Seizure suppression in kindling epilepsy by grafts of fetal GABAergic neurons in rat substantia nigra.

Abstract

Compared with studies on models of neurodegenerative diseases, considerably less work has been performed with neural grafts in experimental epilepsy. The potential value of this approach, however, is already shown by evidence that noradrenergic grafts implanted bilaterally into the hippocampus or amygdala-piriform cortex can suppress seizure development in the kindling model of temporal lobe epilepsy. We previously showed that amygdala kindling results in a significant decrease of GABA and its synthesizing enzyme glutamate decarboxylase in substantia nigra (SN), i.e., a region thought to be critically involved in seizure propagation in various models of epilepsy. Thus, transplantation of fetal GABAergic neurons into SN might be an effective means of permanently blocking seizure generalization in kindling epilepsy and probably also other types of epilepsy. To test this hypothesis, three groups of female Wistar rats (n = 10 per group) were kindled by electrical stimulation via a bipolar electrode in the basolateral amygdala. After all rats were fully kindled, one group was implanted with GABA-rich cells prepared from the striatal eminence of Wistar rat fetuses at embryonic day 14. The striatal neurons were bilaterally microinjected at various sites over the anterior-posterior axis of the SN, aimed at the pars reticulata. The second group received microinjections of spinal cord cell preparations, whereas the third group received microinjections of cell-free medium only. In all rats, the threshold for focal discharges (afterdischarge threshold [ADT]) as well as afterdischarge duration and severity and duration of seizures occurring at ADT current were determined once weekly before and after transplantation. Eleven to 12 weeks following transplantation, the rats were killed, and location and integration of grafts were examined by immunohistological methods. Rats with GABAergic grafts in SN exhibited a significant increase in ADT and marked reduction in seizure severity compared with pretransplantation values, whereas no such alteration was seen in the other groups. However, the seizure-suppressing effect of GABAergic grafts was not permanent but slowly disappeared over the weeks after transplantation. Although the data indicate that intranigral transplantation of GABA-producing cells is no effective means of inducing long-lasting anticonvulsant effects in experimental epilepsy, this approach may be an initial step to develop more efficient strategies for seizure suppression.