (Miki et al., 2001; Bancila et al., 2005; Sun et al., 2006; Huang et al., 2006b) report that Kir 6.2/SUR1 channels, like pancreatic beta cells, seem to be the dominant KATP isoform in the brain. It is thus reasonable to hypothesize that diazoxide protects CNS neurons.

In this study, adult male Sprague-Dawley rats (150-200g) were divided into two groups: the STZ-induced diabetes (STZ) group and the normal saline (NS) group. Both groups were treated with either diazoxide (DZX, 15 mg/kg, i.v.) (STZ+DZX, NS+DZX) or vehicle (STZ+V, NS+V) before lithium-pilocarpine-induced SE. We evaluated seizure susceptibility, severity, and mortality. The rats underwent Morris water-maze tests and hippocampal histopathology analyses 24 hours post-SE. Similar to previous studies, a multi-electrode recording system was used to study fEPSP. Seizures were less severe, post-SE learning and memory were better, and neuron loss in the hippocampal CA3 area was lower in the STZ+DZX than the STZ+V group. In contrast, seizure severity, post-SE learning and memory, and hippocampal CA3 neuron loss were comparable in the NS+DZX and NS+V groups. fEPSP was lower in the STZ+DZX but not in the NS+DZX group. In addition, RNA interference (RNAi) to knockdown Kir 6.2 in a hippocampal cell line was used to evaluate the effect of diazoxide, in the presence of high concentration of ATP. The RNAi study confirmed that diazoxide, with its KATP-opening effects, could counteract the KATP-closing effect by high dose ATP. We conclude that, by opening KATP, diazoxide protects against SE-induced neuron damage during DH (Huang et al., 2010).

We showed in vivo and in vitro evidence that diazoxide indeed protected STZ diabetic rats against SE-induced hippocampal damage. There are reports (Mattia et al., 1994; Yamada et al., 2001; Soundarapandian et al., 2007) that modulated KATP may alter the seizure threshold and epileptiform activity in hippocampal slices in rats. Nevertheless, this class of compounds has not yet been generally effective in some animal models, such as the maximal electroshock model, the kindling model (Wickenden, 2002), and in our NS rats.

[3H] glyburide binding to SUR receptors in the brain appears to be generally upregulated in the state of hyperglycemia (Levin and Dunn-Meynell, 1998). In rats with DH, diazoxide opened KATP, which were frequently attenuated in a state of high extracellular glucose concentration (Huang et al., 2007). Diazoxide reduced glutamate release by opening presynaptic KATP Kir 6.2/SUR1 channels (Bancila et al., 2004). As diazoxide activates KATP by interacting with the SUR1 subunit (transmembrane domain 1 and nucleotide binding domain 1) (Nichols, 2006), opening KATP is potentially beneficial in a seizure during hyperglycemia.

The hippocampus is rich in Kir 6.2/SUR1-based channels (Thomzig et al., 2005; Sun et al., 2006). Hippocampal KATP are involved in processing new information at the mossy fiber CA3 synapses (Quinta-Ferreira and Matias, 2005). Reports (Zarrindast et al., 2006; Betourne et al., 2009) on the effect of diazoxide on contextual memory, however, are inconsistent. During learning, as the energy demand increases, mossy fiber KATP may sense a rise in intracellular ATP, which closes the KATP and increases glutamate release. Conversely, KATP that open immediately after intense electrical activity may also protect CA3 cells from glutamate-mediated excitotoxicity (Betourne et al., 2009). Based on our water-maze and pathology results, diazoxide -induced opening of KATP counteracted SE-related excitotoxicity in STZ rats.

6. Conclusion

Diabetic hyperglycemia might aggravate seizures. An aggressive search for diabetic hyperglycemia and intensive control of glucose in new onset seizures are helpful in management. The outcome of seizures is probably more deteriorating in diabetic patients with epilepsy. Because seizure clustering and status epilepticus in diabetic hyperglycemia are frequently seen in clinical practice, we advocate intensively treating hyperglycemia and seizures in this special population.

Our study provides more direct mechanistic evidence that increments of central neuron excitability, in a state of high glucose levels, can be attributed to KATP channel activity attenuation. KATP agonists are worth investigating as treatments for epileptic seizures in diabetic hyperglycemia.


The study is supported by grants from the National Science Council (NSC-98-2314-B-006-042-MY2), Taiwan.


1 - A. Abulrob, J. S. Tauskela, G. Mealing, E. Brunette, K. Faid, D. Stanimirovic, 2005Protection by cholesterol-extracting cyclodextrins: a role for N-methyl-D-aspartate receptor redistribution.J Neurochem 9214771486
2 - F. M. Ashcroft, F. M. Gribble, 1998Correlating structure and function in ATP-sensitive K+ channels.Trends Neurosci 21288294
3 - V. Bancila, I. Nikonenko, Y. Dunant, A. Bloc, 2004Zinc inhibits glutamate release via activation of pre-synaptic K channels and reduces ischaemic damage in rat hippocampus.J Neurochem 9012431250
4 - V. Bancila, T. Cens, D. Monnier, F. Chanson, C. Faure, Y. Dunant, A. Bloc, 2005Two SUR1-specific histidine residues mandatory for zinc-induced activation of the rat KATP channel.J Biol Chem 28087938799
5 - E. Ben-Menachem, Pregabalin pharmacology and its relevance to clinical practiceEpilepsia2004S138
6 - D. Berry, C. Millington, Analysis of pregabalin at therapeutic concentrations in human plasma/serum by reversed-phase HPLC.Ther Drug Monit 2005274516
7 - A. Betourne, A. M. Bertholet, E. Labroue, H. Halley, H. S. Sun, A. Lorsignol, Z. P. Feng, R. J. French, L. Penicaud, J. M. Lassalle, B. Frances, 2009Involvement of hippocampal CA3 K(ATP) channels in contextual memory. Neuropharmacology 56615625
8 - G. J. Biessels, A. Kamal, I. J. Urban, BM Erkelens. D. W. Spruijt, W. H. Gispen, 1998Water maze learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: effects of insulin treatmentBrain Res 800125135
9 - G. J. Biessels, Laak. M. P. Ter, A. Kamal, W. H. Gispen, 2005Effects of the Ca2+ antagonist nimodipine on functional deficits in the peripheral and central nervous system of streptozotocin-diabetic rats.Brain Res 10358693
10 - A. Björklund, Hansen. J. Bondo, S. Falkmer, V. Grill, 2004Openers of ATP-dependent K+-channels protect against a signal-transduction-linked and not freely reversible defect of insulin secretion in a rat islet transplantation model of Type 2 diabetes. Diabetologia 47885891
11 - Brick JF, Gutrecht JA, Ringel RA1989Reflex epilepsy and nonketotic hyperglycemia in the elderly: a specific neuroendocrine syndrome.Neurology39394399
12 - C. Chabot, G. Massicotte, M. Milot, F. Trudeau, J. Gagné, 1997Impaired modulation of AMPA receptors by calcium-dependent processes in streptozotocin-induced diabetic rats.Brain Res 768249256
13 - Chen JW, Wasterlain CG2006Status epilepticus: pathophysiology and management in adultsLancet Neurol 5246256
14 - L. Covolan, L. E. Mello, 2000Temporal profile of neuron injury following pilocarpine or kainic acid-induced status epilepticus. Epilepsy Res 39133152
15 - G. Curia, D. Longo, G. Biagini, R. S. Jones, M. Avoli, 2008The pilocarpine model of temporal lobe epilepsyThe pilocarpine model of temporal lobe epilepsy. J Neurosci Methods 172143157
16 - Control. Diabetes, Trial. Complications, of. Epidemiology, Interventions. Diabetes, Study. Complications, Group. Research, A. M. Jacobson, G. Musen, C. M. Ryan, N. Silvers, P. Cleary, B. Waberski, A. Burwood, K. Weinger, M. Bayless, W. Dahms, J. Harth, 2007Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med 35618421852
17 - Dunn-Meynell AA, Rawson NE, Levin BE1998Distribution and phenotype of neurons containing the ATP-sensitive K+ channel in rat brainBrain Res 8144154
18 - T. M. Freiman, J. Kukolja, J. Heinemeyer, K. Eckhardt, H. Aranda, A. Rominger, D. J. Dooley, J. Zentner, T. J. Feuerstein, 2001Modulation of K+-evoked [3H]-noradrenaline release from rat and human brain slices by gabapentin: involvement of KATP channels. Naunyn-Schmiedeberg’s Arch Pharmacol 363537542
19 - Gispen WH, Biessels GJ2000Cognition and synaptic plasticity in diabetes mellitusTrends Neurosci 23542549
20 - C. Grant, C. Warlow, 1985Focal epilepsy in diabetic non-ketotic hyperglycaemia.Br. Med. J 29012041205
21 - Greene AE, Todorova MT, Seyfried TN2003Perspectives on the metabolic management of epilepsy through dietary reduction and elevation of ketone bodies. J Neurochem 86529537
22 - C. L. Harden, D. H. Rosenbaum, M. Daras, 1991Hyperglycemia presenting with occipital seizures.Epilepsia32215220
23 - C. Helmstaedter, 2007Cognitive outcome of status epilepticus in adults.EpilepsiaS488590
24 - C. Hernandez-Sanchez, AS Fedorova. I. Basile, H. Arima, B. Stannard, A. M. Fernandez, Y. Ito, D. Le Roith, 2001Mice transgenically overexpressing sulfonylurea receptor 1 in forebrain resist seizure induction and excitotoxic neuron deathProc Natl Acad Sci USA 9835493554
25 - G. A. Hicks, A. L. Hudson, G. Henderson, 1994Localization of high affinity [3H]glibenclamide binding sites within the substantia nigra zona reticulata of the rat brain.Neuroscience61285292
26 - K. Hu, C. S. Huang, Y. N. Jan, L. Y. Jan, 2003ATP-sensitive potassium channel traffic regulation by adenosine and protein kinase C.Neuron38417432
27 - Huang CW, Hsieh YJ, Pai MC, Tsai JJ, Huang CC2005Non-ketotic hyperglycemia-related epilepsia partialis continua with ictal unilateral parietal hyperperfusion. Epilepsia 4618431844
28 - Huang CW, Hsieh YJ, Tsai JJ, Huang CC2006aThe effect of lamotrigine on field potentials, propagation and long-term potentiation in rat prefrontal cortex in multi-electrode recording. J Neurosci Res 8311411150
29 - Huang CW, Huang CC, Wu SN2006bThe Opening Effect of Pregabalin on ATP-Sensitive Potassium Channels in Differentiated Hippocampal Neuron-Derived H19-7 CellsEpilepsia47720726
30 - Huang CW, Huang CC, Cheng JT, Tsai JJ, Wu SN2007Glucose and hippocampal neuronal excitability: The role of ATP-sensitive potassium channels. J Neurosci Res 8514681477
31 - Huang CW, Tsai JJ, Ou HY, Wang ST, Cheng JT, Wu SN, Huang CC2008aDiabetic Hyperglycemia is associated with the severity of epileptic seizures in adultsEpilepsy Res 797177
32 - Huang CW, Cheng JT, Tsai JJ, Wu SN, Huang CC2009Diabetes aggravates epileptic seizures and status epilepticus-induced hippocampal damage. Neurotox Res 157181
33 - Huang CW, Wu SN, Cheng JT, Tsai JJ, Huang CC2010Diazoxide reduces status epilepticus neuron damage in diabetesNeurotox Res 17305316
34 - A. Kamal, G. J. Biessels, S. E. Duis, W. H. Gispen, 2000Learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: interaction of diabetes and ageing.Diabetologia43500506
35 - Lavin PJ2005Hyperglycemic hemianopia: a reversible complication of non-ketotic hyperglycemia.Neurology65616619
36 - T. N. Lehmann, S. Gabriel, A. Eilers, M. Njunting, R. Kovacs, K. Schulze, W. R. Lanksch, U. Heinemann, 2001Fluorescent tracer in pilocarpine-treated rats shows widespread aberrant hippocampal neuronal connectivity. Eur J Neurosci 148395
37 - Levin BE, Dunn-Meynell AA1998Effect of streptozotocin-induced diabetes on rat brain sulfonylurea binding sites.Brain Res Bull 46513518
38 - B. Liss, J. Roeper, 2001A role for neuronal K(ATP) channels in metabolic control of the seizure gate. Trends Pharmacol Sci 22599601
39 - M. Liu, S. Seino, A. L. Kirchgessner, 1999Identification and characterization of glucoresponsive neurons in the enteric nervous system J Neurosci 191030510317
40 - Loeb JN1974The hyperosmolar state.N Engl J Med 29011841187
41 - K. Maedler, J. Størling, J. Sturis, R. A. Zuellig, G. A. Spinas, P. O. Arkhammar, T. Mandrup-Poulsen, M. Y. Donath, 2004Glucose- and interleukin-1beta-induced beta-cell apoptosis requires Ca2+ influx and extracellular signal-regulated kinase (ERK) 1/2 activation and is prevented by a sulfonylurea receptor 1/inwardly rectifying K+ channel 6.2 (SUR/Kir6.2) selective potassium channel opener in human islets.Diabetes5317061713
42 - D. Mattia, T. Nagao, MA Avoli. M. Rogawski, 1994Potassium channel activators counteract anoxic hyperexcitability but not 4-aminopyridine-induced epileptiform activity in the rat hippocampal slice.Neuropharmacology3315151522
43 - T. Miki, B. Liss, K. Minami, T. Shiuchi, A. Saraya, Y. Kashima, M. Horiuchi, F. Ashcroft, Y. Minokoshi, J. Roeper, S. Seino, 2001ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Nat Neurosci 4507512
44 - T. Miki, S. Seino, 2005Roles of KATP channels as metabolic sensors in acute metabolic changes.J Mol Cell Cardiol 38917925
45 - L. Monnier, E. Mas, C. Ginet, F. Michel, L. Villon, J. P. Cristol, C. Colette, 2006Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes.JAMA 29516811687
46 - E. Mukai, H. Ishida, S. Kato, Y. Tsuura, S. Fujimoto, A. Ishida-Takahashi, M. Horie, K. Tsuda, Y. Seino, 1998Metabolic inhibition impairs ATP-sensitive K+ channel block by sulfonylurea in pancreatic beta-cells. Am J Physiol 274:E3844
47 - A. Pielen, M. Kirsch, H. Hofmann, T. J. Feuerstein, W. A. Lagreze, 2004Retinal ganglion cell survival is enhanced by gabapentin-lactam in vitro: evidence for involvement of mitochondrial KATP channels.Graefes Arch Clin Exp Ophthalmol 242240244
48 - J. Pitsch, S. Schoch, N. Gueler, P. J. Flor, H. van der Putten, A. J. Becker, 2007Functional role of mGluR1 and mGluR4 in pilocarpine-induced temporal lobe epilepsyNeurobiol Dis 26623633
49 - Priel MR, Bortolotto ZA, Cavalheiro EA1991Effects of systemic glucose injection on the development of amygdala kindling in rats.Behav Neural Biol 56314318
50 - C. Qiu, M. F. Cotch, S. Sigurdsson, M. Garcia, R. Klein, F. Jonasson, B. E. Klein, G. Eiriksdottir, T. B. Harris, MA Gudnason. V. van Buchem, L. J. Launer, 2008Retinal and cerebral microvascular signs and diabetes: the age, gene/environment susceptibility-Reykjavik study. Diabetes 5716451650
51 - Quinta-Ferreira ME, Matias CM2005Tetanically released zinc inhibits hippocampal mossy fiber calcium, zinc and synaptic responses.Brain Res 104719
52 - M. Raza, R. E. Blair, S. Sombati, DS Deshpande. L. S. Carter, R. J. De Lorenzo, 2004Evidence that injury-induced changes in hippocampal neuronal calcium dynamics during epileptogenesis cause acquired epilepsyProc Natl Acad Sci USA 1011752217527
53 - Rowe IC, Treherne JM, Ashford ML1996Activation by intracellular ATP of a potassium channel in neurones from rat basomedial hypothalamus.J Physiol 49097113
54 - E. M. Schwechter, J. Veliskova, L. Velisek, 2003Correlation between extracellular glucose and seizure susceptibility in adult rats.Ann Neurol 5391101
55 - S. Seino, 1999ATP-sensitive potassium channels: a model of heteromultimeric potassium channel/receptor assemblies.Annu Rev Physiol 61337362
56 - S. Seino, T. Miki, 2003Physiological and pathophysiological roles of ATP-sensitive K+ channelsProg Biophys Mol Biol 81133176
57 - S. Shyng, C. G. Nichols, 1997Octameric stoichiometry of the KATP channel complexJ Gen Physiol 110655664
58 - Singh BM, Strobos RJ1989Epilepsia partialis continua associated with nonketotic hyperglycemia: clinical and biochemical profile of 21 patients.Ann Neurol 8155160
59 - MM Wu. D. Soundarapandian, X. Zhong, R. S. Petralia, L. Peng, W. Tu, Y. Lu, 2007Expression of functional Kir6.1 channels regulates glutamate release at CA3 synapses in generation of epileptic form of seizuresJ Neurochem 10319821988
60 - R. Stewart, D. Liolista, 1999Type 2 diabetesmellitus, cognitive impairment and dementia. Diabet Med 1693112
61 - H. S. Sun, Z. P. Feng, T. Miki, S. Seino, R. J. French, 2006Enhanced neuronal damage after ischemic insults in mice lacking Kir6.2-containing ATP-sensitive Kt channels. J Neurophysiol 9525902601
62 - A. Thomzig, G. Laube, H. Pruss, R. W. Veh, 2005Pore-forming subunits of K-ATP channels, Kir6.1 and Kir6.2, display prominent differences in regional and cellular distribution in the rat brain.J Comp Neurol 484313330
63 - S. Tiamkao, T. Pratipanawatr, S. Tiamkao, B. Nitinavakarn, V. Chotmongkol, S. Jitpimolmard, 2003Seizures in nonketotic hyperglycaemia. Seizure 12409410
64 - Tomlinson DR, Gardiner NJ2008Glucose neurotoxicityNat Rev Neurosci 93645
65 - F. Trudeau, S. Gagnon, G. Massicotte, 2004Hippocampal synaptic plasticity and glutamate receptor regulation: influences of diabetes mellitus.Eur J Pharmacol 490177186
66 - P. Tutka, J. Sawiniec, Z. Kleinrok, 1998Experimental diabetes sensitizes mice to electrical- and bicuculline-induced convulsions.Pol J Pharmacol 509293
67 - N. Venna, T. D. Sabin, 1981Tonic focal seizures in nonketotic hyperglycemia of diabetes mellitusArch Neurol 38512514
68 - White HS, Woodbury DM, Chen CF, Kemp JW, Chow SY, Yen-Chow YC1986Role of glial cation and anion transport mechanisms in etiology and arrest of seizures.Adv Neurol 44695712
69 - K. Yamada, J. J. Ji, H. Yuan, T. Miki, S. Sato, N. Horimoto, T. Shimizu, S. Seino, N. Inagaki, 2001Protective role of ATP-sensitive potassium channels in hypoxia-induced generalized seizure. Science 29215431546
70 - M. R. Zarrindast, M. Ebrahimi, A. Khalilzadeh, 2006Influence of ATP-sensitive potassium channels on lithium state-dependent memory of passive avoidance in miceEur J Pharmacol 550107111
71 - C. Zawar, T. D. Plant, C. Schirra, A. Konnerth, B. Neumcke, 1999Cell-type specific expression of ATP-sensitive potassium channels in the rat hippocampus.J Physiol 514327341
72 - G. Zupan, K. Pilipović, A. Hrelja, S. Peternel, 2008Oxidative stress parameters in different rat brain structures after electroconvulsive shock-induced seizures. Prog Neuropsychopharmacol Biol Psychiatry 32771777