Nicotine as an Antiepileptic Agent in ADNFLE: An N‐of‐One Study

Willoughby, John O.; Pope, Kenneth J.; Eaton, Vaughn

doi:10.1046/j.1528-1157.2003.58102.x-i1

Cited by 67 publications

(26 citation statements)

References 6 publications

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“…Nicotine seizures in L9ЈA mice consist of forelimb clonus and loss of righting response (which can also be described as asymmetrical posturing). (2) Nicotine suppressed ADNFLE seizures in the single patient tested to date (Willoughby et al, 2003). Nicotine pretreatment blocked nicotine-induced seizures in L9ЈA mice.…”

Section: Similarities With Adnflementioning

confidence: 93%

“…6 B, D). The following compounds were tested for their ability to prevent nicotine-induced seizures in L9ЈA and WT mice: (1) carbamazepine, a commonly used antiepileptic; (2) dihydro-␤-erythroidine (DH␤E), a competitive nicotinic antagonist with high affinity for ␣4/␤2 receptors; (3) hexamethonium, a nicotinic antagonist with poor brain-barrier permeability and thus suspected of preferentially targeting nicotinic receptors in the periphery; (4) mecamylamine, a potent wide-spectrum nicotinic antagonist, and (5) nicotine, reported to prevent seizures in an otherwise drug-resistant AD-NFLE patient (Willoughby et al, 2003). All pretreatment drugs were dissolved in saline, except for carbamazepine, which was suspended in 1% Tween 80.…”

Section: Methodsmentioning

confidence: 99%

“…This suggests that nicotineinduced seizures in L9ЈA mice are initiated by the activation, not desensitization, of mutated hypersensitive ␣4* nAChRs. A similar mechanism could account for the effects of nicotine on an ADNFLE patient resistant to conventional antiepileptic drugs (including carbamazepine) but successfully treated with a nicotine patch (Willoughby et al, 2003). That nicotine pretreatment did not prevent nicotine-induced seizures in WT mice suggests a different seizure mechanism, perhaps involving desensitization of ␣4* receptors on inhibitory interneurons, leading to neuronal synchronization and to overexcitation (Mody, 1998;Dobelis et al, 2003).…”

Section: Nicotine-induced Seizures: Type Sensitivity and Pharmacologymentioning

confidence: 97%

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Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4^*Nicotinic Receptors

Fonck¹,

Cohen²,

Nashmi³

et al. 2005

J. Neurosci.

120

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A leucine to alanine substitution (L9ЈA) was introduced in the M2 region of the mouse ␣4 neuronal nicotinic acetylcholine receptor (nAChR) subunit. Expressed in Xenopus oocytes, ␣4(L9ЈA)␤2 nAChRs were Ն30-fold more sensitive than wild type (WT) to both ACh and nicotine. We generated knock-in mice with the L9ЈA mutation and studied their cellular responses, seizure phenotype, and sleepwake cycle. Seizure studies on ␣4-mutated animals are relevant to epilepsy research because all known mutations linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) occur in the M2 region of ␣4 or ␤2 subunits. Thalamic cultures and synaptosomes from L9ЈA mice were hypersensitive to nicotine-induced ion flux. L9ЈA mice were ϳ15-fold more sensitive to seizures elicited by nicotine injection than their WT littermates. Seizures in L9ЈA mice differed qualitatively from those in WT: L9ЈA seizures started earlier, were prevented by nicotine pretreatment, lacked EEG spike-wave discharges, and consisted of fast repetitive movements. Nicotine-induced seizures in L9ЈA mice were partial, whereas WT seizures were generalized. When L9ЈA homozygous mice received a 10 mg/kg nicotine injection, there was temporal and phenomenological separation of mutant and WT-like seizures: an initial seizure ϳ20 s after injection was clonic and showed no EEG changes. A second seizure began 3-4 min after injection, was tonic-clonic, and had EEG spike-wave activity. No spontaneous seizures were detected in L9ЈA mice during chronic video/EEG recordings, but their sleep-wake cycle was altered. Our findings show that hypersensitive ␣4* nicotinic receptors in mice mediate changes in the sleep-wake cycle and nicotineinduced seizures resembling ADNFLE.

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Section: Similarities With Adnflementioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Nicotine-induced Seizures: Type Sensitivity and Pharmacologymentioning

confidence: 97%

See 1 more Smart Citation

Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4^*Nicotinic Receptors

Fonck¹,

Cohen²,

Nashmi³

et al. 2005

J. Neurosci.

120

View full text Add to dashboard Cite

show abstract

“…Mutations of gene coding for neuronal nicotinic acetylcholine receptors can result in a form of autosomal dominant nocturnal frontal lobe epilepsy. Willoughby et al (75) used a nicotine patch treatment for a patient with a defined mutation for autosomal dominant nocturnal frontal lobe epilepsy whose seizures were refractory to standard antiepileptic therapy. In this N-of-one study, the patient responded remarkably well to the patch.…”

Section: Treatment Of Nocturnal Seizures: Are We Still In the Dark? Bmentioning

confidence: 99%

Sleep and Epilepsy: A Summary of the 2011 Merritt-Putnam Symposium

et al. 2013

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Lennox and Lennox, 1960 (1) Despite the long history of sleep and epilepsy research, the relationship between the two remains poorly understood (2, 3). An abundance of evidence suggests a bidirectional relationship between sleep and epilepsy, where sleep disorders are common comorbidities in individuals with epilepsy; and sleep, slow-wave sleep (SWS) in particular, may provide a physiological milieu for epileptiform activity. Sleep is also critical in postencoding evolution including a range of sleep-dependent memory processes, from simple stabilization of memories to the discovery of insights. The chronobiology of sleep results in the need to understand the chronopharmacology of antiepileptic drug therapy in individuals with epilepsy. At the 2011 Merritt-Putnam Symposium, the dynamic symbiotic relationship between sleep and epilepsy was explored. Objectives of the symposium were to 1) identify distinguishing clinical and EEG features of nocturnal seizures and parasomnias, which allow accurate diagnosis; 2) understand how sleep disturbances can exacerbate epilepsy and epilepsy can adversely alter sleep; 3) review common pathophysiological mechanisms between sleep and epilepsy; 4) recognize the consequences of nocturnal seizures and epileptiform discharges on cognition; and 5) learn to manage nocturnal seizures and epileptiform activity using current treatment options. The symposium addressed one of the NIH research benchmarks: Area III: Prevent, limit, and reverse the comorbidities associated with epilepsy and its treatment (4). Specifically, the topics aimed to prevent or limit other adverse consequences occurring in people with epilepsy, identify the range and

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“…The wide variations in incidence of epilepsy are explained by differences in diagnostic criteria and selection of patients. Those with short febrile seizures were mainly in prospective studies and rarely developed spontaneous seizures, whereas patients with complicated febrile seizures had often presented at a later age with epilepsy, and 17% had records of brain injury at birth [2]. In a prospective study of 110 unselected FS patients followed for ~2 years by the author, spontaneous nonfebrile seizures occurred in 17%, they were recurrent in 12%, and were frequent in 4% [3].…”

mentioning

confidence: 99%

Epilepsy Comorbidities

Millichap¹

2014

Pediatr Neurol Briefs

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Nicotine as an Antiepileptic Agent in ADNFLE: An N‐of‐One Study

Cited by 67 publications

References 6 publications

Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4^*Nicotinic Receptors

Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4^*Nicotinic Receptors

Sleep and Epilepsy: A Summary of the 2011 Merritt-Putnam Symposium

Epilepsy Comorbidities

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Nicotine as an Antiepileptic Agent in ADNFLE: An N‐of‐One Study

Cited by 67 publications

References 6 publications

Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4*Nicotinic Receptors

Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4*Nicotinic Receptors

Sleep and Epilepsy: A Summary of the 2011 Merritt-Putnam Symposium

Epilepsy Comorbidities

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Product

Resources

About

Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4^*Nicotinic Receptors

Novel Seizure Phenotype and Sleep Disruptions in Knock-In Mice with Hypersensitive α4^*Nicotinic Receptors