Role of Nitric Oxide Synthase in the Function of the Central Nervous System under Normal and Infectious Conditions

Abstract

Nitric oxide (NO) was discovered as an endothelium-derived relaxing factor more than two decades ago. Since then, it has been shown to participate in many pathways. NO has been described as a key mediator of different pathways in the central nervous system (CNS) in both healthy and diseased processes. The three isoforms of nitric oxide synthase differ in their activity patterns and expression in different cells. Neuronal nitric oxide synthase (nNOS) is localized in synaptic spines, astrocytes, and the loose connective tissue surrounding blood vessels in the brain; eNOS is present in both cerebral vascular endothelial cells and motor neurons; and iNOS is induced in astrocytes and microglia under pathological conditions. During physiological processes, NO produced by eNOS/nNOS, respectively, controls blood flow activation, and act as a messenger during long-term potentiation (LTP). However, under pathological conditions, eNOS appears to be impaired, leading to a reduction in blood flow and, consequently, low oxygen/metabolites delivery, efflux of toxicological agents from the brain tissue and disturbance in the blood-brain barrier. The NO produced by iNOS in glial cells and nNOS, which triggers the NMDA-excitotoxic pathway, combines with superoxide anion and results in peroxynitrite synthesis, a potent free radical that contributes to tissue damage in the brain. Here, we intend to show the controversial role of the nitric oxide delivered by the three isoforms of the nitric oxide synthase in the CNS, assess its impact under healthy/pathological conditions and speculate on its possible sequela, particularly in long-term cognitive decline.

The Yin and Yang of Tyrosine Kinase Inhibition During Experimental Polymicrobial Sepsis

“…Next, we checked the production of nitrite as readout for NO production in the peritoneal cavity after treatment with 1 mg/kg dasatinib. NO and superoxide generate antimicrobial molecules called reactive nitrogen species that act together with ROS in damaging cells and microbes ( 46 , 47 ). Our results show that dasatinib increased local nitrite production during CLP, which contributes to bacterial clearance (Figure 7 C).…”

The Glycolysis Inhibitor 2-Deoxy-d-Glucose Exerts Different Neuronal Effects at Circuit and Cellular Levels, Partially Reverses Behavioral Alterations and does not Prevent NADPH Diaphorase Activity Reduction in the Intrahippocampal Kainic Acid Model of Temporal Lobe Epilepsy

“…To explain more, increased NADPH will bring about increased reduction of nitro blue tetrazolium to diformazan (the visible dye) inside the neurons containing NADPH diaphorase which were not NADPH-d + when PPP and, subsequently NADPH concentration was low. Interestingly, NADPH-d + neurons in the hippocampus are demonstrated to release GABA too, indicating that NO acts as a paracrine/retrograde co-transmitter [ 65 ]. If so, loss of these GABAergic neurons could be a cause of disappeared IPSPs following the kainic acid injection, mentioned above.…”

Caloric Restriction (CR) Plus High-Nitrate Beetroot Juice Does Not Amplify CR-Induced Metabolic Adaptation and Improves Vascular and Cognitive Functions in Overweight Adults: A 14-Day Pilot Randomised Trial

“…Justice et al [ 72 ] showed a similar result in healthy older subjects as time to complete TMT-B was improved by 18% and 14% in response to supplementation with high and low doses of sodium nitrite for 10 weeks, respectively. Potential mechanisms explaining the cognitive effects could include a CR-induced Akt phosphorylation through the insulin-PI3K-Akt signalling pathway [ 73 , 74 ], increased NO production, and potentiation of pre-synaptic neurotransmission [ 75 , 76 ] occurring alongside an enhancement of neurovascular and metabolic coupling [ 77 ].…”