Protection of dopaminergic neurons by 5-lipoxygenase inhibitor

Kang, Kai-Hsiang; Liou, Horng-Hui; Hour, Mann‐Jen; Liou, Houng‐Chi; Fu, Wen‐Mei

doi:10.1016/j.neuropharm.2013.06.014

Cited by 50 publications

(45 citation statements)

References 42 publications

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“…As a rate-limiting enzyme, TH is required for catecholamine synthesis and is a hallmark indicator for evaluating the neuroprotective ability of compounds in PD, since a decrease of TH activity is positively correlated with PD severity [74]. We found ATR-I to restore the population of surviving dopaminergic neurons in the STR and SNpc, in response to MPTP intoxication, thus asserting the neuroprotective effect of ATR-I in the MPTP model of PD.…”

Section: Discussionmentioning

confidence: 89%

Neuroprotective Role of Atractylenolide-I in an In Vitro and In Vivo Model of Parkinson’s Disease

Choi

2017

Nutrients

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Parkinson’s disease (PD) is an age-related neurological disorder characterized by a loss of dopaminergic neurons within the midbrain. Neuroinflammation has been nominated as one of the key pathogenic features of PD. Recently, the inadequate pharmacotherapy and adverse effects of conventional drugs have spurred the development of unconventional medications in the treatment of PD. The purpose of this study is to investigate the anti-neuroinflammatory mechanisms of Atractylenolide-I (ATR-I) in in vivo and in vitro models of PD. Nitrite assay was measured via Griess reaction in lipopolysaccharide (LPS) stimulated BV-2 cells. mRNA and protein levels were determined by a reverse transcription-polymerase chain reaction (RT-PCR) and immunoblot analysis, respectively. Further, flow cytometry, immunocytochemistry, and immunohistochemistry were employed in BV-2 cells and MPTP-intoxicated C57BL6/J mice. Pre-treatment with ATR-I attenuated the inflammatory response in BV-2 cells by abating the nuclear translocation of nuclear factor-κB (NF-κB) and by inducing heme oxygenase-1 (HO-1). The intraperitoneal administration of ATR-I reversed MPTP-induced behavioral deficits, decreased microglial activation, and conferred protection to dopaminergic neurons in the mouse model of PD. Our experimental reports establish the involvement of multiple benevolent molecular events by ATR-I in MPTP-induced toxicity, which may aid in the development of ATR-I as a new therapeutic agent for the treatment of PD.

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Section: Discussionmentioning

confidence: 89%

Neuroprotective Role of Atractylenolide-I in an In Vitro and In Vivo Model of Parkinson’s Disease

Choi

2017

Nutrients

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“…Recent research has primarily focused on therapeutic approaches based around anti-inflammatory molecules such as NADPH oxidase (i.e. minocycline), COX2 and 5-LO inhibitors that disrupt pro-inflammatory activation (Choi et al, 2011; Kang et al, 2013; Klegeris and McGeer, 2002; Manev et al, 2001). However, there have been mixed results in pre-clinical and clinical studies with minocycline (2008; Diguet et al, 2004; Du et al, 2001; Yang et al, 2003) that suggest it might actually worsen neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Alternative microglial activation is associated with cessation of progressive dopamine neuron loss in mice systemically administered lipopolysaccharide

Beier

Neal

Alam

et al. 2017

Neurobiology of Disease

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Inflammation arising from central and/or peripheral sources contributes to the pathogenesis of multiple neurodegenerative diseases including Parkinson's disease (PD). Emerging data suggest that differential activation of glia could lead to the pathogenesis and progression of PD. Here, we sought to determine the relationship between lipopolysaccharide (LPS) treatment, loss of dopaminergic neurons and differential activation of glia. Using a model of repeated injections with LPS (1 mg/kg, i.p. for 4 days), we found that LPS induced a 34% loss of dopamine neurons in the substantia nigra 19 days after initiation of treatment, but no further cell loss was observed at 36 days. LPS induced a strong pro-inflammatory response with increased mRNA expression of pro-inflammatory markers, including tumor necrosis factor-α (4.8-fold), inducible nitric oxide synthase (2.0-fold), interleukin-1 beta (8.9-fold), interleukin-6 (10.7-fold), and robust glial activation were observed at 1 day after final dose of LPS. These pro-inflammatory genes were then reduced at 19 days after treatment, when there was a rise in the anti-inflammatory genes Ym1 (1.8-fold) and arginase-1 (2.6-fold). Additionally, 36 days after the last LPS injection there was a significant increase in interleukin-10 (2.1-fold) expression. The qPCR data results were supported by protein data, including cytokine measurements, western blotting, and immunofluorescence in brain microglia. Taken together, these data demonstrate that progressive neurodegeneration in the substantia nigra following LPS is likely arrested by microglia shifting to an anti-inflammatory phenotype. Thus, strategies to promote resolution of neuroinflammation may be a promising avenue to slow the progressive loss of dopamine neurons in PD.

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“…Indeed, 5-LOX upregulation was shown in MPTP-induced animal model of PD [137] and the overactivation of the 5-LOX pathway may lead to neurodegeneration by lipid peroxidation [138]. On the contrary, the inhibition of 5-LOX attenuates LPS-induced oxidative stress and dopaminergic neurodegeneration [139].…”

Section: Cerebral Localization Of Cyslt Receptorsmentioning

confidence: 99%

“…On the contrary, the inhibition of 5-LOX attenuates LPS-induced oxidative stress and dopaminergic neurodegeneration [139]. Furthermore, MK-886 treatment antagonized the MPP + -induced toxicity of dopaminergic neurons in SH-SY5Y cell line, a common cellular model for PD, and in midbrain neuron-glia cocultures [137]. Of note, LTB4, but not LTD4 or 5-HETE, enhanced the MPP + -induced cytotoxicity in the rat midbrain culture.…”

Section: Cerebral Localization Of Cyslt Receptorsmentioning

confidence: 99%

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Cysteinyl Leukotrienes as Potential Pharmacological Targets for Cerebral Diseases

Gelosa

Colazzo

Tremoli

et al. 2017

Mediators of Inflammation

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Cysteinyl leukotrienes (CysLTs) are potent lipid mediators widely known for their actions in asthma and in allergic rhinitis. Accumulating data highlights their involvement in a broader range of inflammation-associated diseases such as cancer, atopic dermatitis, rheumatoid arthritis, and cardiovascular diseases. The reported elevated levels of CysLTs in acute and chronic brain lesions, the association between the genetic polymorphisms in the LTs biosynthesis pathways and the risk of cerebral pathological events, and the evidence from animal models link also CysLTs and brain diseases. This review will give an overview of how far research has gone into the evaluation of the role of CysLTs in the most prevalent neurodegenerative disorders (ischemia, Alzheimer's and Parkinson's diseases, multiple sclerosis/experimental autoimmune encephalomyelitis, and epilepsy) in order to understand the underlying mechanism by which they might be central in the disease progression.

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Protection of dopaminergic neurons by 5-lipoxygenase inhibitor

Cited by 50 publications

References 42 publications

Neuroprotective Role of Atractylenolide-I in an In Vitro and In Vivo Model of Parkinson’s Disease

Neuroprotective Role of Atractylenolide-I in an In Vitro and In Vivo Model of Parkinson’s Disease

Alternative microglial activation is associated with cessation of progressive dopamine neuron loss in mice systemically administered lipopolysaccharide

Cysteinyl Leukotrienes as Potential Pharmacological Targets for Cerebral Diseases

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