Termination of epileptiform activity by cooling in rat hippocampal slice epilepsy models

Motamedi, Gholam K.; Salazar, Pedro; Smith, Eric L.; Lesser, Ronald P.; Webber, W. R.; Ortinski, Pavel I.; Vicini, Stefano; Rogawski, Michael A.

doi:10.1016/j.eplepsyres.2006.05.001

Cited by 49 publications

(36 citation statements)

References 23 publications

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“…It has been hypothesized that a loss of function caused by alterations in sodium channel gating properties during hypothermia could interrupt neuronal depolarization and abort the epileptiform discharges [5,22]. Indeed, we observed blockade of action potentials in hippocampal pyramidal neurons that was associated with either depolarization or hyperpolarization.…”

Section: Discussionmentioning

confidence: 57%

“…Therefore, heat-sensitive molecular compounds seem to be essential for brain functions at physiological temperature. Furthermore, hypothermia has been shown to terminate experimentally induced seizure activity of in vitro and in vivo models of epilepsy within seconds, without causing acute or delayed injury to the cooled brain [4][5][6][7]. It is suggested by these studies that cooling could represent a new approach to seizure control in intractable focal epilepsies as an alternative to resective surgery, which may result in suboptimal seizure control and possible neurological deficits.…”

Section: Introductionmentioning

confidence: 99%

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Cellular Mechanisms of Desynchronizing Effects of Hypothermia in an In Vitro Epilepsy Model

et al. 2012

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Hypothermia can terminate epileptiform discharges in vitro and in vivo epilepsy models. Hypothermia is becoming a standard treatment for brain injury in infants with perinatal hypoxic ischemic encephalopathy, and it is gaining ground as a potential treatment in patients with drug resistant epilepsy. However, the exact mechanism of action of cooling the brain tissue is unclear. We have studied the 4-aminopyridine model of epilepsy in mice using single-and dual-patch clamp and perforated multielectrode array recordings from the hippocampus and cortex. Cooling consistently terminated 4-aminopyridine induced epileptiform-like discharges in hippocampal neurons and increased input resistance that was not mimicked by transient receptor potential channel antagonists. Dual-patch clamp recordings showed significant synchrony between distant CA1 and CA3 pyramidal neurons, but less so between the pyramidal neurons and interneurons. In CA1 and CA3 neurons, hypothermia blocked rhythmic action potential discharges and disrupted their synchrony; however, in interneurons, hypothermia blocked rhythmic discharges without abolishing action potentials. In parallel, multi-electrode array recordings showed that synchronized discharges were disrupted by hypothermia, whereas multi-unit activity was unaffected. The differential effect of cooling on transmitting or secreting γ-aminobutyric acid interneurons might disrupt normal network synchrony, aborting the epileptiform discharges. Moreover, the persistence of action potential firing in interneurons would have additional antiepileptic effects through tonic γ-aminobutyric acid release.

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Section: Discussionmentioning

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Cellular Mechanisms of Desynchronizing Effects of Hypothermia in an In Vitro Epilepsy Model

et al. 2012

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“…It is possible that our preparation leads us to overestimate the degree of cooling required for seizure termination, because another group has shown that paroxysmal discharges in a slice model of epilepsy were eliminated by rapid temperature reductions of only 1°C. 24 After completing our initial cooling experiments, we developed a frequency-based seizure detection algorithm for the 4-aminopyridine seizures, which allowed us to use a closed-loop system to abort seizures. To minimize false positives, we set a relatively high threshold before cooling was activated.…”

Section: Results With Experimental Epilepsymentioning

confidence: 99%

The Therapeutic Potential of Focal Cooling for Neocortical Epilepsy

Rothman

2009

Neurotherapeutics

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Summary:The therapy of the focal cortical epilepsies remains unsatisfactory. Close to a third of patients fail to gain adequate control with antiepileptic drugs and a portion of those who do, experience unacceptable side effects. Morever, the favorable response rate after surgical resection, approximately 60%, is not nearly as high as the response rate of complex partial seizures caused by mesial temporal sclerosis. The suppressive effect of cooling on neuronal activity has been recognized for over a century. Therefore, we have begun to explore the possible application of cooling as a therapy for focal cortical seizures. In initial brain slice experiments, we found that cooling to 20°C could rapidly terminate paroxysmal activity. Then we developed an in vivo model of focal seizures using a local injection of the convulsant 4-aminopyridine and found that cooling the injected area to less than 24°C with a thermoelectric Peltier device aborted seizures within a few seconds. Other laboratories have independently confirmed our initial observations. More recent experiments from our laboratory have shown that cooling, per se, is not associated with significant cortical damage, even at surface temperatures as low as 5°C. Advances in the fabrication of extremely thin thermoelectric devices, less than a few hundred microns thick, has raised the possibility of incorporating an implantable cooling unit into a closed loop seizure detection and treatment system.

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“…To record spontaneous field activity, recording electrodes were placed in the CA1 stratum pyramidale. Spontaneous epileptiform activity (burst-firing) was induced by bath perfusion with aCSF containing 75 M 4-AP, a potassium channel blocker (Perreault and Avoli, 1991;Yonekawa et al, 1995;Motamedi et al, 2006), for 30 min. The epileptiform activity was quantified by determining the frequency of bursts during the last 10 min of 4-AP application, when burst-firing is stable and most robust (Salazar et al, 2003).…”

Section: Methodsmentioning

confidence: 99%

Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats

Galic¹,

Riazi²,

Heida³

et al. 2008

Journal of Neuroscience

260

211

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There are critical postnatal periods during which even subtle interventions can have long-lasting effects on adult physiology. We asked whether an immune challenge during early postnatal development can alter neuronal excitability and seizure susceptibility in adults. Postnatal day 14 (P14) male Sprague Dawley rats were injected with the bacterial endotoxin lipopolysaccharide (LPS), and control animals received sterile saline. Three weeks later, extracellular recordings from hippocampal slices revealed enhanced field EPSP slopes after Schaffer collateral stimulation and increased epileptiform burst-firing activity in CA1 after 4-aminopyridine application. Six to 8 weeks after postnatal LPS injection, seizure susceptibility was assessed in response to lithium-pilocarpine, kainic acid, and pentylenetetrazol. Rats treated with LPS showed significantly greater adult seizure susceptibility to all convulsants, as well as increased cytokine release and enhanced neuronal degeneration within the hippocampus after limbic seizures. These persistent increases in seizure susceptibility occurred only when LPS was given during a critical postnatal period (P7 and P14) and not before (P1) or after (P20). This early effect of LPS on adult seizures was blocked by concurrent intracerebroventricular administration of a tumor necrosis factor ␣ (TNF␣) antibody and mimicked by intracerebroventricular injection of rat recombinant TNF␣. Postnatal LPS injection did not result in permanent changes in microglial (Iba1) activity or hippocampal cytokine [IL-1␤ (interleukin-1␤) and TNF␣] levels, but caused a slight increase in astrocyte (GFAP) numbers. These novel results indicate that a single LPS injection during a critical postnatal period causes a longlasting increase in seizure susceptibility that is strongly dependent on TNF␣.

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Termination of epileptiform activity by cooling in rat hippocampal slice epilepsy models

Cited by 49 publications

References 23 publications

Cellular Mechanisms of Desynchronizing Effects of Hypothermia in an In Vitro Epilepsy Model

Cellular Mechanisms of Desynchronizing Effects of Hypothermia in an In Vitro Epilepsy Model

The Therapeutic Potential of Focal Cooling for Neocortical Epilepsy

Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats

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