Introduction Since the th century nitrates and nitrites were
Since the 19th century, nitrates and nitrites were known to be vasoactive, being applied in medicine however the mechanisms activated by such compounds were unknown . At the beginning of the 80's of the last century the effect of endothelial cells in vasodilatation was demonstrated by stimulation with 11078-21-0 (ACh)  and later the endothelial-derived relaxing factor (EDRF) was identified as Nitric Oxide (NO) [3,4]. At the same decade the production of NO in cerebellar glutamatergic neurons was demonstrated after activation of N-methyl-d-aspartate receptor (NMDAR) . From that time to the present a deep knowledge on the physiological and pathological roles of NO has been unveiled.
NO has pleiotropic effects in the different tissues of the body, and even it is present in plants, sharing similar production systems and signaling with animals . In this review we will focus on the effects that NO carries out in brain.
Nitric oxide NO is a gaseous molecule that can diffuse easily to the surrounding tissue. It is mostly synthesized by an enzymatic activity carried out by the family of NO synthases (NOS), which oxidize l-arginine (l-Arg) to yield citrulline and NO. Neurons, glia and vascular cells can express NOS and are potential sources of NO in brain . l-Arg is a semi essential amino acid and it is not a limiting factor in NO production under physiological conditions since it can be produced from citrulline or glutamic acid, however a depletion of l-Arg can occurs when iNOS is active for long periods and therefore iNOS produces superoxide anion (O2−). NO is produced mainly by NOS, but there are other alternative sources of NO such as the non-enzymatic oxidation of l-Arg , xanthine oxidase  and others reductases able to transform nitrates into nitrites that will finally produce NO [10,11]. The generation of nitrates and nitrites is also a mechanism to store biological NO , but other sources as the foods have to be considered since nitrates and nitrites are present naturally in some foods and they seem to contribute to NO physiological effects [, , ].
Oxidative stress ROS physiological production at very low concentrations regulates mitochondrial activity, transcription factors, signaling pathways, LTP regulation and even vascular tone by NADPH oxidase (NOX) [, , , ]. Also in the physiological immune response ROS are released at high concentrations during the respiratory burst by the NOX from leukocytes and microglia [157,158]. The pathological production of free radicals is high and continuous generating oxidative stress. Oxidative stress is the consequence of the imbalance between ROS production and their elimination by the antioxidant defenses. ROS react with proteins, lipids and nucleic acids damaging cells and yielding to apoptosis being tightly associated to the onset and progression of neurodegenerative processes [159,160] and also playing a key role in ischemic brain stroke [7,161].
Peroxynitrite NO is modified in the cells and tissues forming nitrites (NO2−) and nitrates (NO3−). NO pathological effects are due to its secondary intermediates mainly peroxynitrite anion (ONOO-) a kind of RNS. NO reacts with O2− forming ONOO- that is not impaired by SOD since O2− affinity is ten times higher for NO than for SOD [221,222]. Therefore ONOO- formation avoids the action of the antioxidant systems. ONOO– has an action radius of 100 dm but it is very reactive resulting in a quite short half-life of 1–20 ms . It can be scavenged by reacting with CO2/bicarbonate to yield nitrosoperoxycarbonate (ONOOCO2−) . It is thermodynamically unstable however some authors consider that CO2 would be contributing significantly to eliminate ONOO- .
Conclusions NO is a molecule with pleiotropic effects in brain. NO favors synaptic functions by LTP maintenance and protein translation at dendritic spines. It is also critical to guarantee the proper blood supply to neurons and it has been demonstrated to be an antiapoptotic molecule and a regulator of neuronal function by nitrosylation. However, when NO is produced in a pro-oxidant environment, as during aging or in AD, reacts with O2− producing ONOO-, which nitrotyrosinates proteins damaging brain cells. The physiological functions of NO are so critical for brain and vascular system that therapies aiming the direct regulation of its production will be harmful. However, the inhibition of free radical burst, the use of ONOO- scavengers or the stimulation of NO down-stream effects, such as the increase in cGMP levels or phosphodiesterase activity, will be more proper therapeutic approaches.