Abstract
Activated microglia are crucial in the regulation of neuronal homeostasis and neuroinflammation. They also contribute to neuropathological processes after ischemic stroke. Thus, finding new approaches for reducing neuroinflammation has gained considerable attention. The metal ruthenium has gained notable attention because of its ability to form new complexes that can be used in disease treatment. [Ru(η6-cymene)2-(1H-benzoimidazol-2-yl)-quinoline Cl]BF4 (TQ-6), a potent ruthenium (II)-derived compound, was used in this study to investigate its neuroprotective action against microglia activation, middle cerebral artery occlusion (MCAO)-induced embolic stroke, and platelet activation, respectively. TQ-6 (2 μM) potently diminished inflammatory mediators (nitric oxide/inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2)) expression, nuclear factor kappa B (NF-κB) p65 phosphorylation, nuclear translocation, and hydroxyl radical (OH•) formation in LPS-stimulated microglia. Conversely, TQ-6 increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Moreover, it significantly reduced brain infarct volume and edema in MCAO mice. Additionally, it drastically inhibited platelet aggregation and OH• production in mice platelets. This study confirmed that TQ-6 exerts an anti-neuroinflammatory effect on microglia activation through neuroprotection, antiplatelet activation, and free radical scavenging. The authors propose that TQ-6 might mitigate neurodegenerative pathology by inhibiting the NF-κB-mediated downstream pathway (iNOS and COX-2) and enhancing Nrf2/HO-1 signaling molecules in microglia.
Highlights
Microglia are the chief macrophages associated with inflammatory reaction in the central nervous system (CNS), and are essential regulators of homeostasis and neuroinflammation [1]
This study investigated the capacity of a novel ruthenium complex [Ru(η6-cymene)2-(1H-benzoimidazol-2-yl)-quinoline Cl]BF4 (TQ-6) to prevent LPS-induced inflammation in microglia, middle cerebral artery occlusion (MCAO)-induced ischemic stroke, and platelet activation in mice; it elucidated the underlying defensive mechanisms of TQ-6 by examining the participation of NF-κB and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling molecules in these experiments
The results revealed that TQ-6 (1 or 2 μM) did not affect the viability of the microglia (Figure 1B), and TQ-6 was used at concentrations of 1 or 2 μM in further studies
Summary
Microglia are the chief macrophages associated with inflammatory reaction in the central nervous system (CNS), and are essential regulators of homeostasis and neuroinflammation [1]. In abnormal states, such as infection or inflammation, microglia are triggered, leading to the discharge of various inflammatory mediators, such as reactive oxygen species (ROS) and nitric oxide (NO) [2]. LPS induces the expression of M1 markers, such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS) such as nitric oxide (NO), and several proinflammatory cytokines including interleukin (IL)-1β [7]. Arginase 1 and CD206 (a mannose receptor), which are markers of M2 that localize in the inflammatory zone, block the expression of proinflammatory mediators such as iNOS, and promote neuroprotection [8]
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