Abstract
Neuroinflammation is the neuropathological feature of Parkinson's disease (PD) and causes microglial activation and activated microglia-derived oxidative stress in the PD patients and PD animal models, resulting in neurodegeneration. The present study examined whether norfluoxetine (a metabolite of fluoxetine) could regulate neuroinflammation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP) mouse model of PD and rescue dopamine neurons. Analysis by tyrosine hydroxylase (TH) immunohistochemistry demonstrated that norfluoxetine prevents degeneration of nigrostriatal dopamine neurons in vivo in MPTP-lesioned mice compared to vehicle-treated MPTP-lesioned control mice. MAC-1 immunostaining and hydroethidine histochemical staining showed that norfluoxetine neuroprotection is accompanied by inhibiting MPTP-induced microglial activation and activated microglia-derived reactive oxygen species production in vivo, respectively. In the separate experiments, treatment with norfluoxetine inhibited NADPH oxidase activation and nitrate production in LPS-treated cortical microglial cultures in vitro. Collectively, these in vivo and in vitro results suggest that norfluoxetine could be employed as a novel therapeutic agent for treating PD, which is associated with neuroinflammation and microglia-derived oxidative stress.
Highlights
Parkinson’s disease (PD) is one of the most common neurodegenerative disorders associated with loss of dopamine (DA) in striatum and death of DA neurons in substantia nigra (SN) [1]
Consistent with our previous study [4], analysis by tyrosine hydroxylase (TH) immunostaining revealed a significant loss of TH+ cells (Figures 1(e) and 1(f)) at 7 days in the MPTP-injected SN compared with PBS-treated controls (Figures 1(a) and 1(b))
As NADPH oxidase is the source of O2− production in microglia, we investigated whether norfluoxetine altered NADPH oxidase by measuring the levels and localization of p47phox, which is one of the cytosolic components of NADPH oxidase
Summary
Parkinson’s disease (PD) is one of the most common neurodegenerative disorders associated with loss of dopamine (DA) in striatum and death of DA neurons in substantia nigra (SN) [1]. Activated microglia-derived oxidative stress is observed in the SN of PD patients and in the SN of MPTP-treated mouse and lipopolysaccharide- (LPS-) treated rat, which contributes to degeneration of DA neuron [4,5,6,7]. ROS and/or RNS generating enzyme, such as NADPH oxidase and inducible nitric oxide synthase (iNOS), are upregulated in the SN of PD patients and in the SN of MPTP-treated mouse and LPS-treated rat [6, 7]. Fluoxetine prevents degeneration of midbrain DA neurons in MPTP-lesioned mice through inhibiting activated microglia-derived oxidative damage and inflammatory response in vivo apart from the effect on Mediators of Inflammation serotonin uptake [5]. Understanding the property of fluoxetine and its derivatives is applicable to develop the new therapeutic agents to treat PD patients
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