Abstract
Myeloperoxidase (MPO) functions as a key molecular component of the host defense system against diverse pathogens. We have previously reported that increased MPO levels and activity is a distinguishing feature of rotenone-exposed glial cells, and that either overactivation or deficiency of MPO leads to pathological conditions in the brain. Here, we provide that modulation of MPO levels in glia by resveratrol confers protective effects on rotenone-induced neurotoxicity. We show that resveratrol significantly reduced MPO levels but did not trigger abnormal nitric oxide (NO) production in microglia and astrocytes. Resveratrol-induced down-regulation of MPO, in the absence of an associated overproduction of NO, markedly attenuated rotenone-triggered inflammatory responses including phagocytic activity and reactive oxygen species production in primary microglia and astrocytes. In addition, impaired responses of primary mixed glia from Mpo −/− mice to rotenone were relieved by treatment with resveratrol. We further show that rotenone-induced neuronal injury, particularly dopaminergic cell death, was attenuated by resveratrol in neuron-glia co-cultures, but not in neurons cultured alone. Similar regulatory effects of resveratrol on MPO levels were observed in microglia treated with MPP+, another Parkinson’s disease-linked neurotoxin, supporting the beneficial effects of resveratrol on the brain. Collectively, our findings provide that resveratrol influences glial responses to rotenone by regulating both MPO and NO, and thus protects against rotenone-induced neuronal injury.
Highlights
Myeloperoxidase (MPO) is an oxidant-generating enzyme that catalyzes the formation of the potent oxidant hypochlorous acid (HOCl) and other chlorinating species derived from hydrogen peroxide (H2O2) [1,2]
Our recent report suggested that MPO triggers pro-inflammatory responses in glia under rotenone-exposed conditions, but showed that an MPO deficiency further exacerbates rotenoneinduced generation of reactive oxygen species (ROS) such as nitric oxide (NO) in microglia and astrocytes, thereby increasing neuronal cell death [11]
In a screening of anti-inflammatory agents, we found that resveratrol significantly reduced both MPO levels and NO release in rotenone-exposed microglia
Summary
Myeloperoxidase (MPO) is an oxidant-generating enzyme that catalyzes the formation of the potent oxidant hypochlorous acid (HOCl) and other chlorinating species derived from hydrogen peroxide (H2O2) [1,2]. Increasing evidence has suggested potential links between MPO and the development of disease such as ischemia, atherosclerosis, and acute myeloid leukemia [4,5,6]. Studies have shown that blockade of MPO activity in mouse models and in humans can reduce pathological responses in diseases such as renal ischemia [4,7]. It has been reported that MPO deficiency can lead to pathological conditions in animal models and patients. There are reports that MPO-deficient mice have a significantly increased incidence of inflammation-associated diseases including experimental autoimmune encephalomyelitis, atherosclerosis, and lung inflammation [8,9]. MPO-deficient patients have been shown to have a greater occurrence of severe infections and chronic inflammatory processes [10]. We found that glial cells from MPO-knockout (Mpo2/2) mice exhibit marked pathological properties under rotenone-exposed conditions [11]
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