Spontaneous recurrent seizures in an intra-amygdala kainate microinjection model of temporal lobe epilepsy are differentially sensitive to antiseizure drugs

West, Peter J.; Thomson, Kyle; Billingsley, P. R.; Pruess, Timothy H.; Rueda, Carlos B.; Saunders, Gerald W.; Smith, Michael L.; Metcalf, Cameron S.; Wilcox, Karen S.

doi:10.1016/j.expneurol.2021.113954

Cited by 19 publications

(22 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3, E to H). In a chronic model of epilepsy, we achieved a greater decrease in seizure frequency than previously reported for gene therapy with constitutive promoters or with widely used antiseizure drugs (11)(12)(13)43), and without deleterious effects on normal behaviors (Figs. 4 and 5).…”

Section: Discussionmentioning

confidence: 64%

On-demand cell-autonomous gene therapy for brain circuit disorders

Qiu

O’Neill

Maffei

et al. 2022

Science

View full text Add to dashboard Cite

Several neurodevelopmental and neuropsychiatric disorders are characterized by intermittent episodes of pathological activity. Although genetic therapies offer the ability to modulate neuronal excitability, a limiting factor is that they do not discriminate between neurons involved in circuit pathologies and “healthy” surrounding or intermingled neurons. We describe a gene therapy strategy that down-regulates the excitability of overactive neurons in closed loop, which we tested in models of epilepsy. We used an immediate early gene promoter to drive the expression of Kv1.1 potassium channels specifically in hyperactive neurons, and only for as long as they exhibit abnormal activity. Neuronal excitability was reduced by seizure-related activity, leading to a persistent antiepileptic effect without interfering with normal behaviors. Activity-dependent gene therapy is a promising on-demand cell-autonomous treatment for brain circuit disorders.

show abstract

Section: Discussionmentioning

confidence: 64%

On-demand cell-autonomous gene therapy for brain circuit disorders

Qiu

O’Neill

Maffei

et al. 2022

Science

View full text Add to dashboard Cite

show abstract

“…Future studies may extend these observations to more etiologically relevant animals models consisting of spontaneous seizures, wherein both male and female animals can be studied. Central injections were used for galanin analogs based on previously established protocols for ICV ( Lee et al, 2009 ; Green et al, 2011 ; Platt et al, 2012 ) and IA ( West et al, 2022 ) injections. However, verification of injection location was not performed in the current studies.…”

Section: Discussionmentioning

confidence: 99%

“…Procedures were similar to those described previously for implantation of unilateral cannulas for drug administration ( West et al, 2022 ). Buprenorphine (0.01–0.2 mg/kg) was administered 1 h prior to surgery.…”

Section: Methodsmentioning

confidence: 99%

“…We have previously used ICV free-hand injections for central administration of neuropeptides ( Lee et al, 2009 ; Green et al, 2011 ; Platt et al, 2012 ). Similarly, the methods described for IA administration utilize a guide cannula and the same surgical procedures, coordinates, and injection techniques used in our lab as those described for central administration of kainic acid to the amygdala ( West et al, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Galanin analogs prevent mortality from seizure-induced respiratory arrest in mice

Collard

Aziz

Rapp

et al. 2022

Front. Neural Circuits

Self Cite

View full text Add to dashboard Cite

ObjectiveSudden Unexpected Death in Epilepsy (SUDEP) accounts for 20% of mortality in those with recurrent seizures. While risk factors, monitoring systems, and standard practices are in place, the pathophysiology of SUDEP is still not well understood. Better knowledge of SUDEP and its potential mechanisms of action is crucial to reducing risk in this patient population and developing potential treatment options. Clinical studies and animal models of SUDEP suggest that diminished post-ictal respiratory control may be the dominant mechanism contributing to mortality. Recently, it was demonstrated that the depletion of the neuropeptide galanin in the amygdala occurs in human SUDEP. The amygdala plays a key role in the central integration of respiratory signaling; the depletion of galanin may represent a critical change that predisposes individuals to SUDEP.Materials and methodsTo evaluate the impact of enhancing galaninergic signaling to potentially protect against SUDEP, we studied seizure-induced respiratory arrest (S-IRA) following central (intracerebroventricular, intra-amygdala) and systemic (intraperitoneal, subcutaneous) administration of galanin analogs. Seizure naïve and seizure experienced (fully kindled) mice were tested.ResultsCentral and systemically administered galanin analogs protect against S-IRA in naïve C57Bl/6J mice. Differential efficacy between receptor subtype-selective analogs varied based on the route of administration. Sub-chronic systemic administration at doses that reduced 6 Hz seizures also protected against S-IRA. Acute treatment benefits also extended to fully kindled mice experiencing tonic extension.SignificanceThese data demonstrate that galanin analogs may be protective against post-ictal respiratory collapse.

show abstract

“…Procedures are similar to those described previously for implantation of unilateral cannulae for drug administration 39 . Buprenorphine (0.01-0.2 mg/kg) was administered 1h prior to surgery.…”

Section: Methodsmentioning

confidence: 99%

Galanin Analogs Prevent Seizure-Induced Respiratory Arrest

Collard

Aziz

Rapp

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

SUMMARYObjectiveSudden Unexpected Death in Epilepsy (SUDEP) accounts for 20% of mortality in those with recurrent seizures. While risk factors, monitoring systems, and standard practices are in place, the pathophysiology of SUDEP is still not well understood. Better knowledge of SUDEP and its potential mechanisms of action is crucial to reducing risk in this patient population and developing potential treatment options. Clinical studies and animal models of SUDEP suggest that diminished post-ictal respiratory control may be the dominant mechanism contributing to mortality. Recently, it was demonstrated that the depletion of the neuropeptide galanin in the amygdala occurs in human SUDEP. The amygdala plays a key role in the central integration of respiratory signaling; the depletion of galanin may represent a critical change that predisposes individuals to SUDEP.MethodsTo evaluate the potential benefit of enhancing galaninergic signaling as a means to protect against SUDEP, we studied seizure-induced respiratory arrest (S-IRA) following central (intracerebroventricular, intra-amygdala) and systemic (intraperitoneal, subcutaneous) administration of galanin agonists. Seizure naïve and seizure experienced (fully kindled) mice were tested.ResultsCentral and systemically-administered galanin analogs protect against S-IRA in naïve C57Bl/6J mice. Differential efficacy between receptor subtype-selective analogs varied based on the route of administration. Sub-chronic systemic administration at doses that reduced 6 Hz seizures also protected against S-IRA. Acute treatment benefits also extended to fully kindled mice subjected to tonic extension.SignificanceThese data demonstrate that galanin agonists may be protective against post-ictal respiratory collapse.KEY POINTSCentral and systemic galanin agonists prevent seizure-induced respiratory arrest.Efficacy was observed in three separate mouse strains under various experimental conditions.Sub-chronic administration demonstrated galanin agonist protection against respiratory arrest.Acute systemic administration also conferred protection against respiratory arrest following tonic extension.Galanin analogs may represent a novel potential therapy in SUDEP-susceptible individuals.

show abstract

Spontaneous recurrent seizures in an intra-amygdala kainate microinjection model of temporal lobe epilepsy are differentially sensitive to antiseizure drugs

Cited by 19 publications

References 50 publications

On-demand cell-autonomous gene therapy for brain circuit disorders

On-demand cell-autonomous gene therapy for brain circuit disorders

Galanin analogs prevent mortality from seizure-induced respiratory arrest in mice

Galanin Analogs Prevent Seizure-Induced Respiratory Arrest

Contact Info

Product

Resources

About