Beta adrenergic blockade prevents cardiac dysfunction following status epilepticus in rats

Little, Jason G.; Bealer, Steven L.

doi:10.1016/j.eplepsyres.2011.12.003

Cited by 19 publications

(30 citation statements)

References 31 publications

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“…Delayed mortality in patients after SE is often associated with acute or gradual cardiac decompensation (32). Pilocarpine-treated rats also develop chronic changes in autonomic control of cardiac function characterized by decreased parasympathetic activity leading to sympathetic dominance (33)(34)(35) and increased risk for ventricular arrhythmias. The location of the EP2 receptor responsible for SE-associated delayed mortality is not known, although a similar reduction in delayed mortality was observed in a conditional knockout of COX-2 limited to principal forebrain neurons (11), suggesting the relevant EP2 receptor is central rather than peripheral.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the prostaglandin receptor EP2 following status epilepticus reduces delayed mortality and brain inflammation

Jiang

Quan

Ganesh

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

147

250

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Prostaglandin E2 is now widely recognized to play critical roles in brain inflammation and injury, although the responsible prostaglandin receptors have not been fully identified. We developed a potent and selective antagonist for the prostaglandin E2 receptor subtype EP2, TG6-10-1, with a sufficient pharmacokinetic profile to be used in vivo. We found that in the mouse pilocarpine model of status epilepticus (SE), systemic administration of TG6-10-1 completely recapitulates the effects of conditional ablation of cyclooxygenase-2 from principal forebrain neurons, namely reduced delayed mortality, accelerated recovery from weight loss, reduced brain inflammation, prevention of blood-brain barrier opening, and neuroprotection in the hippocampus, without modifying seizures acutely. Prolonged SE in humans causes high mortality and morbidity that are associated with brain inflammation and injury, but currently the only effective treatment is to stop the seizures quickly enough with anticonvulsants to prevent brain damage. Our results suggest that the prostaglandin receptor EP2 is critically involved in neuroinflammation and neurodegeneration, and point to EP2 receptor antagonism as an adjunctive therapeutic strategy to treat SE.inflammatory cytokine | electroencephalography | epileptogenesis | gliosis | neuronal injury A s a dominant product of cyclooxygenase-2 (COX-2 or PTGS2) in the brain, prostaglandin E2 (PGE 2 ) is emerging as a crucial mediator of many COX-2-driven pathological events in the central nervous system (CNS) (1). PGE 2 acts on four G protein-coupled receptors named EP1, EP2, EP3, and EP4. Among these, the EP2 receptor is widely expressed in the brain and plays important physiologic functions, such as in neuronal plasticity (2, 3). However, recent studies have identified a possible link between EP2 signaling and secondary neurotoxicity in models of chronic inflammation and neurodegeneration (1,(4)(5)(6). In a rodent model of amyotrophic lateral sclerosis, for example, EP2 receptor knockout mice exhibit improved survival, down-regulation of proinflammatory enzymes, and reduced oxidative stress (6).Prolonged status epilepticus (SE) in humans is associated with brain injury and substantial morbidity. Mortality is high during refractory SE that requires general anesthesia (7,8), and the 30-d mortality is about 35-37% for adults who experience at least 60 min of SE (9). Outcome in humans is dependent upon age, etiology, and SE duration (8-10), and currently the only effective treatment is to stop the seizures quickly enough to prevent brain damage (10). Most deaths from nonrefractory SE occur in the 2-wk period after successful treatment rather than during the seizure episode itself (9), pointing to a delayed but cascading set of responsible events. In mice, prolonged SE induced by pilocarpine causes >25% delayed mortality (11), and is associated with a series of molecular and cellular events in the brain, including neurodegeneration, and selective inflammatory reactions involving reactive microglia and a...

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Section: Discussionmentioning

confidence: 99%

Inhibition of the prostaglandin receptor EP2 following status epilepticus reduces delayed mortality and brain inflammation

Jiang

Quan

Ganesh

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

147

250

View full text Add to dashboard Cite

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“…In contrast to earlier studies (3,4,38,46,47,62), this investigation used implantable transmitters in con-scious (nonanesthetized) animals to simultaneously assess cardiac function and encephalographic activity during and following seizure activity. Using an adaptation of a previously validated protocol of excitotoxic seizure induction (73), intrahippocampal KA administration was employed to produce seizures while excluding any direct systemic effects of the excitotoxin.…”

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confidence: 99%

Progressive development of cardiomyopathy following altered autonomic activity in status epilepticus

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McCann

Millen

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Seizures are associated with altered autonomic activity, which has been implicated in the development of cardiac dysfunction and structural damage. This study aimed to investigate the involvement of the autonomic nervous system in seizure-induced cardiomyopathy. Male Sprague-Dawley rats (320 -350 g) were implanted with EEG/ECG electrodes to allow simultaneous telemetric recordings during seizures induced by intrahippocampal (2 nmol, 1 l/min) kainic acid and monitored for 7 days. Seizure activity occurred in conjunction with increased heart rate (20%), blood pressure (25%), and QTc prolongation (15%). This increased sympathetic activity was confirmed by the presence of raised plasma noradrenaline levels at 3 h post-seizure induction. By 48 h post-seizure induction, sympathovagal balance was shifted in favor of sympathetic dominance, as indicated by both heart rate variability (LF/HF ratio of 3.5 Ϯ 1.0) and pharmacological autonomic blockade. Functional cardiac deficits were evident at 7 and 28 days, as demonstrated by echocardiography showing a decreased ejection fraction (14% compared with control, P Ͻ 0.05) and dilated cardiomyopathy present at 28 days following seizure induction. Histological changes, including cardiomyocyte vacuolization, cardiac fibrosis, and inflammatory cell infiltration, were evident within 48 h of seizure induction and remained present for up to 28 days. These structural changes most probably contributed to an increased susceptibility to aconitine-induced arrhythmias. This study confirms that prolonged seizure activity results in acute and chronic alterations in cardiovascular control, leading to a deterioration in cardiac structure and function. This study further supports the need for modulation of sympathetic activity as a promising therapeutic approach in seizure-induced cardiomyopathy.

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“…Status epilepticus may be accompanied by prolonged QTc, and this may be a marker of susceptibility to ventricular arrhythmias [5,10]. While potentially detrimental in the setting of hypotension, which often occurs as a result of either antiseizure drugs or failure of physiologic compensatory mechanisms, there is experimental evidence that B-adrenergic blockade during status epilepticus may prevent the increased susceptibility to arrhythmias [6,15]. Patients may also present with a syndrome of reversible acquired cardiomyopathy due to neurogenic myocardial stunning, also known as stress cardiomyopathy, takotsubo cardiomyopathy (named for the similarity in appearance of the left ventriculogram in systole to the shape of a Japanese octopus trapping pot), or apical ballooning syndrome.…”

Section: Early Systemic Complicationsmentioning

confidence: 99%

Systemic complications of status epilepticus — An update

Hocker

2015

Epilepsy & Behavior

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Beta adrenergic blockade prevents cardiac dysfunction following status epilepticus in rats

Cited by 19 publications

References 31 publications

Inhibition of the prostaglandin receptor EP2 following status epilepticus reduces delayed mortality and brain inflammation

Inhibition of the prostaglandin receptor EP2 following status epilepticus reduces delayed mortality and brain inflammation

Progressive development of cardiomyopathy following altered autonomic activity in status epilepticus

Systemic complications of status epilepticus — An update

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