Antikindling effects of locus coeruleus stimulation: Mediation by ascending noradrenergic projections

Weiss, Gerald K.; Lewis, Johnnye; Jiménez‐Rivera, Carlos A.; Vigil, Anthony; Corcoran, Michael E.

doi:10.1016/0014-4886(90)90020-s

Cited by 58 publications

(21 citation statements)

References 23 publications

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“…[5][6][7] The anatomy and biology of the trigeminal nerve support potential mechanisms by which TNS may impact epilepsy and mood disorders, and animal data demonstrate that stimulation of the trigeminal nerve and its related structures inhibits seizures. [8][9][10][11][12][13][14][15][16][17] In a rat pentylenetetrazole model, TNS resulted in reductions in the number of seizures (range 236% to 58%) depending on stimulus intensity. 11,12 The magnitude of the seizure-reduction effect increased as the amplitude and frequency of stimulation increased, and bilateral stimulation was more effective than unilateral stimulation.…”

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confidence: 99%

Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy

et al. 2013

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Objective: To explore the safety and efficacy of external trigeminal nerve stimulation (eTNS) in patients with drug-resistant epilepsy (DRE) using a double-blind randomized controlled trial design, and to test the suitability of treatment and control parameters in preparation for a phase III multicenter clinical trial.Methods: This is a double-blind randomized active-control trial in DRE. Fifty subjects with 2 or more partial onset seizures per month (complex partial or tonic-clonic) entered a 6-week baseline period, and then were evaluated at 6, 12, and 18 weeks during the acute treatment period. Subjects were randomized to treatment (eTNS 120 Hz) or control (eTNS 2 Hz) parameters.Results: At entry, subjects were highly drug-resistant, averaging 8.7 seizures per month (treatment group) and 4.8 seizures per month (active controls). On average, subjects failed 3.35 antiepileptic drugs prior to enrollment, with an average duration of epilepsy of 21.5 years (treatment group) and 23.7 years (active control group), respectively. eTNS was well-tolerated. Side effects included anxiety (4%), headache (4%), and skin irritation (14%). The responder rate, defined as .50% reduction in seizure frequency, was 30.2% for the treatment group vs 21.1% for the active control group for the 18-week treatment period (not significant, p 5 0.31, generalized estimating equation [GEE] model). The treatment group experienced a significant within-group improvement in responder rate over the 18-week treatment period (from 17.8% at 6 weeks to 40.5% at 18 weeks, p 5 0.01, GEE). Subjects in the treatment group were more likely to respond than patients randomized to control (odds ratio 1.73, confidence interval 0.59-0.51). eTNS was associated with reductions in seizure frequency as measured by the response ratio (p 5 0.04, analysis of variance [ANOVA]), and improvements in mood on the Beck Depression Inventory (p 5 0.02, ANOVA). Conclusions:This study provides preliminary evidence that eTNS is safe and may be effective in subjects with DRE. Side effects were primarily limited to anxiety, headache, and skin irritation. These results will serve as a basis to inform and power a larger multicenter phase III clinical trial. Drug-resistant epilepsy (DRE) affects 30% of all people with epilepsy, and may lead to disability and death. [1][2][3][4] Trigeminal nerve stimulation (TNS) is a novel investigational neuromodulation therapy for patients with DRE. Classification of evidence:5 TNS can be delivered noninvasively, bilaterally, and at high frequencies, with positive effects on mood.5-7 The anatomy and biology of the trigeminal nerve support potential mechanisms by which TNS may impact epilepsy and mood disorders, and animal data demonstrate that stimulation of the trigeminal nerve and its related structures

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confidence: 99%

Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy

et al. 2013

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“…Lesions of, or a deficiency in, these pathways enhance susceptibility to a variety of experimental seizures (34)(35)(36)(37)(38), whereas stimulation of the locus coeruleus can suppress seizures (39). A recent report by Krahl et al (40) demonstrated the importance of the locus coeruleus for the anticonvulsant effects of vagal nerve stimulation, by showing that lesions of the locus coeruleus suppressed the anticonvulsant effects of vagal nerve stimulation.…”

Section: Relation To Other Brainstem Nucleimentioning

confidence: 99%

Regulation of Limbic Motor Seizures by GABA and Glutamate Transmission in Nucleus Tractus Solitarius

Walker¹,

Easton²,

Gale³

1999

Epilepsia

139

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Summary:Purpose: The nucleus of the solitary tract (NTS) is a primary site at which vagal afferents terminate. Because afferent vagal nerve stimulation has been demonstrated to have anticonvulsant effects, it is likely that changes in synaptic transmission in the NTS can regulate seizure susceptibility. We tested this hypothesis by examining the influence of y-aminobutyric acid (GABA) ergic and glutamatergic transmission in the NTS on seizures evoked by systemic and focal bicuculline and systemic pentylenetetrazol (PTZ) in rats.Methods: Muscimol (256 pmol), a GABA,-receptor agonist, bicuculline methiodide ( 1 77 pmol), a GABA,-receptor antagonist, kynurenate (634 pmol), a glutamate-receptor antagonist, or lidocaine (100 nl; 5%), a local anesthetic, was microinjected into the mediocaudal (m)NTS. Ten minutes later, seizure activity was induced by either a focal microinfusion of bicuculline methiodide ( I77 pmol) into the rostral piriform cortex, systemic PTZ (50 mg/kg, i.p.), or systemic bicuculline (0.35 mg/kg, i.v.).Results: Muscimol in mNTS (but not in adjacent regions of NTS) attenuated seizures in all seizure models tested, whereas bicuculline methiodide into mNTS did not alter seizure responses. Kynurenate infusions into mNTS significantly reduced the severity of seizures evoked both systemically and focally. Anticonvulsant effects also were obtained with lidocaine application into the same region of mNTS. Unilateral injections were sufficient to afford seizure protection.Conclusions: Our results demonstrate that an increase in GABA transmission or a decrease in glutamate transmission in the rat mNTS reduces susceptibility to limbic motor seizures. This suggests that inhibition of mNTS outputs enhances seizure resistance in the forebrain and provides a potential mechanism for the seizure protection obtained with vagal stimulation.

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“…NE also has documented antiepileptic properties (Giorgi et al, 2004). Reduced levels of endogenous NE are associated with an increased susceptibility to seizures (Weinshenker and Szot, 2002), whereas increased brain NE release inhibits seizure activity (Weiss et al, 1990). Furthermore, several clinically used antiepileptic therapies have been shown to either increase brain NE levels (Baf et al, 1994) or require intact NE innervation for their clinical efficacy (Krahl et al, 1998;Szot et al, 2001).…”

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confidence: 99%

α_2AAdrenergic Receptor Activation Inhibits Epileptiform Activity in the Rat Hippocampal CA3 Region

Jurgens¹,

Hammad²,

Lichter³

et al. 2007

Mol Pharmacol

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Norepinephrine has potent antiepileptic properties, the pharmacology of which is unclear. Under conditions in which GABAergic inhibition is blocked, norepinephrine reduces hippocampal cornu ammonis 3 (CA3) epileptiform activity through ␣ 2 adrenergic receptor (AR) activation on pyramidal cells. In this study, we investigated which ␣ 2 AR subtype(s) mediates this effect. First, ␣ 2 AR genomic expression patterns of 25 rat CA3 pyramidal cells were determined using real-time single-cell reverse transcription-polymerase chain reaction, demonstrating that 12 cells expressed ␣ 2A AR transcript; 3 of the 12 cells additionally expressed mRNA for ␣ 2C AR subtype and no cells possessing ␣ 2B AR mRNA. Hippocampal CA3 epileptiform activity was then examined using field potential recordings in brain slices. The selective ␣AR agonist 6-fluoronorepinephrine caused a reduction of CA3 epileptiform activity, as measured by decreased frequency of spontaneous epileptiform bursts. In the presence of ␤AR blockade, concentration-response curves for AR agonists suggest that an ␣ 2 AR mediates this response, as the rank order of potency was 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK-14304) Ն epinephrine Ͼ6-fluoronorepinephrine Ͼ norepinephrine phenylephrine. Finally, equilibrium dissociation constants (K b ) of selective ␣AR antagonists were functionally determined to confirm the specific ␣ 2 AR subtype inhibiting CA3 epileptiform activity. Apparent K b values calculated for atipamezole (1.7 nM), MK-912 (4.8 nM), BRL-44408 (15 nM), yohimbine (63 nM), ARC-239 (540 nM), prazosin (4900 nM), and terazosin (5000 nM) correlated best with affinities previously determined for the ␣ 2A AR subtype (r ϭ 0.99, slope ϭ 1.0). These results suggest that, under conditions of impaired GABAergic inhibition, activation of ␣ 2A ARs is primarily responsible for the antiepileptic actions of norepinephrine in the rat hippocampal CA3 region.The noradrenergic system is a key modulator of numerous physiological and pathological processes. Within the central nervous system (CNS), noradrenergic neurons innervate copious neural networks and regulate a number of essential neurological functions, including attention and arousal, sleep, and learning and memory (Pupo and Minneman, 2001).

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Antikindling effects of locus coeruleus stimulation: Mediation by ascending noradrenergic projections

Cited by 58 publications

References 23 publications

Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy

Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy

Regulation of Limbic Motor Seizures by GABA and Glutamate Transmission in Nucleus Tractus Solitarius

α_2AAdrenergic Receptor Activation Inhibits Epileptiform Activity in the Rat Hippocampal CA3 Region

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Antikindling effects of locus coeruleus stimulation: Mediation by ascending noradrenergic projections

Cited by 58 publications

References 23 publications

Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy

Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy

Regulation of Limbic Motor Seizures by GABA and Glutamate Transmission in Nucleus Tractus Solitarius

α2AAdrenergic Receptor Activation Inhibits Epileptiform Activity in the Rat Hippocampal CA3 Region

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α_2AAdrenergic Receptor Activation Inhibits Epileptiform Activity in the Rat Hippocampal CA3 Region