C.M.P. acknowledges funding from a Whitaker International Scholar grant administered by the Institute for International Education. A.K. was sponsored by the Marie Curie IEF (No. 625372). A.W. acknowledges funding from the European Research Council (ERC) under the European Union&#8217;s Horizon 2020 research and innovation programme (grant agreement No. 716867). A.W. additionally acknowledges the Excellence Initiative of Aix-Marseille University - A*MIDEX, a French &#8220;Investissements d&#8217;Avenir&#8221; programme. The authors acknowledge Dr. Ilke Uguz, Dr. Sahika Inal, Dr. Vincenzo Curto, Dr. Mary Donahue, Dr. Marc Ferro, and Zs&#243;fia Magl&#243;czky for their participation in fruitful discussions.

All experimental procedures were performed according to the ethical guidelines of the Institut de Neurosciences des Syst&#232;mes and approved by the local Ethical Committees and Veterinary Offices.
NOTE: Seventeen adult male OF1 mice were used for the experiments. Mice were entrained to a 12 h light/dark cycle with food and water available ad libitum.
1. Anesthesia
<ol>
	<li>Inject intraperitoneally a mixture of ketamine and xylazine (10...

<ol>
	<li>Kwan, P., Palmini, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Association+between+switching+antiepileptic+drug+products+and+healthcare+utilization:+A+systematic+review.">Association between switching antiepileptic drug products and healthcare utilization: A systematic review.</a> Epilepsy &amp; Behavior. 73, 166-172 (2017).</li><li>Belleudi, V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Studies+on+drug+switchability+showed+heterogeneity+in+methodological+approaches:+a+scoping+review.">Studies on drug switchability showed heterogeneity in methodological approaches: a scoping review.</a> Journal of Clinical Epidemiology. 101, 5-16 (2018).</li><li>Chen, B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Psychiatric+and+behavioral+side+effects+of+antiepileptic+drugs+in+adults+with+epilepsy.">Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy.</a> Epilepsy &amp; Behavior. 76, 24-31 (2017).</li><li>Brodie, M. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Epilepsy,+Antiepileptic+Drugs,+and+Aggression:+An+Evidence-Based+Review.">Epilepsy, Antiepileptic Drugs, and Aggression: An Evidence-Based Review.</a> Pharmacological Reviews. 68 (3), 563-602 (2016).</li><li>Hamed, S. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+auditory+and+vestibular+toxicities+induced+by+antiepileptic+drugs.">The auditory and vestibular toxicities induced by antiepileptic drugs.</a> Expert Opinion on Drug Safety. 16 (11), 1281-1294 (2017).</li><li>Hamed, S. 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A., Freestone, D. R., Lai, A., Cook, M. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Epilepsy:+Ever-changing+states+of+cortical+excitability.">Epilepsy: Ever-changing states of cortical excitability.</a> Neuroscience. 222, 89-99 (2012).</li><li>Loscher, W., Brandt, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Prevention+or+modification+of+epileptogenesis+after+brain+insults:+experimental+approaches+and+translational+research.">Prevention or modification of epileptogenesis after brain insults: experimental approaches and translational research.</a> Pharmacological Reviews. 62 (4), 668-700 (2010).</li><li>Porter, R. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mechanisms+of+action+of+new+antiepileptic+drugs.">Mechanisms of action of new antiepileptic drugs.</a> Epilepsia. 30, (1989).</li><li>Rogawski, M. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Diverse+mechanisms+of+antiepileptic+drugs+in+the+development+pipeline.">Diverse mechanisms of antiepileptic drugs in the development pipeline.</a> Epilepsy Research. 69 (3), 273-294 (2006).</li><li>Czapinski, P., Blaszczyk, B., Czuczwar, S. 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Prospects for new therapeutic approaches in temporal-lobe epilepsy.</a> Lancet Neurology. 1 (3), 173-181 (2002).</li><li>Cohen, I., Navarro, V., Clemenceau, S., Baulac, M., Miles, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=On+the+origin+of+interictal+activity+in+human+temporal+lobe+epilepsy+in+vitro.">On the origin of interictal activity in human temporal lobe epilepsy in vitro.</a> Science. 298 (5597), 1418-1421 (2002).</li><li>Huberfeld, G., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Glutamatergic+pre-ictal+discharges+emerge+at+the+transition+to+seizure+in+human+epilepsy.">Glutamatergic pre-ictal discharges emerge at the transition to seizure in human epilepsy.</a> Nature Neuroscience. 14 (5), 627-634 (2011).</li><li>Bui, A., Kim, H. 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The authors have nothing to disclose.

By developing a new experimental protocol in an acute mouse model of epilepsy, SLEs could be successfully controlled with the help of a &#181;FIP implanted in the epileptic focus. Thanks to its capability to deliver GABA with temporal and spatial precision, 4AP-induced SLEs were controlled at the onset of the seizures. Treatment of epilepsy is theoretically possible if the control of the neural network discharges is achieved at the place of the seizure start. The presented protocol proved this possible if the localizatio...

Epilepsy is the fourth most common neurological disorder: about 1% of the population suffers from epilepsy, and about one-third of the affected have recurrent seizures. In most cases, seizures can be controlled with medication. However, drug treatment needs to be set for every patient individually, where proper dosing can take years to find1,2. Additionally, most of the medication has serious side effects that reduce the quality of life3,4,5,6,7. Finally, in 30% of the cases patients are resistant to medication, and in case of a constant single seizure generator locus, only resective neurosurgery can attenuate the occurrence of seizures8. Therefore, a major initiative in modern epilepsy research is to discover new strategies which can prevent recurrent seizures in patients at risk, while reducing the necessity of strong drug therapies and invasive resective surgeries.
Epileptic seizures occur when there is an imbalance within excitatory and inhibitory circuits either throughout the brain (generalized epilepsy) or in a localized part of the brain (focal epilepsy), such that neurons discharge in an abnormal fashion9,10,11. Antiepileptic drugs can act in two different ways in seizure prevention: either decreasing excitation or enhancing inhibition12. Specifically, they can either modify the electrical activity of neuronal cells by affecting ion channels in the cell membrane13 or act on chemical transmission between neurons by affecting the inhibitory neurotransmitter GABA or the excitatory glutamate in the synapses14,15. For some medications, the mode of action is unknown18. Also, drug treatments have a continuous effect on patients and cannot adapt to the prevalence dynamics of seizures. Ideally, drugs with specific mechanisms of action would act on the underlying epileptic processes. An optimal treatment would not touch the brain interictally but would act immediately when a seizure starts developing. In contrast to that, in all cases of epilepsy, medication now means a systematic treatment, affecting the whole brain and the whole body of the patient9.
Epileptic seizures can appear many years after the initial insult such as brain trauma. The period between the initial insult and the occurrence of the first spontaneous seizures is characterized by considerable molecular and cellular reorganizations, including neuronal death with the disappearance of neuronal network connections and axonal sprouting/neosynaptogenesis with the appearance of new connections19,20,21. Once seizures become recurrent, their frequency and severity tend to increase, involving more brain regions. It is important to distinguish the sites of seizure onset (epileptogenic regions) from propagation networks, as the rules of seizure genesis and propagation may differ. Research performed on human tissue and experimental models of epilepsy have provided important data regarding the reorganization of circuits and their ability to generate seizures20,21,22,23. However, it is difficult to determine if these reorganizations are adaptive responses or whether they are causally related to epileptogenesis or seizure genesis and propagation12.
Therefore, localizing the epileptic focus and applying antiepileptic drugs locally are one of the main challenges in contemporary epilepsy research. Several experiments using animal models of epilepsy and some clinical studies aimed to find the onset of the seizure events and define the underlying mechanisms in the brain24,25,26,27. To this end, we developed a new experimental protocol using the 4AP-induced epilepsy model28,29,30,31 in an acute mouse preparation, which allows the precise insertion of three devices into the given area of the hippocampus, where network activity in vivo is manipulated in a highly localized manner. Localized 4AP injection by a glass micropipette helps to induce epileptic SLEs in a localized spot in the hippocampus, while with the help of the novel polymer-based &#181;FIP probe the control of the seizure activity is achieved simultaneously by recording the neuronal electrical activity with the device&#8217;s recording sites. Hippocampal local field activity is also monitored with a multichannel silicon probe in a layer-specific manner in the cortex and in the hippocampus simultaneously.
The recently invented &#181;FIP probes work by using an applied electric field to push charged drugs stored in a microfluidic channel across an ion exchange membrane (IEM) and out to the surrounding tissue (Figure 1). The IEM selectively transports only one type of ion (cation or anion) and, thus, works to limit both passive diffusion in the &#8220;off&#8221; state and&#160; transport of oppositely charged species from the surrounding tissue into the device. The electric field is created on demand by applying a small voltage (&#60;1 V) between the source electrode which is internal to the microfluidic channel and a target electrode which is external to the device (in this case, the head screw on the animal model). The rate of drug delivery is proportional to the applied voltage and the measured current between the source and target electrodes. The precise tunability of drug delivery is one of the primary advantages of the &#181;FIP. Another critical advantage, compared to fluidic or pressure-based drug delivery systems, is that in the &#181;FIP there is only a negligible pressure increase at the drug delivery outlet as drugs are delivered across the IEM without their carrier solution.
There is a small amount of passive leaking of GABA when the &#181;FIP is &#8220;off&#8221;, but this was found not to effect SLEs. The &#181;FIP are custom-made following conventional microfabrication methods that we reported previously31.
Since one way of preventing recurrent seizures is the blockade of network discharges at the very beginning or even before the first seizure event, the presented method for delivering the inhibitory neurotransmitter GABA into the epileptic focus has great therapeutic potential for seizure control in patients with focal epilepsy. Since GABA is an endogenous substrate, it leaves intrinsic neuronal properties unchanged in physiological concentrations. The local application of low levels of GABA will only affect cells naturally responsive to inhibition, and will only cause similar effects to physiological inhibition, contrary to deep brain stimulation (DBS), which has unspecific actions by stimulating all cells of the neuronal network in its environment, causing a mixed response involving both excitation and inhibition. In conclusion, the proposed method provides a more specific approach to seizure control than DBS.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr >
			<td >4AP</td>
			<td >Sigma</td>
			<td >275875</td>
			<td ></td>
		</tr>
		<tr >
			<td >Alexa Fluor 488</td>
			<td>Abcam</td>
			<td>ab15007</td>
			<td></td>
		</tr>
		<tr >
			<td >Amplifier</td>
			<td>Neuralynx, Montana, USA</td>
			<td >Digital Lynx 4SX</td>
			<td ></td>
		</tr>
		<tr >
			<td >Amplifier</td>
			<td >Ampliplex</td>
			<td >KJE-1001</td>
			<td ></td>
		</tr>
		<tr >
			<td >Atlas Stereotaxique&#160;</td>
			<td>Allen Atlas</td>
			<td>978-0470054086</td>
			<td></td>
		</tr>
		<tr >
			<td >Borosilica glass pipette</td>
			<td >Sutter</td>
			<td >BF120-69-15</td>
			<td ></td>
		</tr>
		<tr >
			<td >Brain Matrix</td>
			<td >WPI&#160;</td>
			<td >RBMA-200C</td>
			<td ></td>
		</tr>
		<tr >
			<td >Bone trimmer</td>
			<td >FST</td>
			<td >16109-14</td>
			<td ></td>
		</tr>
		<tr >
			<td >Confocal microscope</td>
			<td>Zeiss</td>
			<td>LSM 510</td>
			<td ></td>
		</tr>
		<tr >
			<td >Connector</td>
			<td>INSTECH</td>
			<td>SC20/15</td>
			<td ></td>
		</tr>
		<tr >
			<td >Coton tige</td>
			<td>Monoprix</td>
			<td>EMD 6107OD</td>
			<td></td>
		</tr>
		<tr >
			<td >Cover slip</td>
			<td >Menzel-Glass</td>
			<td >15747592</td>
			<td ></td>
		</tr>
		<tr >
			<td >DiI Stain&#160;</td>
			<td >Thermo Fisher</td>
			<td >D282</td>
			<td ></td>
		</tr>
		<tr >
			<td >DMSO</td>
			<td >Sigma</td>
			<td >11412-11</td>
			<td ></td>
		</tr>
		<tr >
			<td >Drill</td>
			<td>FOREDOM</td>
			<td>K1070</td>
			<td></td>
		</tr>
		<tr >
			<td >Forceps</td>
			<td >F.S.T.</td>
			<td >11412-11</td>
			<td ></td>
		</tr>
		<tr >
			<td >GABA</td>
			<td>Sigma</td>
			<td>A2129</td>
			<td></td>
		</tr>
		<tr >
			<td >GFAP Monoclonal Antibody</td>
			<td>Thermofisher</td>
			<td>53-9892-80</td>
			<td></td>
		</tr>
		<tr >
			<td >GOPS</td>
			<td>Sigma</td>
			<td>440167-100M</td>
			<td></td>
		</tr>
		<tr >
			<td >Hamilton seringe&#160;</td>
			<td>Hamilton&#160;</td>
			<td>80330</td>
			<td></td>
		</tr>
		<tr >
			<td >Headscrew</td>
			<td>Component Supply</td>
			<td>TX00-2FH</td>
			<td></td>
		</tr>
		<tr >
			<td >Heating pad&#160;</td>
			<td>Harvard apparatus</td>
			<td>341446</td>
			<td></td>
		</tr>
		<tr >
			<td >Injection Pump</td>
			<td>WPI&#160;</td>
			<td>UMP3-3</td>
			<td></td>
		</tr>
		<tr >
			<td >Keithley</td>
			<td >Tektoronix</td>
			<td >216A</td>
			<td ></td>
		</tr>
		<tr >
			<td >Ketamine</td>
			<td>Renaudin</td>
			<td>5787419</td>
			<td></td>
		</tr>
		<tr >
			<td >Magnetic holder</td>
			<td>Narishige</td>
			<td>GJ-1</td>
			<td></td>
		</tr>
		<tr >
			<td >Mice</td>
			<td>Charles River</td>
			<td>612</td>
			<td ></td>
		</tr>
		<tr >
			<td >Motoric manipulator</td>
			<td>Scientifica, UK</td>
			<td >IVM</td>
			<td ></td>
		</tr>
		<tr >
			<td >Na2HPO4</td>
			<td >Sigma</td>
			<td >255793</td>
			<td ></td>
		</tr>
		<tr >
			<td >NaH2PO4</td>
			<td >Sigma</td>
			<td >7558807</td>
			<td ></td>
		</tr>
		<tr >
			<td >NeuroTrace DiI&#160;</td>
			<td>Thermofisher</td>
			<td>N22880</td>
			<td></td>
		</tr>
		<tr >
			<td >Paper towel</td>
			<td>KIMBERLY CLARK</td>
			<td>7552000</td>
			<td></td>
		</tr>
		<tr >
			<td >PB</td>
			<td>Sigma</td>
			<td>P4417</td>
			<td></td>
		</tr>
		<tr >
			<td >PEDOT:PSS</td>
			<td>CLEVIOS</td>
			<td>81076212</td>
			<td></td>
		</tr>
		<tr >
			<td >PFA</td>
			<td>Acros Organic</td>
			<td>30525-89-4</td>
			<td></td>
		</tr>
		<tr >
			<td >Rectal temperature probe</td>
			<td>Harvard apparatus</td>
			<td>521591</td>
			<td></td>
		</tr>
		<tr >
			<td >Ropivacaine&#160;</td>
			<td>KABI</td>
			<td>1260216</td>
			<td></td>
		</tr>
		<tr >
			<td >Saline</td>
			<td>Sigma</td>
			<td>7982</td>
			<td></td>
		</tr>
		<tr >
			<td >Scalpel</td>
			<td>F.S.T</td>
			<td>AUST R195806</td>
			<td></td>
		</tr>
		<tr >
			<td >Seringue&#160;</td>
			<td>BD Medical</td>
			<td>324826</td>
			<td></td>
		</tr>
		<tr >
			<td >Serrefine clamp</td>
			<td>F.S.T</td>
			<td>18050-28</td>
			<td>4 is recommended</td>
		</tr>
		<tr >
			<td >Silicon probe</td>
			<td>NeuroNexus, Michigan, USA</td>
			<td>A2x16-10mm-50-500-177 or A1x16-5mm-150-703</td>
		</tr>
		<tr >
			<td >Stereotoxic frame</td>
			<td>Stoelting</td>
			<td>51733U</td>
			<td></td>
		</tr>
		<tr >
			<td >Superfrost Slide</td>
			<td >ThermoScientific</td>
			<td >J38000AMNZ</td>
			<td ></td>
		</tr>
		<tr >
			<td >Tubing</td>
			<td >INSTECH</td>
			<td >LS20</td>
			<td ></td>
		</tr>
		<tr >
			<td >Vaseline&#160;</td>
			<td>Laboratoire Gilbert</td>
			<td>3518646126611</td>
			<td></td>
		</tr>
		<tr >
			<td >Vectashield DAPI</td>
			<td>Vector Laboratories, California, USA</td>
			<td>H-1200-10</td>
			<td></td>
		</tr>
		<tr >
			<td >Vibratome, Leica VT1200S</td>
			<td>Leica Microsystems</td>
			<td>1491200S001</td>
			<td ></td>
		</tr>
		<tr >
			<td >Xylazine&#160;</td>
			<td>Bayer</td>
			<td>4007221032311</td>
			<td></td>
		</tr>
	</tbody>
</table>

electrophoretic delivery of &#x3b3;-aminobutyric acid (gaba) into epileptic focus prevents seizures in mice

Epilepsy is a group of neurological disorders which affects millions of people worldwide. Although treatment with medication is helpful in 70% of the cases, serious side effects affect the quality of life of patients. Moreover, a high percentage of epileptic patients are drug resistant; in their case, neurosurgery or neurostimulation are necessary. Therefore, the major goal of epilepsy research is to discover new therapies which are either capable of curing epilepsy without side effects or preventing recurrent seizures in drug-resistant patients. Neuroengineering provides new approaches by using novel strategies and technologies to find better solutions to cure epileptic patients at risk.
As a demonstration of a novel experimental protocol in an acute mouse model of epilepsy, a direct in situ electrophoretic drug delivery system is used. Namely, a neural probe incorporating a microfluidic ion pump (&#181;FIP) for on-demand drug delivery and simultaneous recording of local neural activity is implanted and demonstrated to be capable of controlling 4-aminopyridine-induced (4AP-induced) seizure-like event (SLE) activity. The &#947;-aminobutyric acid (GABA) concentration is kept in the physiological range by the precise control of GABA delivery to reach an antiepileptic effect in the seizure focus but not to cause overinhibition-induced rebound bursts. The method allows both the detection of pathological activity and intervention to stop seizures by delivering inhibitory neurotransmitters directly to the epileptic focus with precise spatiotemporal control.
As a result of the developments to the experimental method, SLEs can be induced in a highly localized manner that allows seizure control by the precisely tuned GABA delivery at the seizure onset.

Using the procedure presented here with a 4AP epilepsy model in anesthetized mice, control of epileptic seizures can be achieved in the epileptic focus. The precise localization of the implants (Figure 2) helped to record hippocampal local field potentials (LFPs, Figure 4), to induce small hippocampal seizures and to deliver GABA at the seizure onset. The localization of the implants was verified after each experiment by post hoc...

Watch this Scientific Journal Video about Electrophoretic Delivery of ÃŽÂ³-aminobutyric Acid GABA into Epileptic Focus Prevents Seizures in Mice at JoVE.com

Electrophoretic Delivery of &#947;-aminobutyric Acid GABA into Epileptic Focus Prevents Seizures in Mice

The challenge of epilepsy research is to develop novel treatments for patients where classical therapy is inadequate. Using a new protocol&#8212;with the help of an implantable drug delivery system&#8212;we are able to control seizures in anesthetized mice by the electrophoretic delivery of GABA into the epileptic focus.

Electrophoretic Delivery of &#x3B3;-aminobutyric Acid (GABA) into Epileptic Focus Prevents Seizures in Mice

Epilepsy is a group of neurological disorders which affects millions of people worldwide. Although treatment with medication is helpful in 70% of the ...

electrophoretic-delivery-aminobutyric-acid-gaba-into-epileptic-focus

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Unit 1

Pharmacotherapy of the Epilepsies

SCIENTISTS IN ACTION

8.8K ビュー.  Aix Marseille Université, Institut de Neurosciences des Systèmes (INS). 我々のプロトコルは、てんかん発作の治療に新しい解決策を提案することができる非常に新しい装置を使用して天然の抑制性神経伝達物質GABAの局所投与を利用する。微気性イオンポンプは、いつどこで医薬品を送達しているかを正確に制御することを可能にします。正確にスレッド化された電気泳動性分娩は、他の神経疾患を標的にするために変更することができる。