Steven M. Rothman

Levetiracetam (LEV) is one of the most commonly prescribed antiepileptic drugs, but its mechanism of action is uncertain. Based on prior information that LEV binds to the vesicular protein synaptic vesicle protein 2A and reduces presynaptic neurotransmitter release, we wanted to more rigorously characterize its effect on transmitter release and explain the requirement for a prolonged incubation period for its full effect to manifest. During whole cell patch recordings from rat hippocampal pyramidal neurons in vitro, we found that LEV decreased synaptic currents in a frequency-dependent manner and reduced the readily releasable pool of vesicles. When we manipulated spontaneous activity and stimulation paradigms, we found that synaptic activity during LEV incubation alters the time at which LEV's effect appears, as well as its magnitude. We believe that synaptic activity and concomitant vesicular release allow LEV to enter recycling vesicles to reach its binding site, synaptic vesicle protein 2A. In support of this hypothesis, a vesicular “load-unload” protocol using hypertonic sucrose in the presence of LEV quickly induced LEV's effect. The effect rapidly disappeared after unloading in the absence of LEV. These findings are compatible with LEV acting at an intravesicular binding site to modulate the release of transmitter and with its most marked effect on rapidly discharging neurons. Our results identify a unique neurobiological explanation for LEV's highly selective antiepileptic effect and suggest that synaptic vesicle proteins might be appropriate targets for the development of other neuroactive drugs.

Objective: There is enormous clinical potential in exploiting the spatial and temporal resolution of optical techniques to modulate pathophysiological neuronal activity, especially intractable focal epilepsy. We have recently utilized a new ruthenium‐based caged compound, ruthenium‐bipyridine‐triphenylphosphine–γ‐aminobutyric acid (RuBi‐GABA), which releases GABA when exposed to blue light, to rapidly terminate paroxysmal activity in vitro and in vivo.Methods: The convulsant 4‐aminopyridine was used to induce interictal activity and seizures in rat neocortical slices and anesthetized rats. We examined the effect of blue light, generated by a small, light‐emitting diode (LED), on the frequency and duration of ictal activity in the presence and absence of RuBi‐GABA.Results: Neither blue light alone, nor low concentrations of RuBi‐GABA, affected interictal activity or baseline electrical activity in neocortical slices. However, brief, blue illumination of RuBi‐GABA, using our LED, dramatically reduced extracellular spikes and bursts. More impressively, illumination of locally applied RuBi‐GABA rapidly terminated in vivo seizures induced by topical application of 4‐aminopyridine. The RuBi‐GABA effect was blocked by the GABA_A antagonist picrotoxin, but not duplicated by direct application of GABA.Interpretation: This is the first example of optical control of in vivo epilepsy, proving that there is sufficient cortical light penetration from an LED and diffusion of caged GABA to quickly terminate intense focal seizures. We are aware that many obstacles need to be overcome before this technique can be translated to patients, but at the moment, this represents a feasible method for harnessing optical techniques to fabricate an implantable device for the therapy of neocortical epilepsy. ANN NEUROL 2012;71:68–75

Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder characterized by the abnormal beta-oxidation of very long chain fatty acids (VLCFA). In 35-40% of children with ALD, an acute inflammatory process occurs in the central nervous system (CNS) leading to demyelination that is rapidly progressive, debilitating and ultimately fatal. Allogeneic hematopoietic stem cell transplantation (HSCT) can halt disease progression in cerebral ALD (C-ALD) if performed early. In contrast, for advanced patients the risk of morbidity and mortality is increased with transplantation. To date there is no means of quantitating neuroinflammation in C-ALD, nor is there an accepted measure to determine prognosis for more advanced patients.

Summary: Purpose:  To determine if a small ultraviolet emitting diode (UV LED) could release sufficient γ‐aminobutyric acid (GABA) from a caged precursor to suppress paroxysmal activity in rat brain slices.Methods:  Electrophysiologic recordings were obtained from rat brain slices bathed with caged GABA: 4‐[[(2H‐benzopyran‐2‐one‐7‐amino‐4‐methoxy)carbonyl]amino]butanoic acid (BC204), at concentrations between 3 and 30 μm. Seizure‐like activity was induced by perfusing slices with extracellular medium lacking magnesium and containing 4‐aminopyridine (4‐AP; 100 μm). A small, high‐power UV LED was used to uncage BC204 and determine whether an increase in ambient GABA could alter normal or paroxysmal activity in the slice.Results:  UV LED illumination, in the absence of BC204, had no effect on CA1 population spikes or seizure‐like activity. The light did induce a small temperature elevation (A receptors.Discussion:  These experiments establish that illumination of a low concentration of caged GABA with a tiny UV LED can release sufficient GABA to attenuate seizure‐like activity in brain slices. Because our seizure model is very severe, it is probable that this technique would have a robust effect in human focal epilepsy.