Synthetic Ruthenium Complex TQ-6 Potently Recovers Cerebral Ischemic Stroke: Attenuation of Microglia and Platelet Activation

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.

Anti-Inflammatory Mechanisms of Novel Synthetic Ruthenium Compounds

“…Also, LPS induce macrophage activation through NO production. Our studies have found TQ compounds TQ-4 inhibits NO and iNOS [39], and TQ-6 inhibits NO, iNOS and COX-2 in LPS induced macrophages and microglia [42], respectively, as shown in Figures 2 and 3.…”

“…Inhibition of NF-κB signaling in microglia was proposed as the major target of drugs to exhibit the protective effect against the neuropathology of ischemic stroke [48]. As shown in Figures 2 and 3, LPS induces NF-κB activation and its nuclear translocation and IκBα degradation in LPS treated macrophages was found to be recovered by TQ-4 [39] and TQ-6 [42].…”

“…Nrf2 protects brain cells from ischemic stroke injury, as evidenced by increasing cerebral infarction ratio and neurological deficits score in Nrf2 knockout ischemic reperfusion induced rats [52]. The novel ruthenium compound TQ-6 potently reduced brain infarct volume and edema in middle cerebral artery occlusion (MCAO) induced mice (Figure 5) [42]. Consequently, the protective effect of TQ-6 in microglia by regulating Nrf2/HO-1 could be regarded as an ideal therapeutic target for the treatment of stroke associated inflammatory events.…”

“…For instance, thymoquinone, a major component of Nigella sativa inhibits neuroinflammation by activating Nrf2 and inhibiting NF-κB [51]. Thus, we also explored the anti-inflammatory effects of TQ-6 through NF-κB and Nrf2 signaling; the results determined that TQ-6 inhibited NF-κB expression and its nuclear translocation, and also increased the expression of Nrf2 and HO-1 [42]. Nrf2 protects brain cells from ischemic stroke injury, as evidenced by increasing cerebral infarction ratio and neurological deficits score in Nrf2 knockout ischemic reperfusion induced rats [52].…”

“…In the event of ischemia-induced neuronal injury, ROS contribute destructive role by damaging lipids, proteins and nucleic acids, resulting to brain damage and cellular death [54]. An earlier finding discovered hydroxyl radicals (OH•) dramatically increased in LPS-stimulated microglia [42]. LPS stimulates liver injury via increased ROS production and thus antioxidants are regarded as the greatest choice to repair this injury [55].…”