5. Role of iNOS-Derived ROS Signaling in PD
Apart from the above-discussed NADPH-oxidase-derived ROS systems, focus also points to nitrogen dioxide-derived reactive species such as ONOO−, NO, and other unrecognized potential reactive nitrogen species as the main culprits [113]. Due to their highly unstable nature and reactivity, biological molecules such as proteins, DNA, and lipids in dopaminergic neurons in the brains of parkinsonian patients could be targeted for oxidation resulting in extensive cellular injury and cell death. Normally, inducible NO synthase (iNOS) is not expressed in the brain, but in pathological situations, especially those associated with gliosis, iNOS can be induced.
In experimental PD models and MPTP neurotoxin-induced models, induction of iNOS expression has been observed [14, 114]. Earlier studies have also suggested that inhibition of iNOS showed neuroprotection in the MPTP-induced PD model. In addition, inflammatory mediators such as LPS and cytokines also cause an increase in iNOS expression in microglia and astrocytes [115] and possibly in neurons [116]. Once expressed, iNOS produces high levels of NO continuously from microglia or astrocytes [117, 118].
Nitric oxide, a lipophilic diatomic molecule, can travel several micrometers away from its site of production and freely cross the plasma membrane to reach the intracellular space of dopaminergic neurons. Also, the interaction of NO and O2 − will result in the formation of OONO−, a highly reactive species. Peroxynitrite is a potent cytotoxic oxidant, which in turn will inflict oxidative damage to biological targets such as inactivating ion channels, damaging DNA, and nitrating tyrosine residues that can potentially inactivate enzymes and disrupt signal transduction [119]. Therefore, inhibition of glial activation-mediated oxidative stress by reducing the iNOS may have therapeutic value in the treatment of neuroinflammation related to PD. In the following section, we describe recently available agents and patented compounds that selectively inhibit iNOS activity and may show a promising role in PD treatment.