Transient Inhibition of TrkB Kinase after Status Epilepticus Prevents Development of Temporal Lobe Epilepsy

Liu, Gumei; Gu, Bin; He, Xiang; Joshi, Rasesh B.; Wackerle, Harold D.; Rodriguiz, Ramona M.; Wetsel, William C.; McNamara, James O

doi:10.1016/j.neuron.2013.04.027

Cited by 186 publications

(183 citation statements)

References 29 publications

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“…One remarkable exception was recently reported by Liu et al [44]. By using a mouse model of SE-induced epilepsy, in which kainate is injected into the basolateral amygdala, leading to limbic SE (which is interrupted after 40 mins by diazepam and lorazepam) and development of SRS after a seizure-free latent period of several days, inhibition of the SE-induced activation of brain-derived neurotrophic factor receptor TrkB was shown to prevent SRS, ameliorate anxiety-like behavior, and limit loss of hippocampal neurons when tested weeks to months later [44]. This study thus provides a proof-of-concept that antiepileptogenesis is possible, provided that models are used that avoid the massive brain alterations associated with induction of SE by systemic administration of convulsants such as kainate or pilocarpine.…”

Section: Studies With Experimental Compounds Targeting Mechanisms Of mentioning

confidence: 87%

“…As discussed in this review, exciting new data from the McNamara laboratory [44], using a pharmacological and genetic approach, suggests that inhibition of one such target, that is, TrkB, shortly after initiation of SE prevents SRS and anxietylike behavior and limits hippocampal neuronal loss. Other potential targets include NKCC1 [57,62] and modulators of neuroinflammation, that is, IL-1, COX-2, and transforming growth factor β [63].…”

Section: Discussionmentioning

confidence: 99%

“…However, similar to studies with AEDs, most studies using such experimental compounds, including neuroprotective, neuromodulatory, or anti-inflammatory drugs, failed to prevent the development of SRS, but, at best, exerted disease-modifying effects [4]. One remarkable exception was recently reported by Liu et al [44]. By using a mouse model of SE-induced epilepsy, in which kainate is injected into the basolateral amygdala, leading to limbic SE (which is interrupted after 40 mins by diazepam and lorazepam) and development of SRS after a seizure-free latent period of several days, inhibition of the SE-induced activation of brain-derived neurotrophic factor receptor TrkB was shown to prevent SRS, ameliorate anxiety-like behavior, and limit loss of hippocampal neurons when tested weeks to months later [44].…”

Section: Studies With Experimental Compounds Targeting Mechanisms Of mentioning

confidence: 97%

See 2 more Smart Citations

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

White

Löscher²

2014

Neurotherapeutics

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A major unmet medical need is the lack of treatments to prevent (or modify) epilepsy in patients at risk, for example, after epileptogenic brain insults such as traumatic brain injury, stroke, or prolonged acute symptomatic seizures like complex febrile seizures or status epilepticus. Typically, following such brain insults there is a seizure-free interval ("latent period"), lasting months to years before the onset of spontaneous recurrent epileptic seizures. The latent period after a brain insult offers a window of opportunity in which an appropriate treatment may prevent or modify the epileptogenic process induced by a brain insult. A similar latent period occurs in patients with epileptogenic gene mutations. Studies using animal models of epilepsy have led to a greater understanding of the factors underlying epileptogenesis and have provided significant insight into potential targets by which the development of epilepsy may be prevented or modified. This review focuses largely on some of the most common animal models of epileptogenesis and their potential utility for evaluating proposed antiepileptogenic therapies and identifying useful biomarkers. The authors also describe some of the limitations of using animal models in the search for therapies that move beyond the symptomatic treatment of epilepsy. Promising results of previous studies designed to evaluate antiepileptogenesis and the role of monotherapy versus polytherapy approaches are also discussed. Recent data from both models of genetic and acquired epilepsies strongly indicate that it is possible to prevent or modify epileptogenesis, and, hopefully, such promising results can ultimately be translated into the clinic.

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Section: Studies With Experimental Compounds Targeting Mechanisms Of mentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Studies With Experimental Compounds Targeting Mechanisms Of mentioning

confidence: 97%

See 1 more Smart Citation

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

White

Löscher²

2014

Neurotherapeutics

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“…The animal model we used features spontaneous seizures at a frequency of approximately six per day with attendant clinical (tonic, clonic) features (Mouri et al, 2008;Jimenez-Mateos et al, 2010;Liu et al, 2013). This has advantages relative to other models for testing AEDs where spontaneous seizures may show marked clustering or are mainly subclinical Klein et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Transient P2X7 Receptor Antagonism Produces Lasting Reductions in Spontaneous Seizures and Gliosis in Experimental Temporal Lobe Epilepsy

et al. 2016

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Neuroinflammation is thought to contribute to the pathogenesis and maintenance of temporal lobe epilepsy, but the underlying cell and molecular mechanisms are not fully understood. The P2X7 receptor is an ionotropic receptor predominantly expressed on the surface of microglia, although neuronal expression has also been reported. The receptor is activated by the release of ATP from intracellular sources that occurs during neurodegeneration, leading to microglial activation and inflammasome-mediated interleukin 1␤ release that contributes to neuroinflammation.UsingareportermouseinwhichgreenfluorescentproteinisinducedinresponsetothetranscriptionofP2rx7,weshowthat expression of the receptor is selectively increased in CA1 pyramidal and dentate granule neurons, as well as in microglia in mice that developed epilepsy after intra-amygdala kainic acid-induced status epilepticus. P2X7 receptor levels were increased in hippocampal subfields in the mice and in resected hippocampus from patients with pharmacoresistant temporal lobe epilepsy. Cells transcribing P2rx7 in hippocampal slices from epileptic mice displayed enhanced agonist-evoked P2X7 receptor currents, and synaptosomes from these animals showed increased P2X7 receptor levels and altered calcium responses. A 5 d treatment of epileptic mice with systemic injections of the centrally available, potent, and specific P2X7 receptor antagonist JNJ-47965567 (30 mg/kg) significantly reduced spontaneous seizures during continuous video-EEG monitoring that persisted beyond the time of drug presence in the brain. Hippocampal sections from JNJ-47965567-treated animals obtained Ͼ5 d after treatment ceased displayed strongly reduced microgliosis and astrogliosis. The present study suggests that targeting the P2X7 receptor has anticonvulsant and possibly disease-modifying effects in experimental epilepsy.

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“…Interestingly, antiepileptogenic effects of FGF-2 and BDNF might involve inhibition of neuroinflammatory mechanisms [164]. These exiting observations have been confirmed recently and extended to another post-SE model of epileptogenesis in which transient inhibition of TrkB achieved by a chemical-genetic approach prevented the onset of recurrent seizures, ameliorated anxiety-like behaviors, and limited loss of hippocampal neurons [165]. These recent findings have more firmly established FGF-2 and TrkB signaling as an attractive target for developing preventive treatments for human epilepsies.…”

Section: Neurotrophic Factorsmentioning

confidence: 83%

The Potential of Antiseizure Drugs and Agents that Act on Novel Molecular Targets as Antiepileptogenic Treatments

2014

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A major goal of contemporary epilepsy research is the identification of therapies to prevent the development of recurrent seizures in individuals at risk, including those with brain injuries, infections, or neoplasms; status epilepticus; cortical dysplasias; or genetic epilepsy susceptibility. In this review we consider the evidence largely from preclinical models for the antiepileptogenic activity of a diverse range of potential therapies, including some marketed antiseizure drugs, as well as agents that act by immune and inflammatory mechanisms; reduction of oxidative stress; activation of the mammalian target of rapamycin or peroxisome proliferatoractivated receptors γ pathways; effects on factors related to thrombolysis, hematopoesis, and angiogenesis; inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reducatase; brainderived neurotrophic factor signaling; and blockade of α2 adrenergic and cannabinoid receptors. Antiepileptogenesis refers to a therapy of which the beneficial action is to reduce seizure frequency or severity outlasting the treatment period. To date, clinical trials have failed to demonstrate that antiseizure drugs have such disease-modifying activity. However, studies in animal models with levetiracetam and ethosuximide are encouraging, and clinical trials with these agents are warranted. Other promising strategies are inhibition of interleukin 1β signaling by drugs such as VX-765; modulation of sphingosine 1-phosphate signaling by drugs such as fingolimod; activation of the mammalian target of rapamycin by drugs such as rapamycin; the hormone erythropoietin; and, paradoxically, drugs such as the α2 adrenergic receptor antagonist atipamezole and the CB1 cannabinoid antagonist SR141716A (rimonabant) with proexcitatory activity. These approaches could lead to a new paradigm in epilepsy drug therapy where treatment for a limited period prevents the occurrence of spontaneous seizures, thus avoiding lifelong commitment to symptomatic treatment.

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Transient Inhibition of TrkB Kinase after Status Epilepticus Prevents Development of Temporal Lobe Epilepsy

Cited by 186 publications

References 29 publications

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

Transient P2X7 Receptor Antagonism Produces Lasting Reductions in Spontaneous Seizures and Gliosis in Experimental Temporal Lobe Epilepsy

The Potential of Antiseizure Drugs and Agents that Act on Novel Molecular Targets as Antiepileptogenic Treatments

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