Endothelial nitric oxide synthase inhibition triggers inflammatory responses in the brain of male rats exposed to ischemia‐reperfusion injury

Abstract

Nitric oxide (NO) derived from endothelial NO synthase (eNOS) plays a role in preserving and maintaining the brain's microcirculation, inhibiting platelet aggregation, leukocyte adhesion, and migration. Inhibition of eNOS activity results in exacerbation of neuronal injury after ischemia by triggering diverse cellular mechanisms, including inflammatory responses.To examine the relative contribution of eNOS in stroke-induced neuroinflammation, we analyzed the effects of systemic treatment with l-N-(1-iminoethyl)ornithine (L-NIO), a relatively selective eNOS inhibitor, on the expression of MiR-155-5p, a key mediator of innate immunity regulation and endothelial dysfunction, in the cortex of male rats subjected to transient middle cerebral artery occlusion (tMCAo) followed by 24 hr of reperfusion. Inducible NO synthase (iNOS) and interleukin-10 (IL-10) mRNA expression were evaluated by real-time polymerase chain reaction in cortical homogenates and in resident and infiltrating immune cells isolated from ischemic cortex. These latter cells were also analyzed for their expression of CD40, a marker of M1 polarization of microglia/macrophages.tMCAo produced a significant elevation of miR155-5p and iNOS expression in the ischemic cortex as compared with sham surgery. eNOS inhibition by L-NIO treatment further elevated the cortical expression of these inflammatory mediators, while not affecting IL-10 mRNA levels. Interestingly, modulation of iNOS occurred in resident and infiltrating immune cells of the ischemic hemisphere. Accordingly, L-NIO induced a significant increase in the percentage of CD40 1 events in CD68 1 microglia/macrophages of the ischemic cortex as compared with vehicle-injected animals.These findings demonstrate that inflammatory responses may underlie the detrimental effects due to pharmacological inhibition of eNOS in cerebral ischemia. K E Y W O R D Scerebral ischemia/reperfusion, IL-10, iNOS, L-NIO, miR-155-5p

Prophylactic Zinc and Therapeutic Selenium Administration Increases the Antioxidant Enzyme Activity in the Rat Temporoparietal Cortex and Improves Memory after a Transient Hypoxia‐Ischemia

“…Therefore, the major contributor to the preconditioning effect in the transient hypoxia-ischemia model was the antioxidant effect and the preservation of NO bioavailability through NOS3 expression. As reported in a similar hypoxia-ischemia model, NOS3 is essential in the preservation and maintenance of microcirculation, inhibiting platelet aggregation, leukocyte adhesion, and migration and decreasing the inflammatory response [ 32 ]. The increased expression of NOS3 induced by zinc might be associated with the zinc finger protein ZFP580 [ 33 ].…”

Diosgenin Glucoside Protects against Spinal Cord Injury by Regulating Autophagy and Alleviating Apoptosis

“…MicroRNAs have gained extensive attention, and could become a novel therapeutic target for the treatment of SCI. A large number of studies have shown that miR-155 is a broad regulator of inflammatory mediators, and plays a key regulatory role in immune and inflammatory disorders [34,35,36,37]. The development of neurodegenerative diseases is closely correlated with immunity and inflammation, suggesting that miR-155 may be a novel target for its treatment.…”

Modulators of microglia activation and polarization in ischemic stroke (Review)

“…accumulating evidence has indicated that activated microglia are the primary source of immunomodulatory molecules, such as cytokines, chemokines and free radicals, in the brain (16)(17)(18); these molecules are closely associated with secondary brain injury and brain tissue repair in ischemic stroke (16)(17)(18). in addition, some molecules, including soluble Fas ligand (19) and endothelial nitric oxide synthase (20,21), which are generated by other cells, such as neurons and endothelial cells, have also been identified to affect the stroke outcome through interacting with microglia in the brain following ischemic stroke (19). Therefore, investigating microglial changes and their function is crucial to understanding ischemic stroke pathophysiology.…”

“…miRNA-155. Increased expression levels of miRNA-155 have been demonstrated to be associated with the neuroinflammatory responses (20,107). in lPS-activated microglia, miRNA-155 expression levels were significantly increased, which could target suppressor of cytokine signaling 1 to trigger M1 microglia-mediated inflammatory responses and aggravate brain damage (18).…”