The Delta-Subunit Selective GABAA Receptor Modulator, DS2, Improves Stroke Recovery via an Anti-inflammatory Mechanism

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.

Antagonistic effects of IL-17 and Astragaloside IV on cortical neurogenesis and cognitive behavior after stroke in adult mice through Akt/GSK-3β pathway

“…1 a, b). Upregulating IL-17 expression indicates a poorer treatment effect and prognosis 5 and decreased IL-17 is relative to improved motor function in mice 6,7 . Administration of IL-17A can nullify the microglial M2 polarization to inhibit anti-inflammation activity 13 .…”

“…Interleukin-17 (IL-17, also called IL-17A), a proinflammatory cytokine mainly derived from γδ T cells and T helper 17 (Th17) cells, also has an important role in a wide variety of neurological diseases 4 . It has been found that expression of IL-17 is upregulated by ischemic stroke and the over-expression of IL-17 indicates a poorer treatment effect and prognosis [5][6][7] . However, IL-17 inhibits autophagy through activating phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway, one of the most popular pathways to regulate cell proliferation and apoptosis, to interrupt the Glycogen synthase kinase-3β (GSK-3β)-mediated degradation of BCL2 in lung epithelial cells 8 .…”

Effects of Aerobic Exercise on Tau and Related Proteins in Rats with the Middle Cerebral Artery Occlusion

“…Regular aerobic exercise has been known to reduce peripheral inflammation and COX-2 levels [34]; however, the effects of aerobic exercise on COX-2 expression in the brain have not been well investigated. A recent study reported that brain COX-2 levels increased after endurance training, and its expression positively correlated with memory functions [34,35]. In another study, treadmill training was found to have time-dependent up and down regulatory effects on the COX-2 pathway [36].…”

Molecular determinants underlying DS2 activity at δ-containing GABAAreceptors

“…Additionally, several neurological disorders such as stroke (20, 21) and epilepsy (22, 23), underline the continued interest in targeting these receptors. This also includes an emerging relevance for immunomodulation via actions on peripheral δ-containing receptors or equivalents (24, 25). However, compared to the synaptic γ-containing receptors, pronounced insight into the physiological and pathophysiological role of δ-containing receptors is still limited by the low number of potent and selective compounds.…”

“…confirmed the reported selectivity for δ-containing receptors, using δ -/- mice showing that this effect is clearly dependent on the δ-subunit (31). DS2 displays limited brain permeability (31) but was, nonetheless, shown to improve recovery after stroke in mice, plausibly by dampening peripheral immune activation (24). Recently, a methoxy analog of DS2, termed DS2OMe, was identified and confirmed to have a similar potency and subtype selectivity as DS2.…”