Anticonvulsant Effects by Bilateral and Unilateral Transplantation of GABA-Producing Cells into the Subthalamic Nucleus in an Acute Seizure Model

Abstract

Neural transplantation of GABA-producing cells into key structures within seizure-suppressing circuits holds promise for medication-resistant epilepsy patients not eligible for resection of the epileptic focus. The substantia nigra pars reticulata (SNr), a basal ganglia output structure, is well known to modulate different seizure types. A recent microinjection study by our group indicated that the subthalamic nucleus (STN), which critically regulates nigral activity, might be a more promising target for focal therapy in epilepsies than the SNr. As a proof of principle, we therefore assessed the anticonvulsant efficacy of bilateral and unilateral allografting of GABA-producing cell lines into the STN using the timed intravenous pentylenetetrazole seizure threshold test, which allows repeated seizure threshold determinations in individual rats. We observed (a) that grafted cells survived up to the end of the experiments, (b) that anticonvulsant effects can be induced by bilateral transplantation into the STN using immortalized GABAergic cells derived from the rat embryonic striatum and cells additionally transfected to obtain higher GABA synthesis than the parent cell line, and (c) that anticonvulsant effects were observed even after unilateral transplantation into the STN. Neither grafting of control cells nor transplantation outside the STN induced anticonvulsant effects, emphasizing the site and cell specificity of the observed anticonvulsant effects. To our knowledge, the present study is the first showing anticonvulsant effects by grafting of GABA-producing cells into the STN. The STN can be considered a highly promising target region for modulation of seizure circuits and, moreover, has the advantage of being clinically established for functional neurosurgery.

GABA-ergic cell therapy for epilepsy: Advances, limitations and challenges

“…This evidence has guided a straightforward concept that grafting of cells that release the inhibitory neurotransmitter GABA into the seizure focus would greatly restrain SRS (Loscher et al, 2008). Indeed, grafting of GABA-soaked beads, immortalized GABA-ergic cells, cells engineered to produce GABA or fetal GABA-ergic cells into the epileptic foci produces anticonvulsant effects in a variety of animal models (Kokaia et al, 1994; Loscher et al, 1998; Gernert et al, 2002; Thompson, 2005; Castillo et al, 2006, 2008; Nolte et al, 2008; Handreck et al, 2014). However, anti-seizure effects were either modest or transient in most of these studies, presumably because of poor graft cell survival.…”

Interneuron transplantation: a prospective surgical therapy for medically refractory epilepsy

“…Targeting interneurons to a critical, common seizure network node or "choke point," 46 or to a neuromodulatory center that broadly projects to cortical areas, could prove an effective method for treating both focal and generalized forms of epilepsy. 21,36 Finally, the recipient background may influence the cellular development and circuit integration of transplanted interneurons. Epilepsies arise from numerous etiologies, including structural, genetic, infectious, immune, and met-…”

Cortical GABAergic Interneuron/Progenitor Transplantation as a Novel Therapy for Intractable Epilepsy

“…However, considering the preponderance of interneuron pathologies in TLE, more recent studies have focused on transplanting GABAergic interneurons/progenitors into seizure foci. Preclinical studies in animal models of epilepsy have shown the efficacy of GABAergic interneuron/progenitor transplantation in ameliorating seizures ( Löscher et al, 1998 ; Hattiangady et al, 2008 ; Baraban et al, 2009 ; Calcagnotto et al, 2010 ; Handreck et al, 2012 ; Maisano et al, 2012 ; Hunt et al, 2013 ; Cunningham et al, 2014 ; Hammad et al, 2014 ; Henderson et al, 2014 ; Table 1 ). Pioneering work by Löscher et al (1998) revealed that transplanting rat fetal GABAergic neurons into the substania nigra (SN) led to a dramatic increase in afterdischarge thresholds and significant reductions in the severity of seizures.…”

“…In 2012, Handreck et al observed the anticonvulsant effects of GABA-producing cells implanted bilaterally/unilaterally into the subthalamic nucleus (STN) using a pentylenetetrazole (PTZ)-induced acute seizure model in adult rats. In addition, they observed that grafting into the STN caused more pronounced anticonvulsant effects than grafting into the SN ( Handreck et al, 2012 ). In these two studies, GABA-producing cells were placed into sites that modulate seizures rather than the seizure focus.…”