Microglial Cells Are Involved in the Susceptibility of NADPH Oxidase Knockout Mice to 6-Hydroxy-Dopamine-Induced Neurodegeneration

Abstract

We explored the impact of Nox-2 in modulating inflammatory-mediated microglial responses in the 6-hydroxydopamine (6-OHDA)-induced Parkinson’s disease (PD) model. Nox1 and Nox2 gene expression were found to increase in striatum, whereas a marked increase of Nox2 expression was observed in substantia nigra (SN) of wild-type (wt) mice after PD induction. Gp91phox-/- 6-OHDA-lesioned mice exhibited a significant reduction in the apomorphine-induced rotational behavior, when compared to wt mice. Immunolabeling assays indicated that striatal 6-OHDA injections reduced the number of dopaminergic (DA) neurons in the SN of wt mice. In gp91phox-/- 6-OHDA-lesioned mice the DA degeneration was negligible, suggesting an involvement of Nox in 6-OHDA-mediated SN degeneration. Gp91phox-/- 6-OHDA-lesioned mice treated with minocycline, a tetracycline derivative that exerts multiple anti-inflammatory effects, including microglial inhibition, exhibited increased apomorphine-induced rotational behavior and degeneration of DA neurons after 6-OHDA injections. The same treatment also increased TNF-α release and potentiated NF-κB activation in the SN of gp91phox-/--lesioned mice. Our results demonstrate for the first time that inhibition of microglial cells increases the susceptibility of gp91phox-/- 6-OHDA lesioned mice to develop PD. Blockade of microglia leads to NF-κB activation and TNF-α release into the SN of gp91phox-/- 6-OHDA lesioned mice, a likely mechanism whereby gp91phox-/- 6-OHDA lesioned mice may be more susceptible to develop PD after microglial cell inhibition. Nox2 adds an essential level of regulation to signaling pathways underlying the inflammatory response after PD induction.

Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson’s Disease

“…Recently, several studies have implicated Nox1-derived ROS in dopaminergic cell death induced by paraquat and 6-OHDA, and both of these toxins upregulated Nox1 (Choi et al, 2012; Cristovao et al, 2012; Hernandes et al, 2013). NADPH oxidase- and mitochondria-derived ROS both play equally important key roles in proinflammatory microglial activation (Dikalov, 2011; Mead et al, 2012; Bordt and Polster, 2014).…”

Microglia antioxidant systems and redox signalling

“…Neurotoxin-induced dopaminergic degeneration in the substantia nigra depends on expression of NOX2 (Gao et al, 2003;Wu et al, 2003;Hernandes et al, 2013). However, curiously, treatment of gp91phox(À/À) mice with minocycline results in enhanced microglia activation and neuronal loss relative to wild-type mice also treated with minocycline (Hernandes et al, 2013). Disregarding non-cell-autonomous effects, these data, together with the observations of Block et al (Taetzsch et al, 2015), suggest that NOX2 activity can be required for anti-inflammatory effects in M2-activated microglia.…”

“…The antibiotic minocycline selectively inhibits development of the M1, but not the M2, activation response (Kobayashi et al, 2013). Neurotoxin-induced dopaminergic degeneration in the substantia nigra depends on expression of NOX2 (Gao et al, 2003;Wu et al, 2003;Hernandes et al, 2013). However, curiously, treatment of gp91phox(À/À) mice with minocycline results in enhanced microglia activation and neuronal loss relative to wild-type mice also treated with minocycline (Hernandes et al, 2013).…”

NADPH oxidase in brain injury and neurodegenerative disorders

“…In support of this contention, NOX1 expression has been reported to increase after striatal injection of 6-OHDA and is associated with a simultaneous increase in DNA oxidative stress [216]. Additionally, following 6-OHDA induction, there is an increase in NOX1 and NOX2 gene expression in the mouse striatum, and NOX2 expression in the substantia nigra [217]. In vivo and in vitro studies of PD induced by paraquat have shown increased expression of NOX1 and synucleins [217].…”

“…Additionally, following 6-OHDA induction, there is an increase in NOX1 and NOX2 gene expression in the mouse striatum, and NOX2 expression in the substantia nigra [217]. In vivo and in vitro studies of PD induced by paraquat have shown increased expression of NOX1 and synucleins [217]. NOX2 expression has also been shown to increase in mouse brains after administration of MPTP [218] and to be elevated in PD human brains [218].…”