Genetically Engineered GABA-Producing Cells Demonstrate Anticonvulsant Effects and Long-Term Transgene Expression When Transplanted into the Central Piriform Cortex of Rats

Gernert, Manuela; Thompson, Kerry; Löscher, Wolfgang; Tobin, Allan J.

doi:10.1006/exnr.2002.7914

Cited by 86 publications

(66 citation statements)

References 32 publications

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“…60,61 One of such substances is GABA, which can be released by genetically manipulated cells. It has been shown that such cells, genetically manipulated to produce and release GABA under a regulable promoter, are able to modulate electrically induced seizures after their transplantation into the substantia negra, 62,63 the pyriform cortex, 64 or the hippocampus. 65 Also, adenosine-producing cells have been shown to be effective.…”

Section: Transplantation Of Gaba-releasing Cellsmentioning

confidence: 99%

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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Section: Transplantation Of Gaba-releasing Cellsmentioning

confidence: 99%

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

Barcia

Gallego

2009

Neurotherapeutics

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“…For example, Gernert and coworkers [17] found that transplantion of cells modified to express the GABA-synthesizing enzyme GAD65, elevated initial seizure thresholds. Seizure thresholds subsequent to kindling were not significantly elevated, although the transplanted cells continued to express GAD65 at least for the duration of the experiment, i.e.…”

Section: Introductionmentioning

confidence: 99%

Intranigral transplants of a GABAergic cell line produce long-term alleviation of established motor seizures

Castillo

Mendoza-Trejo

Aguilar

et al. 2008

Behavioural Brain Research

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We have previously shown that intranigral transplants of immortalized GABAergic cells decrease the number of kainic acid-induced seizures [5] in an animal model. In the present study, recurrent NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript spontaneous behavioral seizures were established by repeated systemic injections of this excitotoxin into male Sprague Dawley rats. After the seizures had been established, cells were transplanted into the substantia nigra. Animals with transplants of control cells (without hGAD67 expression) or with sham transplants showed a death rate of more than 40% over the 12 weeks of observation, whereas in animals with M213-2O Cl4 transplants, the death rate was reduced to less than 20%. The M213-2O Cl4 transplants significantly reduced the percentage of animals showing behavioral seizures; animals with these transplants also showed a lower occurrence of stage V seizures than animals in the other groups. In vivo and in vitro analyses provided evidence that the GABAergic cells show sustained expression of both GAD67 and hGAD67cDNA, as well as increased GABA levels in the ventral mesencephalon of transplanted animals. Therefore, transplantation of GABA-producing cells can produce long-term alleviation of behavioral seizures in an animal model.

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“…Furthermore, prior transplantation strategies did not focus on generation of a specific cell type from grafted cells. Interneuron loss is a characteristic feature of the epileptic brain (5,6), and genetically engineered cells that produce GABA, the primary inhibitory neurotransmitter in the mammalian nervous system, also attenuate seizure-like activity when transplanted into hippocampal and cortical sites (7)(8)(9). As such, a cell transplantation procedure to introduce functional cortical GABAergic neurons could be an effective strategy to reduce the abnormal electrical activity associated with epilepsy.…”

mentioning

confidence: 99%

Reduction of seizures by transplantation of cortical GABAergic interneuron precursors into Kv1.1 mutant mice

Baraban

Southwell

Estrada

et al. 2009

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

199

259

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Epilepsy, a disease characterized by abnormal brain activity, is a disabling and potentially life-threatening condition for nearly 1% of the world population. Unfortunately, modulation of brain excitability using available antiepileptic drugs can have serious side effects, especially in the developing brain, and some patients can only be improved by surgical removal of brain regions containing the seizure focus. Here, we show that bilateral transplantation of precursor cells from the embryonic medial ganglionic eminence (MGE) into early postnatal neocortex generates mature GABAergic interneurons in the host brain. In mice receiving MGE cell grafts, GABA-mediated synaptic and extrasynaptic inhibition onto host brain pyramidal neurons is significantly increased. Bilateral MGE cell grafts in epileptic mice lacking a Shaker-like potassium channel (a gene mutated in one form of human epilepsy) resulted in significant reductions in the duration and frequency of spontaneous electrographic seizures. Our findings suggest that MGE-derived interneurons could be used to ameliorate abnormal excitability and possibly act as an effective strategy in the treatment of epilepsy.epilepsy ͉ inhibition ͉ neocortex ͉ therapy ͉ graft

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Genetically Engineered GABA-Producing Cells Demonstrate Anticonvulsant Effects and Long-Term Transgene Expression When Transplanted into the Central Piriform Cortex of Rats

Cited by 86 publications

References 32 publications

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

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

Intranigral transplants of a GABAergic cell line produce long-term alleviation of established motor seizures

Reduction of seizures by transplantation of cortical GABAergic interneuron precursors into Kv1.1 mutant mice

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