The Neuronal Nitric Oxide Synthase (nNOS) Gene and Neuroprotection Against Alcohol Toxicity

Abstract

When a mother abuses alcohol during pregnancy, the offspring can suffer a myriad of abnormalities, collectively known as Fetal Alcohol Spectrum Disorder (FASD). Foremost among these abnormalities is central nervous system dysfunction, which commonly manifests itself as mental retardation, clumsiness, hyperactivity, and poor attention span. These behavior problems are due, in large part, to alcohol-induced neuronal losses in the developing fetal brain. However, not all fetuses are equally affected by maternal alcohol consumption during pregnancy. While some fetuses are severely affected and develop hallmarks of FASD later in life, others exhibit no evident neuropathology or behavioral abnormalities. This variation is likely due, at least in part, to differences in fetal genetics. This review focuses on one particular gene, neuronal nitric oxide synthase, whose mutation worsens alcohol-induced neuronal death, both in vitro and in vivo. In addition, ectopic expression of the nNOS gene protects neurons against alcohol toxicity. The gene encodes an enzyme that produces nitric oxide (NO), which facilitates the protective effects of neuronal growth factors and which underlies the ability of neurons to resist alcohol toxicity as they mature. Nitric oxide exerts its protective effects against alcohol via a specific signaling pathway, the NO-cGMP-PKG pathway. Pharmacologic manipulation of this pathway could be of therapeutic use in preventing or ameliorating FASD.

Evidence for Detrimental Cross Interactions between Reactive Oxygen and Nitrogen Species in Leber’s Hereditary Optic Neuropathy Cells

“…Together with CO and H 2 S, NO forms the gasotransmitter triad acting as a redox-signalling regulator of several physiological functions, the mitochondrial one included [ 40 ]. NO, particularly at low concentrations, protects against cell death [ 41 – 44 ], whereas in the presence of superoxide it becomes toxic by forming ONOO − [ 30 ]. It should be kept in mind, however, that, even in the absence of ONOO − , depending on the electron flux level through the respiratory chain, that is, on the concentration of mitochondrial ferrocytochrome c , and particularly under low O 2 tension (hypoxia), inhibition of mitochondrial complex IV by NO can be severe and persistent [ 29 , 45 , 46 ].…”

Effects of Estrogen, Nitric Oxide, and Dopamine on Behavioral Locomotor Activities in the Embryonic Zebrafish: A Pharmacological Study

“…In addition, NO can act as a free radical, which damages critical metabolic enzymes and can react with superoxide to form the even more potent peroxynitrite (OONO-) [ 11 ]. However, at lower concentrations, NO can act as a cellular protectant through the prevention of neuronal depolarization, apoptosis, and regulation of the redox state within the mitochondria [ 12 , 13 ]. Abnormal nNOS/NO metabolism is suggested to contribute to the pathogenesis and pathophysiology of PD [ 11 ].…”

“…It is under these conditions that NO is thought to play a role in the genesis of PD [ 11 ]. On the other hand, NO at lower concentrations can act as a cellular protectant through prevention of apoptosis, excitotoxicity, neuronal depolarization, and regulation of the redox state in the mitochondria [ 12 , 13 ]. Indeed, several studies have indicated that NOS containing neurons within the striatum of the BG are resistant to neurodegeneration [ 14 ].…”

Ketamine Produces Anesthesia and Analgesia in Miniature Pigs Via NO-cGMP Signaling Pathway

“…It is produced by NOS catalyzed by L-arginine and acts as an endogenous activator of soluble guanylyl cyclase (sGC), which can further activate sGC to catalyze the generation of cGMP by GTP. As a central part of the NO-cGMP pathway, cyclic GMP (cGMP) can act on cGMP ligand-gated ion channels and exert biological effects by regulating cGMP dependent protein kinase (PKG) production and phosphodiesterase (PDE) activity which depends on a Ca/CaM signal, and directly controls channel opening via cyclic nucleotide-gated ion channel (CNG) (Neitz et al, 2014;Karaçay and Bonthius, 2015;Shen et al, 2016). Interestingly, the NO-cGMP pathway plays an important role in a variety of anesthetics (Ding et al, 2017;Wang et al, 2017).…”