Interplay among norepinephrine, NOX2, and neuroinflammation: key players in Parkinson’s disease and prime targets for therapies

The role of norepinephrine (NE) in the pathogenesis of Parkinson’s disease (PD) has not been well investigated until recently. The purpose of this perspective article is to review evidence supporting the idea that dysfunction of the locus coeruleus (LC)/NE system in the brain may be fundamentally linked to the pathogenesis of PD. Compelling evidence demonstrates that loss of NE neurons in the LC is sufficient to initiate chronic neuroinflammation, resulting in a progressive and sequential loss of neuronal populations in the brain. This article summarizes the critical role of both microglial and neuronal NADPH oxidase 2 (NOX2), the superoxide and reactive oxygen species generating enzyme, as an important regulator of chronic neuroinflammation. Moreover, NOX2 inhibitors show high efficacy in halting chronic neuroinflammation, oxidative damage, and neurodegeneration in several animal PD models. This line of research offers a promising disease-modifying therapeutic strategy for PD.