Neuroinflammation underlies the pathogenesis of various neurodegenerative disorders including Parkinson's disease (PD). Despite intense investigations, no effective therapy is available to stop its onset or halt its progression. RNS60 is a novel therapeutic containing charge-stabilized nanobubbles in saline, generated by subjecting normal saline to Taylor-Couette-Poiseuille flow under elevated oxygen pressure. Recently, we have delineated that RNS60 inhibits the expression of proinflammatory molecules in glial cells via type 1A phosphatidylinositol-3 kinase (PI3K)-mediated upregulation of IκBα. In this study, we demonstrate that RNS60 inhibited the expression of proinflammatory molecules in cultured microglial cells stimulated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridium ion (MPP(+)) and in vivo in the nigra of MPTP-intoxicated mice. While investigating the underlying mechanisms, we found that MPTP intoxication rapidly stimulated the activation of type IB PI3K p110γ in the nigra, while suppressing the activation of type IA PI3K p110α/β. Interestingly, RNS60 treatment suppressed the activation of p110γ PI3K, while inducing the activation of p110α/β PI3K in the nigra of MPTP-intoxicated mice. Accordingly, RNS60 treatment increased the level of IκBα and inhibited the activation of NF-κB in the SNpc of MPTP-intoxicated mice. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP-intoxicated mice. These results strongly suggest a promising therapeutic role of this simple modified saline in PD and other neuroinflammatory disorders.