Focal treatment for refractory epilepsy: hope for the future?

Nilsen, Karen E.; Cock, Hannah R.

doi:10.1016/j.brainresrev.2003.11.003

Cited by 64 publications

(34 citation statements)

References 104 publications

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“…Thus, therapeutic alternatives are urgently needed and several focal treatment approaches for refractory epilepsy have been evaluated as potential strategies to circumvent side-effects frequently associated with classical antiepileptic drugs (Nilsen and Cock, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, focal treatment approaches for refractory epilepsy have been evaluated as an alternative to systemic drug delivery. In several approaches it was demonstrated that focal drug delivery is generally well tolerated and devoid of major side effects (Nilsen and Cock, 2004). Recently, focal adenosine-based cell therapies have been investigated as an approach for the therapy of partial epilepsy (Boison, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Lentiviral RNAi-induced downregulation of adenosine kinase in human mesenchymal stem cell grafts: A novel perspective for seizure control

Ren

Lan

et al. 2007

Experimental Neurology

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Cell therapies based on focal delivery of the inhibitory neuromodulator adenosine were previously shown to provide potent seizure suppression in animal models of epilepsy. However, hitherto used therapeutic cells were derived from rodents and thus not suitable for clinical applications. Autologous patient-derived adenosine-releasing cell implants would constitute a major therapeutic advance to avoid both xenotransplantation and immunosuppression. Here we describe a novel approach based on lentiviral RNAi mediated downregulation of adenosine kinase (ADK), the major adenosineremoving enzyme, in human mesenchymal stem cells (hMSCs), which would be compatible with autologous cell grafting in patients. Following lentiviral transduction of hMSCs with anti-ADK miRNA expression cassettes we demonstrate up to 80% downregulation of ADK and a concentration of 8.5 ng adenosine per ml of medium after incubating 10 5 cells for 8 hours. hMSCs with a knockdown of ADK or cells expressing a scrambled control sequence were transplanted into hippocampi of mice 1 week prior to the intraamygdaloid injection of kainic acid (KA). While mice with control implants expressing a scrambled miRNA sequence or sham treated control animals were characterized by KAinduced status epilepticus and subsequent CA3 neuronal cell loss, animals with therapeutic ADK knockdown implants displayed a 35% reduction in seizure duration and 65% reduction in CA3 neuronal cell loss, when analyzed 24h after KA-injection. We conclude that lentiviral expression of anti-ADK miRNA constitutes a versatile tool to generate therapeutically effective adenosine releasing hMSCs, thus representing a model system to generate patient identical autologous adult stem cell grafts.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lentiviral RNAi-induced downregulation of adenosine kinase in human mesenchymal stem cell grafts: A novel perspective for seizure control

Ren

Lan

et al. 2007

Experimental Neurology

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“…Thus, inactivation of part of the network system may be sufficient to deactivate at least part of the mechanisms responsible for seizure initiation or generalization. 29 …”

Section: Election Of the Target Area For Brain Infusionmentioning

confidence: 99%

“…Also, these studies have been developed in acute seizure-provoking models rather than in spontaneous seizures models. 29 Among the strategies sought to prolong the effect of the drug on the epileptic focus, self-degradable polymers liberating anticonvulsant drugs, such as phenytoin, have been tried. 44 Another option is to use a pump to continuously infuse the drug through a catheter.…”

Section: Intracerebral Infusion In the Epileptic Focusmentioning

confidence: 99%

“…68 The use of grafting as prevention of the development of kindling would limit its application to already instituted clinical epilepsy. 29 Transplantation of neural precursor cells may be also anticonvulsant in already epileptic animals. Grafts of hippocampal cells, obtained from 13 to 14 day rat fetuses into the hippocampi of kindled rats may suppress kindled seizures.…”

Section: Transplantation Of Neural Precursor Cellsmentioning

confidence: 99%

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Intraventricular and Intracerebral Delivery of Anti-epileptic Drugs in the Kindling Model

Barcia

Gallego

2009

Neurotherapeutics

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Summary:A means to avoid the pharmacokinetic problems affecting the anti-epileptic drugs may be their direct intracerebroventricular (ICV) or intracerebral delivery. This approach may achieve a greater drug concentration at the epileptogenic area while minimizing it in other brain or systemic areas, and thus it could be an interesting therapeutic alternative in drug-resistant epilepsies. The objective of this article is to review a series of experiments, ranging from actute ICV injection to continuous intracerebral infusion of anti-epileptic drugs or grafting of neurotransmitter producing cells, in experimental models, especially in the kindling model of epilepsy in the rat.Acute ICV injection of phenytoin, phenobarbital or carbamacepine is able to diminish the intensity of kindling seizures, but it is also associated with a high neurologic toxicity, especially phenobarbital. Continuous ICV infusion of anti-epileptic drugs can effectively control seizures, but neurologic toxicity is not improved compared with systemic delivery. However, systemic toxicity may be improved, as in the case of valproic acid, whose continuous ICV infusion results in very low plasmatic or hepatic drug concentrations. Continuous intracerebral infusion at the epileptogenic area was studied as an alternative to minimize neurologic toxicity. Thus, intra-amygdalar infusion of gamma-aminobutyric acid (GABA) controls seizures with minimal neurotoxicity in amygdala-kindled rats. Similarly, continuous infusion of GABA into the dorsomedian nucleus of the thalamus improves seizure spread, while not affecting the local epileptogenic activity at the amygdala. Grafting of GABA releasing cells may reduce kindling parameter severity without behavioral side effects.We may conclude that ICV or intracerebral delivery of antiepileptic drugs or neurotransmitters may be a useful technique to modulate epilepsy.

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Future focal treatment approaches to epilepsy

Ritter¹,

Cock²

2015

The Treatment of Epilepsy

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Focal treatment for refractory epilepsy: hope for the future?

Cited by 64 publications

References 104 publications

Lentiviral RNAi-induced downregulation of adenosine kinase in human mesenchymal stem cell grafts: A novel perspective for seizure control

Lentiviral RNAi-induced downregulation of adenosine kinase in human mesenchymal stem cell grafts: A novel perspective for seizure control

Intraventricular and Intracerebral Delivery of Anti-epileptic Drugs in the Kindling Model

Future focal treatment approaches to epilepsy

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