Photolysis of Caged-GABA Rapidly Terminates Seizures In Vivo: Concentration and Light Intensity Dependence

Abstract

The therapy of focal epilepsy remains unsatisfactory for as many as 25% of patients. The photolysis of caged-γ-aminobutyric acid (caged-GABA) represents a novel and alternative option for the treatment of intractable epilepsy. Our previous experimental results have demonstrated that the use of blue light produced by light-emitting diode to uncage ruthenium-bipyridine-triphenylphosphine-c-GABA (RuBi-GABA) can rapidly terminate paroxysmal seizure activity both in vitro and in vivo. However, the optimal concentration of RuBi-GABA, and the intensity of illumination to abort seizures, remains unknown. The aim of this study was to explore the optimal anti-seizure effects of RuBi-GABA by using implantable fibers to introduce blue light into the neocortex of a 4-aminopyridine-induced acute seizure model in rats. We then investigated the effects of different combinations of RuBi-GABA concentrations and light intensity upon seizure. Our results show that the anti-seizure effect of RuBi-GABA has obvious concentration and light intensity dependence. This is the first example of using an implantable device for the photolysis of RuBi-GABA in the therapy of neocortical seizure, and an optimal combination of RuBi-GABA concentration and light intensity was explored. These results provide important experimental data for future clinical translational studies.

Implanted microelectrode arrays for evaluating inhibited seizure modulated by light-responsive hydrogel

“…As a nongenetic optical method, RuBi-GABA provides the property of high temporal and spatial resolution. Although, it has been utilized in many neuronal regulatory experiments [24][25][26], its effects are still limited by its fast drug metabolism. Hydrogels as one of the outstanding drug delivery carriers can form three-dimensional network to deliver drugs in various fields [34,35], and have been shown to perform excellent properties for neuromodulation according to our results.…”

“…Figures 8(a) and (b) show the power components of spikes and LFPs in the 0-30 Hz frequency band during the three modulation periods, respectively, and the increased power in the frequency domain reflected enhanced neural activities. The frequency band of 0-30 Hz can be divided into five different frequency bands, including slow band (0-1 Hz), delta band (1-4 Hz), theta band (4-8 Hz), alpha band (8-13 Hz) and beta band (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). As shown in figure 8, in the pre-seizure period, the power of both spikes and LFPs peaked at around 2 Hz in the delta band.…”

“…Recently, optical methods are emerging for neuromodulation due to their high spatial and temporal precision [21]. Among various strategies, the use of caged compounds is a simpler and more affordable alternative in comparison to optogenetics [22][23][24]. As a nongenetic optical method, caged compounds have been proposed to modulate the activities of neurons by quickly releasing active molecules under the specific wavelength light.…”

Electrical stimulation of the endopiriform nucleus attenuates epilepsy in rats by network modulation

“…58 A previous study in pilocarpine-induced epilepsy rats reported that much of the increased preictal firing of neurons in the subiculum and CA1 correlated with preictal theta activity. 59 Furthermore, studies of rapid focal cooling 60 and photolysis of cage-GABA 61 in controlling seizures also demonstrated that theta band power reduction is a mechanistic marker for seizure reduction in these models. Several studies in other epilepsy models have found enhanced theta oscillations to be associated with reduced seizures 62,63 ; however, the correlation between the change in theta-band power and epileptic seizures needs to be further clarified.…”

Wireless Closed-Loop Optical Regulation System for Seizure Detection and Suppression In Vivo

“…Yang et al (2012) reported that RuBi-GABA with blue light could quickly terminate the seizure activity. In the years that followed, the team optimized the optimal concentration and light intensity of RuBi-GABA to achieve the best inhibition effect (Wang et al, 2017). RuBi-GABA contains a photolabile protecting group that can be removed by exposure to light.…”