Abstract
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 GABAA 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 GABAA 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.
Highlights
Stroke is the leading cause of lasting disability, with patients experiencing varied levels of functional recovery, and with more than 50% of survivors being discharged into care (Dobkin, 2008; Go et al, 2014)
It has previously been shown that reduction of extrasynaptic GABAergic signaling from 3 days after stroke improves functional recovery (Clarkson et al, 2010)
We show that cerebral ischemia significantly increases peripheral cytokine levels of IL1β, tumor necrosis factor (TNF)-α, IL-6, and IL-17
Summary
Stroke is the leading cause of lasting disability, with patients experiencing varied levels of functional recovery, and with more than 50% of survivors being discharged into care (Dobkin, 2008; Go et al, 2014). Immune cells play a critical role in contributing to brain damage initiated by ischemic stroke. As a consequence of stroke, immune cells migrate to the brain in response to danger signals (damage-associated molecular patterns, DAMPs), in an effort to repair the damage (Brait et al, 2010; Gelderblom et al, 2015). These cells can promote further inflammation and damage. The injured brain has an immune-suppressive effect that promotes life-threating infections, which threaten the survival of stroke patients (Liesz et al, 2015)
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