Abstract
Neuroinflammation is implicated in dopaminergic neurodegeneration. We have previously demonstrated that (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP), a selective signal transducer and activator of transcription 3 (STAT3) inhibitor, has anti-inflammatory properties in several inflammatory disease models. We investigated whether MMPP could protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic cell loss and behavioral impairment. Imprinting control region (ICR) mice (8 weeks old, n = 10 per group) were administered MMPP (5 mg/kg) in drinking water for 1 month, and injected with MPTP (15 mg/kg, four times with 2 h intervals) during the last 7 days of treatment. MMPP decreased MPTP-induced behavioral impairments in rotarod, pole, and gait tests. We also showed that MMPP ameliorated dopamine depletion in the striatum and inflammatory marker elevation in primary cultured neurons by high-performance liquid chromatography and immunohistochemical analysis. Increased activation of STAT3, p38, and monoamine oxidase B (MAO-B) were observed in the substantia nigra and striatum after MPTP injection, effects that were attenuated by MMPP treatment. Furthermore, MMPP inhibited STAT3 activity and expression of neuroinflammatory proteins, including ionized calcium binding adaptor molecule 1 (Iba1), inducible nitric oxide synthase (iNOS), and glial fibrillary acidic protein (GFAP) in 1-methyl-4-phenylpyridinium (MPP+; 0.5 mM)-treated primary cultured cells. However, mitogen-activated protein kinase (MAPK) inhibitors augmented the activity of MMPP. Collectively, our results suggest that MMPP may be an anti-inflammatory agent that attenuates dopaminergic neurodegeneration and neuroinflammation through MAO-B and MAPK pathway-dependent inhibition of STAT3 activation.
Highlights
Parkinson’s Disease (PD) is a major age-related progressive movement disorder
To examine the motor deficits induced by MPTP administration, we conducted a pole test and measured the time to reach the base of the pole
Activation of microglia and astrocytes observed in PD patients and PD animal models suggests that neuroinflammation plays an important role in the progression of PD [31]
Summary
Parkinson’s Disease (PD) is a major age-related progressive movement disorder. The prevalence of PD increases with age, affecting 1.6% of the population over the age of 65 years old [1]. PD is characterized by the loss of dopamine neurons in the substantia nigra, with decreased striatal dopamine levels and consequent extrapyramidal motor dysfunction [2,3]. Mice treated with MPTP share specific biological features with those of PD, including dopamine depletion in the striatum and loss of dopaminergic neurons in the substantia nigra [4,5]. MPTP-induced dopaminergic neurotoxicity was linked to rapid activation of signal transducer and activator of transcription 3 (STAT3) in striatal astrocytes [11,12]. Yuan et al reported that microglia-derived inflammation and behavioral changes in PD models can be suppressed via inhibiting the mitogen-activated protein kinase (MAPK) and STAT3 pathways [16]. MAPK signaling pathways are important for MAO-B gene expression, since the dominant negative JNK and p38 can selectively inhibit MAO-B promoter activation [23]
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