Brain Nitric Oxide and Its Dual Role in Neurodegeneration / Neuroprotection: Understanding Molecular Mechanisms to Devise Drug Approaches

Abstract

Nitric oxide (NO) has been established as an important messenger molecule in various steps of brain physiology, from development to synaptic plasticity, learning and memory. However, NO has also been viewed as a major agent of neuropathology when, escaping controlled production it may directly or indirectly promote oxidative and nitrosative stress. The exact borderline between physiological, and therefore neuroprotective, and pathological, and therefore neurodegenerative, actions of NO is a matter of controversy among researchers in the field. This is reflected in the present status of drug research, that is focused on finding ways to block NO production, and therefore limit neuropathology, as well as on finding ways to increase NO availability and therefore elicit neuroprotection. As an unavoidable consequence, both classes of drugs are reported to have neurodegenerative or neuroprotective effects, depending on the models in which they are tested. Aim of the present paper is to provide the reader with a survey, as much complete as possible, on the main aspects of NO biology, from biochemistry and chemical reactivity to the molecular signals elicited in neural cells target of its neurodegenerative or neuroprotective action. In doing that, many controversial aspects related to basic biology and to neuropathology of NO are taken into account. In the final sections, main classes of drugs able to interfere with NO physiopathology are examined, in order to try to devise possible directions for future NO-based therapeutical strategies.

Antagonism by NOS Inhibition of the Behavioral Effects of Benzodiazepine and GABAA Receptor Agonists in the Mouse Elevated Plus-Maze

“…NO may have biphasic influences (ie both excitatory and inhibitory) based on a complex interaction among glutamatergic, GABAergic, and other (eg opioid) neuronal systems, all of which are modulated by NO (Lovick and Key, 1996;Wang et al, 1997;Hall and Behbehani, 1998;Lin et al, 2000). This may account for the contradictory results that NO appears to both enhance and suppress not only anxiety but also other functions such as pain (Moore et al, 1993;McDonald et al, 1994), seizure activity (Buisson et al, 1993;De Sarro et al, 1993), and neurotoxicity (Contestabile et al, 2003). These findings are contributing to a more complete understanding of the role of NO in brain function, which would potentially have many ramifications for more effective treatment of not only anxiety but other brain dysfunctions as well.…”

Neuronal-glial Interactions Define the Role of Nitric Oxide in Neural Functional Processes

“…Details on the enzyme structure, role of co-factors and reaction mechanism have been reviewed elsewhere [16]. In addition to NO, NOSs can produce, under some reaction conditions, both superoxide anion and hydrogen peroxide [17, 18].…”

Nitric oxide inhibits gastric cancer cell growth through the modulation of the Akt pathway

“…Nitric oxide (NO), a highly versatile free radical gas of physiological significance, is capable of controlling multiple cellular signaling processes in organisms ranging from bacteria to humans (1)(2)(3). It has been reported that NO is capable of inhibiting cell proliferation in certain cell types and conditions, but stimulates cell proliferation in others (4,5).…”