Inflammatory processes are known to contribute to tissue damage in the central nervous system (CNS) across a broad range of neurological conditions, including
stroke. Gamma amino
butyric acid (
GABA), the main inhibitory
neurotransmitter in the CNS, has been implicated in modulating peripheral immune responses by acting on
GABA A receptors on antigen-presenting cells and lymphocytes. Here, we investigated the effects and mechanism of action of the delta-selective compound, DS2, to improve
stroke recovery and modulate
inflammation. We report a decrease in nuclear factor (NF)-κB activation in innate immune cells over a concentration range in vitro. Following a photochemically induced motor cortex
stroke, treatment with DS2 at 0.1 mg/kg from 1 h post-
stroke significantly decreased circulating
tumor necrosis factor (TNF)-α,
interleukin (IL)-17, and
IL-6 levels, reduced
infarct size and improved motor function in mice. Free brain concentrations of DS2 were found to be lower than needed for robust modulation of central
GABA A receptors and were not affected by the presence and absence of
elacridar, an inhibitor of both
P-glycoprotein and
breast cancer resistance
protein (BCRP). Finally, as DS2 appears to dampen peripheral immune activation and only shows limited brain exposure, we assessed the role of DS2 to promote functional recovery after
stroke when administered from 3-days after the
stroke. Treatment with DS2 from 3-days post-
stroke improved motor function on the grid-walking, but not on the cylinder task. These data highlight the need to further develop subunit-selective compounds to better understand change in
GABA receptor signaling pathways both centrally and peripherally. Importantly, we show that
GABA compounds such as DS2 that only shows limited brain exposure can still afford significant protection and promote functional recovery most likely via modulation of peripheral immune cells and could be given as an adjunct treatment.