Effects of γ‐aminobutyric acid (GABA) agonists and GABA uptake inhibitors on pharmacosensitive and pharmacoresistant epileptiform activity in vitro

Abstract

2 A mechanism possibly underlying the development of sustained seizure-like activity is the loss of synaptically released y-aminobutyric acid (GABA). Drugs which increase the amount of GABA available in presynaptic endings might thus be useful in the treatment of these therapeutically complicated forms of epilepsy. 3 Therefore, we studied the effects of various substances increasing GABA-mediated inhibition on early and late forms of epileptiform activity. GABA and the GABAA receptor agonist muscimol blocked both the pharmacosensitive discharges in the hippocampus and entorhinal cortex as well as the late recurrent discharges in the medial entorhinal cortex. The GABAB receptor agonist baclofen blocked the recurrent short discharges very potently, but did not consistently block seizure-like events and late recurrent discharges in the entorhinal cortex. 4 GABA uptake blockers showed a differential potency to block the various discharge patterns.Whereas nipecotic acid and P-alanine suppressed all forms of epileptiform activity albeit at high concentrations (1-5 mM), tiagabine was much more potent in blocking the hippocampal recurrent short discharges and the seizure-like events in the medial entorhinal cortex, but could not block the late recurrent discharges. 5 Our data support the idea that prolonged neuronal overactivity might result in a loss of synaptically available GABA. Selective block of uptake into glia cells or substitution of the transmitter may therefore be an efficient strategy for the treatment of severe prolonged epileptic discharges whereas block of neuronal GABA uptake fails to counteract synchronized discharges in this situation.

Feedforward Inhibition Contributes to the Control of Epileptiform Propagation Speed

“…It could result either from reduced inhibition or from enhanced excitation. Possible causes for the former include presynaptic depletion (Bekkers and Stevens, 1990), a reduction in GABA A conductance (Thompson and Gahwiler, 1989;Whittington et al, 1995), increased threshold for activation of interneurons, changes in the metabolic processing of GABA after intense neuronal activation (Pfeiffer et al, 1996), internalization of GABA A receptors (Naylor et al, 2005), or even interneuronal death induced by the extreme activity during ictal events (Dinocourt et al, 2003). Enhanced excitation may result from potentiation during ictal events (Bernard and Wheal, 1996;Khalilov et al, 2005), because the combination of synchronous firing and freely conducting NMDA receptors should be a very powerful drive for synaptic modification.…”

“…Studies using slices from entorhinal cortex bathed in 0 Mg 2ϩ suggest that failure of feedforward inhibition coincides with an increased resistance to common antiepileptics; thus, it is crucial to understand the mechanisms behind this failure (Dreier and Heinemann, 1990;Pfeiffer et al, 1996;Dreier et al, 1998). This will require additional study because there are several reasons why the feedforward inhibition in late 0 Mg 2ϩ ictal events might fail.…”

“…We were particularly interested in changes in the spread of activity, and this commonly used model of epilepsy seemed well suited to this end: in 0 Mg 2ϩ , cortical slices show a consistent and characteristic evolution of activity patterns (Dreier and Heinemann, 1990;Pfeiffer et al, 1996) and, crucially, display a range of propagation speeds (Wong and Prince, 1990). Slices were incubated in a conventional, nonepileptogenic ACSF until after the cells were patched and electrophysiology recordings had started.…”

The Source of Afterdischarge Activity in Neocortical Tonic–Clonic Epilepsy

“…The pattern of activity, in the 0 Mg 2ϩ model of epilepsy, changes over time (Dreier and Heinemann, 1990;Whittington et al, 1995a;Pfeiffer et al, 1996;Dreier et al, 1998;Trevelyan et al, 2007). In particular, there is a progressive increase in propagation speed of ictal events, such that the late events generalize across the tissue with great rapidity (Trevelyan et al, 2007).…”

“…Conversely, the integrity of cellular function is essentially maintained, and, importantly, brain slices demonstrably can sustain complex network behavior that closely mimics that in vivo (Whittington et al, 1995b;Cossart et al, 2003;Cunningham et al, 2004;MacLean et al, 2005). The zero magnesium (0 Mg 2ϩ ) in vitro model, in particular, manifests a wide range of epileptiform activity patterns, including interictal activity (Anderson et al, 1986;Flint et al, 1997), slow and rapid patterns of generalization (Wong and Prince, 1990;Trevelyan et al, 2006Trevelyan et al, , 2007, tonic-clonic transitions (Anderson et al, 1986;Flint et al, 1997), and status epilepticus (Dreier and Heinemann, 1990;Pfeiffer et al, 1996;Dreier et al, 1998). The multifaceted nature of this particular model may come from the initial epileptic activity arising from enhanced excitation, whereas the late activity is influenced further by depressed inhibition (Whittington et al, 1995a;Trevelyan et al, 2007).…”